年龄相关的认知衰退：辅酶Q10、烟酰胺核糖、磷脂酰丝氨酸

目  录

一、概述

二、引言

三、背景

四、年龄相关的认知衰退的机制

五、益智药物和认知衰退的新疗法

六、注重饮食和生活方式对大脑健康的影响

七、健康的大脑：综合疗法

八、参考文献

一、概述

概要速览

1. 轻度认知障碍是一种以认知变化为特征的疾病，这种变化超出了年龄的预期，但并不会使人衰弱。据估计，在65岁及以上的成年人中，有10%至20%有轻度认知障碍。

2. 本文将回顾许多导致认知能力下降的潜在因素，并描述几种创新的医疗策略、生活方式和饮食习惯以及综合干预措施，以支持认知功能和大脑终生健康。

3. 积极的生活方式改变、认知训练和营养干预（如磷脂酰丝氨酸和甘油磷酸化胆碱）已被证明可降低智力衰退率，并可能逆转年龄相关的认知衰退。

什么是年龄相关的认知衰退?

衰老与认知功能的逐渐衰退有关。因此，老年人通常会发现智力活动需要更长的时间来完成，他们的记忆力和注意力可能会减弱。与年龄相关的认知能力下降是一个复杂的过程，有许多影响因素，包括细胞衰老、昼夜节律紊乱和神经炎症等。

如果与年龄相关的认知能力衰退发展到认知能力的变化超过年龄预期，但没有使人衰弱，这种情况被称为轻度认知障碍。痴呆症是指严重到足以使人衰弱、干扰人的独立功能的认知能力的衰退。

幸运的是，积极的生活方式改变、认知训练和营养干预，如假马齿苋和石杉碱甲，已被证明可以降低智力衰退的速度，并有可能扭转与年龄相关的认知衰退。

年龄相关的认知衰退的危险因素有哪些?

1. 年龄

2. 女性

3. 静态生活方式

4. 教育程度低

5. 吸烟

6. 肥胖

7. 胰岛素抵抗/ 2型糖尿病

8. 高血压

9. 高胆固醇

10. 抑郁

11. 睡眠障碍

12. 睡眠呼吸暂停

13. 诸如慢性肾病和心血管病的疾病

认知衰退有哪些症状？

认知衰退的人在认知方面会有困难，包括：

1. 计划与组织能力

2. 适应对话中的变化

3. 找单词

4. 专注力

5. 丢东西

6. 丧失同情心或判断力

7. 不恰当行为

认知衰退的新疗法有哪些?

目前还没有专门针对年龄相关的认知衰退的药物。抗痴呆药物似乎不能防止轻度认知损害发展为痴呆。然而，已经发现某些药物具有保护或增强大脑的作用：

1. 吡拉西坦和左乙拉西坦（抗癫痫药物）

2. 司来吉林（用于帕金森症、阿尔茨海默症和重度抑郁症的药物）

3. 齐留通（哮喘药物）

哪些饮食和生活方式的改变有利于保持大脑健康?

1. 从西式饮食（富含单糖和饱和脂肪）转向地中海式饮食（富含单不饱和和多不饱和omega-3脂肪酸、纤维和多酚）

2. 限制热量可以提高学习和记忆能力

3. 认知刺激和训练，包括下棋和说多种语言，可以增强认知储备，并预防大脑功能丧失

4. 控制压力，保证充足的高质量睡眠

5. 参加社交活动——强大的社交网络对认知健康有保护作用

6. 运动可以提高脑源性神经营养因子的水平，从而增强认知功能

7. 适量的咖啡因和咖啡摄入（每天1-2杯）可以预防认知衰退

什么自然干预剂可能对年龄相关的认知衰退有益?

1. 银杏。大量的临床试验和综合分析已经证明银杏有减缓认知衰退的能力。2019年的一篇专家共识论文得出结论，银杏是安全有效的，可以单独或与传统疗法联合用于治疗轻度认知障碍和痴呆症。

2. 假马齿苋。假马齿苋，是在阿育吠陀医学中使用了几个世纪的一种植物，它在许多临床试验中被证明可以改善认知的几个方面。

3. 石杉碱甲。石杉碱甲，一种来自药用植物蛇足石杉的化合物，已经被证明可以抑制乙酰胆碱酯酶，这种酶可以分解神经递质乙酰胆碱。在补充石杉碱甲后，痴呆和阿尔茨海默病患者在标准认知测试中的得分有所提高。

4. 乙酰左旋肉碱。乙酰左旋肉碱水平的下降与认知功能的下降有关。一项来自21项研究的综合分析显示，补充乙酰左旋肉碱可以改善轻度认知障碍和阿尔茨海默病患者的认知缺陷。

5. 苏糖酸镁。苏糖酸镁是一种能有效提高大脑镁含量的镁的形式。临床前研究表明，它能保护大脑功能，保护神经连接。

6. 磷脂酰丝氨酸。磷脂酰丝氨酸是一种磷脂，是髓磷脂和细胞膜的重要组成部分。临床试验表明，补充磷脂酰丝氨酸可以改善有认知障碍的老年受试者的认知功能。

7. α-甘油磷酸化胆碱（α-GPC）。α-GPC是神经递质乙酰胆碱的前体。乙酰胆碱前体，单独或联合乙酰胆碱酯酶抑制剂，有希望治疗痴呆。

8. 其他有益于大脑健康和整体认知功能的自然干预包括多酚、褪黑素、B族维生素、初乳素、锂等。

二、引言

认知功能似乎在20岁左右达到顶峰，并在生命剩下的年岁里稳步下降。^1,2随着上个世纪人类预期寿命的大幅增加，认知能力下降和痴呆症已成为致残和死亡的主要原因。^3,4

衰老与大脑的逐渐变化有关，这种变化减缓并降低了大脑的功能。由于这些变化，老年人（甚至那些没有神经系统疾病的人）很常见地发现，他们需要更长的时间来完成脑力工作，记忆力、注意力、学习、推理和解决问题的能力下降。²虽然在正常的衰老过程中也会发生一些认知能力下降，但其进展速度受到生活方式、环境和遗传因素的影响，⁵其中一些因素是可以改变的。^1,6

衰老是一个复杂的过程，与年龄相关的状况，如认知衰退是多因素的。一些可能导致与年龄相关的认知能力下降的因素是：

1. 干细胞衰老

2. 大脑氧化应激和线粒体功能障碍

3. 神经炎症（大脑中的炎症）

4. 生理节律和代谢紊乱

5. 血管功能障碍

6. 异常蛋白质积累

7. 同型半胱氨酸代谢紊乱

8. 激素水平改变，以及遗传因素——基因表达方式的改变。

这些机制似乎也会导致痴呆和神经退行性疾病，如阿尔茨海默病和帕金森病。¹

目前，人们对促进大脑健康老化的生活方式因素已经有了很多了解，比如吃营养丰富的饮食（如地中海式饮食）、积极锻炼、减少压力、获得充足的睡眠，以及定期参加精神和社会刺激活动。^1,4,6此外，一些综合干预已被证实对大脑功能有保护作用。^7,8

本文将回顾许多导致认知衰退的潜在因素，并描述几种新的医疗策略、生活方式和饮食习惯，以及综合干预措施，以支持认知功能和大脑终生健康。

三、背景

大脑包含大约1000亿个相互连接的神经元，它们共同吸收从全身神经接收到的信息和外部刺激。除了神经元，大脑中还有一些特殊的细胞被称为胶质细胞，主要是星形胶质细胞和小胶质细胞，它们发挥着许多重要的支持作用。^9,10神经胶质细胞也参与大脑中的重要信号传递过程。¹¹

大脑老化

随着年龄的增长，大脑神经元的数量会减少，支持它们的细胞和组织在20岁以后会慢慢退化，而在60岁以后退化得更快。研究发现，到90岁时，大脑质量比50岁时下降了11%。⁵大多数神经元损失发生在大脑皮层以及海马体，大脑皮层是大多数信息处理发生的地方，海马体是一种参与记忆和学习的大脑结构。^2,12,13

衰老也与大脑功能的变化有关。例如，脑血流减少，神经递质的产生减少。此外，控制细胞和分子进出大脑血管的血脑屏障的完整性也会减弱，^2,14而保护神经元并促进信号传输的富含磷脂的髓鞘也会退化。^13,15

这些与年龄相关的大脑变化表现为通常与年龄增长有关的智力下降，即短期记忆和情景记忆减退，难以回忆单词，反应速度变慢，可能还有情绪低落。²

从年龄相关的认知衰退到轻度认知障碍和痴呆

年龄相关的认知衰退是用来描述学习、记忆和处理信息能力的自然下降。轻度认知障碍是一种以认知变化为特征的疾病，这种变化超出了年龄的预期，但并不会使人衰弱。据估计，65岁及以上的成年人中有10-20%有轻度认知障碍。^16,17

当认知衰退严重到足以干扰社交和职业功能以及独立生活的能力时，这种情况被称为痴呆症。^17,18美国65岁及以上的成年人中大约有5-10%患有痴呆症。^17,19阿尔茨海默病是导致老年人痴呆的第一大原因，其次是脑血管功能障碍。¹⁴重要的是，大多数与年龄相关的认知功能丧失的人从未发展出这些更严重的疾病。^18,20

区分正常的年龄相关认知变化和轻度认知障碍是具有挑战性的，但综合评估包括认知变化史、体格检查、神经检查和认知功能测试是准确诊断的基础。¹⁸

表1：认知衰退的领域和功能障碍的迹象¹⁷

与认知衰退相关的危险因素

较老的年龄是年龄相关的认知衰退以及轻度认知障碍和痴呆的头号风险因素。女性患痴呆症的风险比男性高。此外，已经确定了一些老年痴呆潜在可变的风险因素，其中许多因素在中年时对老年认知功能的影响最大。^21-23这些风险因素包括：

1. 静态生活方式^21,22

2. 受教育程度低^21,22

3. 吸烟^21,22

4. 肥胖^21,22

5. 胰岛素抵抗和2型糖尿病^21,22

6. 高血压^21,22

7. 高胆固醇水平^21,22

8. 慢性肾病²¹

9. 心房颤动（一种心律失常）²¹

10. 心血管疾病²⁴

11. 抑郁²¹

12. 睡眠障碍²⁵

13. 睡眠呼吸暂停²⁶

14. 高同型半胱氨酸水平²⁷

15. 重金属毒性²⁸

抗胆碱能药物可以阻断乙酰胆碱的作用，用于治疗多种疾病，包括哮喘、慢性阻塞性肺疾病（COPD）、帕金森病、抑郁症和过敏，以及其他疾病。⁵¹⁰在最近一项对688名认知健康的老年人的研究中，对抗胆碱能药物对认知功能的影响进行了为期10年的评估。每周至少使用抗胆碱能药物治疗6个月以上的患者发展为轻度认知障碍的风险显著增加1.5倍。与使用抗胆碱药物相关的风险增加在APOE ε4基因型患者中尤其明显，他们的风险比未使用抗胆碱药物和无APOE ε4基因型患者增加2.7倍。此外，在脑脊液中有阿尔茨海默病生物标记物的个体中使用抗胆碱能与发展为轻度认知障碍的风险增加近5倍相关。使用抗胆碱能也与记忆力和语言能力的更快下降有关，特别是在APOE ε4基因型或有阿尔茨海默病脑脊液标记物的患者中。⁵¹¹

睡眠药物和认知功能障碍

虽然睡眠障碍是导致急性和慢性认知问题的常见原因，但一些研究表明，一些用于治疗睡眠障碍的药物与痴呆风险的增加有关。这包括处方睡眠药物，如苯二氮卓类，以及一些非处方睡眠辅助药物。^29-31

苯二氮卓类是一类能改变神经传递的镇静药物，适合短期治疗焦虑和失眠；然而，长期使用苯二氮卓类药物是常见的。³⁰长效苯二氮卓类药物，如氯硝西泮（Klonopin）和安定（Valium），比短期作用的苯二氮卓类药物，如三唑仑（Halcion）和咪达唑仑（Versed），更容易导致痴呆风险。³⁰一种被称为Z-drugs的新型镇静剂被批准用于长期治疗失眠症，但一些证据表明，它们的使用可能也会增加痴呆的风险。Z-drugs的例子有唑吡坦（Ambien）、佐匹克隆（Imovane）和埃司匹克隆（Lunesta）。²⁹

四、年龄相关的认知衰退的机制

与年龄相关的认知衰退是一个复杂的过程，有多种相互重叠的机制，但尚未完全了解。下面讨论了目前对一些老年认知衰退过程的理解。

干细胞衰老

20世纪90年代的突破性研究揭示了人类大脑中干细胞（被称为神经干细胞） 所在的特定区域，这种干细胞可能会在整个生命过程中继续修复和再生脑组织。^8,32脑环境中的生长因子如脑源性神经营养因子（BDNF）和其他信号因子似乎刺激神经干细胞增殖以及神经元和神经元连接的形成。^33,34大脑根据环境信号形成新的神经元、连接和重新排列神经网络的能力被称为大脑可塑性，或神经可塑性。³²

随着年龄的增长，神经干细胞对刺激的反应变得不那么灵敏，并且干细胞信号通路可能变得失调。³⁵这种情况被称为干细胞衰老，被认为是导致衰老的大脑可塑性减弱的主要因素。^36-38

生理节律紊乱

生理节律是一种自然循环，影响大脑和身体其他部分的许多重要方面。生物钟使新陈代谢、生理和行为节律与环境周期同步，比如昼夜周期和日常饮食模式。^39,40许多身体功能受生理节律信号调节，包括学习、巩固能力以及唤起回忆。^40,41生物钟失调，比如倒班工作、慢性压力和睡眠障碍，会导致认知能力下降。⁴⁰生理节律紊乱会干扰神经发生，降低神经可塑性。⁴²

脑血管功能障碍

 “脑血管”一词是指供给大脑的血管。脑血管功能障碍是由脑内血管的老化和动脉粥样硬化引起的，导致脑血流减少。随着年龄的增长，大脑血管变得僵硬，对血压变化、氧气和营养需求的反应减弱。此外，大脑中的毛细血管床更容易受到损伤和炎症的影响，增加了形成小血凝块和微出血的风险，从而破坏神经元并对认知功能产生负面影响。^43-46

供给大脑的血管有一种独特的结构特征，称为血脑屏障，由内皮细胞之间的特殊连接组成，内皮细胞形成血管的内层。在健康的个体中，这些连接对血液和大脑之间的化合物移动施加严格的控制。血脑屏障已被观察到随着年龄的增长而丧失完整性，对潜在毒素和促炎因子的渗透性越来越强。¹⁴

神经炎症

衰老与炎症信号升高有关，包括活化的小胶质细胞、星形胶质细胞、血管内皮细胞和其他类型的细胞，导致神经炎症。这会导致自由基和其他神经毒素的产生增加，从而损害神经元并引发神经元退化。^11,47神经炎症还会破坏血脑屏障，使神经元暴露于更多的潜在毒素中。⁹与系统性炎症相关的情况，如缺乏体育活动、不良饮食、肥胖和2型糖尿病，都与年龄相关的认知衰退和痴呆有关。^21,48不健康的肠道微生物群是另一个可能的炎症信号来源，可能会导致血脑屏障的恶化和神经炎症。⁴⁹

线粒体功能障碍和氧化应激

身体休息时大脑消耗大约20%的氧气，其中大约85%的氧气被脑细胞线粒体消耗。大脑对线粒体功能障碍特别敏感，大脑中产生的自由基异常高。^47,50健康的大脑产生的自由基被强大的抗氧化防御平衡；然而，在衰老的大脑中，像谷胱甘肽还原酶和超氧化物歧化酶（SOD）这样的抗氧化酶活性较低，导致一种有利于自由基产生的不平衡，并创造一个高氧化应激的环境。^47,50

氧化应激损伤细胞和线粒体DNA、膜和蛋白质，导致脑细胞活性降低和线粒体功能障碍增加。线粒体功能障碍导致ATP生成减少，自由基生成增多，⁵⁰并导致神经干细胞的损耗。⁵¹脑细胞内代谢活动的能量减少导致他们参与正常神经元活动的能力下降，这些活动包括细胞膜的维护和髓磷脂的产生，¹³以及与学习、记忆和认知相关的活动。⁴⁷此外，氧化应激增加炎症信号，加剧神经元的损伤和损失。⁴⁸

代谢紊乱

胰岛素抵抗和肥胖等代谢紊乱被认为是导致认知障碍和痴呆的原因。据认为，由胰岛素抵抗和肥胖引起的系统性炎症可能导致神经炎症、脑胰岛素抵抗、脑线粒体功能障碍和脑氧化应激。这些症状最终会导致神经元损伤和认知能力下降。^52,53

血脂水平紊乱和高血糖水平一直被发现与认知功能障碍有关，^52-54而2型糖尿病与轻度认知障碍以及发展为痴呆的风险增加有关。⁵⁵此外，阿尔茨海默病会增加患2型糖尿病的风险，这表明两者存在双向关系。⁵⁶虽然这种联系背后的机制尚未完全建立，但胰岛素抵抗和阿尔茨海默氏症之间的关系尤其引人注目，有时它被称为“3型糖尿病”。⁵⁷

脑震荡和认知衰退

脑震荡，也被称为轻度创伤性脑损伤，现在被广泛认为是导致长期认知功能障碍的潜在因素。直到最近，对大多数人来说，脑震荡的影响被认为在几个月的时间内就会自动消除。我们现在知道，有多达一半的脑震荡患者经历过慢性认知障碍。⁵⁸反复的头部创伤在运动员中很常见，可能会进一步增加长期的风险。^59,60

几个机制似乎在脑震荡的认知后遗症中起作用。脑损伤的实验室模型表明，轻度创伤性脑损伤，特别是反复发生时，可能会在大脑中触发一连串的重叠过程，例如^60,61：

1. 神经元线粒体改变葡萄糖代谢和能量产生

2. 关键脂质脑结构的氧化应激和氧化损伤增加

3. 脑血流下降

4. 小胶质细胞活性增强，加剧神经炎症

5. 血脑屏障功能中断

6. 神经传递改变

7. 淀粉样蛋白和tau蛋白的去除减少

此外，脑震荡可能会导致神经元死亡并引发长期的退行性进程。⁶¹利用成像技术的研究已经揭示了头部损伤后的脑组织结构变化与注意力、记忆和执行功能的下降有关。⁶²脑震荡的影响似乎与年龄相关的过程相互作用，加速认知储备的丧失，并增加多年后认知障碍和痴呆的风险。⁶³

临床医生和研究人员仍在探索使脑震荡相关的短期和长期问题最小化的策略。同时，在高风险活动中保护头部是必要的。如果你确实经历过头部受伤，无论你的年龄如何，遵循对保护老化大脑的建议可能是有益的。

异常蛋白质积累

Beta【β】-淀粉样蛋白和tau蛋白在大脑中正常存在，但当这些蛋白水平高时，它们会触发结构变化，破坏神经元功能和信号传递。^2,64在正在老化的大脑中，由于β-淀粉样蛋白的产生增加，清除减少，或两者兼备，β-淀粉样蛋白在神经元之间的间隙中积累。^1,14高浓度时，β-淀粉样蛋白聚合并在神经元周围形成斑块。⁶⁴ Tau蛋白通过一种被称为磷酸化的化学过程被破坏。神经元内磷酸化tau蛋白的聚集触发神经元纤维缠结的形成。⁶⁴这类斑块和缠结干扰正常神经元间的通讯，是阿尔茨海默病的特征，但最近的研究表明，β-淀粉样蛋白和磷酸化tau蛋白可能在临床痴呆发作前几十年就开始积累。^65-68

大脑中β-淀粉样蛋白和tau蛋白的高水平，以及血液中tau蛋白的高水平，分别与老年人的认知能力下降和轻度认知障碍患者的疾病进展独立相关。^65,69,70虽然蛋白质异常积累和认知能力下降之间关系的本质尚不完全清楚，但磷酸化的tau蛋白似乎特别干扰突触功能，甚至在缠结形成之前就引发神经炎症过程，导致神经元功能障碍。^65,71

表观遗传学

 “表观遗传学”是一个术语，用来描述影响细胞如何使用储存在遗传密码中的信息的生物现象。表观遗传过程强调或不强调基因组部分所包含的信息。表观遗传过程强调的部分被称为“表达”，不强调的部分被称为“沉默”。表观遗传过程并没有改变遗传密码，而是改变了细胞“读取”密码的方式。生活习惯、营养和环境（如暴露在空气污染中）等因素可以影响表观遗传基因的表达和沉默。

越来越多的证据表明，表观遗传学在老年人的学习、记忆和认知方面起着至关重要的作用，并影响认知障碍和痴呆的发展。⁷²例如，影响大脑生物钟的表观遗传改变已经被注意到影响与认知衰退相关的关键大脑区域的功能。⁷³可能引发与认知衰退和痴呆相关的表观遗传变化的因素包括呼吸模式紊乱（如换气过度综合征）、不良饮食、酗酒和睡眠不足。⁷⁴

同型半胱氨酸代谢中断

同型半胱氨酸是一种氨基酸衍生物，对血管有害，导致血管炎症、血管壁增厚和内皮功能障碍。它是动脉粥样硬化和增加中风风险的一个促成因素。⁷⁵同型半胱氨酸对脑功能的影响可能与它对脑血管的影响有关，⁷⁵但一些证据也表明，同型半胱氨酸会增加氧化应激和神经炎症，并可能有直接的神经毒性作用。⁷⁶

2018年，一组专家在《阿尔茨海默病期刊》（Journal of Alzheimer 's Disease）上发表的一份共识声明称，血液同型半胱氨酸水平中度升高（>11微克/升）是与年龄相关的认知衰退的一个重要原因。²⁷高同型半胱氨酸水平与脑萎缩有关，⁷⁷而且一直与认知障碍、痴呆和阿尔茨海默病的风险增加有关。²⁷同型半胱氨酸通过需要吡哆醇（B6）的途径转化为半胱氨酸，或者通过甲基化的化学过程转化为蛋氨酸，这依赖于B族维生素叶酸（B9）和钴胺素（B12）。缺乏叶酸和B12在老年人中很常见，是高同型半胱氨酸血症的主要原因。⁷⁶用这些B族维生素治疗可以降低同型半胱氨酸水平，减缓脑萎缩，抑制认知能力下降，改善记忆力。^27,77

纤维蛋白原和认知衰退

在一篇2019年发表的论文中，旧金山格莱斯顿研究所（Gladstone Institutes）的科学家证明，凝血蛋白纤维蛋白原在血管损伤削弱血脑屏障后可以进入大脑，可能导致认知能力下降。⁷⁸研究人员发现，一旦纤维蛋白原进入大脑，就会形成沉积物，激活特定类型的小胶质细胞（中枢神经系统的免疫细胞）。小胶质细胞的激活产生活性氧，破坏树突棘，破坏神经元之间的突触连接，导致认知能力下降。科学家们证明，即使在健康的大脑中，非常少量的纤维蛋白原也会导致突触的丧失，就像阿尔茨海默病一样，甚至在没有淀粉样斑块的情况下。阻断纤维蛋白原与小胶质细胞的结合可减少阿尔茨海默病小鼠模型的突触缺陷和认知能力下降。阿尔茨海默病的血管成分可能是仅仅旨在减少淀粉样斑块的临床试验失败的原因。解决血管变化和淀粉样蛋白沉积的联合治疗在未来可能被证明是更成功的。

一些早期的研究证实了纤维蛋白原水平与认知能力下降之间的联系。在一项对2300多名中老年受试者的研究中，血浆纤维蛋白原基线水平较高预示着五年后认知能力的下降。⁷⁹同一研究小组的另一项研究将一种与认知衰退有关的特定基因型与较高的纤维蛋白原水平联系起来。⁸⁰缺血性中风后较高的纤维蛋白原水平也与认知结果较差相关。⁸¹

激素失衡

大脑是身体激素网络的组成部分，调节激素产生并对激素信号作出反应。下丘脑-垂体-肾上腺（HPA）轴和下丘脑-垂体-性腺（HPG）轴显示了大脑和激素产生腺之间的综合关系。皮质醇、脱氢表雄酮（DHEA）、雌激素和睾酮等激素会影响大脑的结构和功能。与年龄相关的这些激素水平下降和大脑对激素信号的反应减弱可能会影响认知衰退和痴呆的易感性。⁸²

雌激素。雌激素通过增强脑血流、激活神经生长因子和防止神经元损伤来调节大脑功能。它似乎对线粒体的能量产生也有关键的影响。在女性中，发生在绝经期的雌激素水平下降可能是与年龄相关的认知衰退的一个促成因素。^83,84的确，许多妇女报告说在绝经前后认知功能发生了变化，尽管客观测量表明手术绝经比自然绝经更严重。对女性的临床试验表明，在绝经后不久开始雌激素治疗可能对降低老年痴呆症的风险有最大的好处。事实上，在老年时开始雌激素治疗对认知功能没有影响或没有有害影响。^84,85在临床试验中的一个复杂因素是使用孕激素与雌激素结合：虽然天然孕激素可能增加雌激素的神经保护作用，合成黄体酮如醋酸甲羟孕酮（MPA）（通常是与雌激素一起用于绝经后妇女激素替代治疗）似乎产生相反的效果。⁸⁴更多信息可在《女性激素恢复》文章中获取。

睾酮。睾酮是认知和情绪的重要调节器，在一些研究中，中老年男性睾酮水平较低与抑郁症状、认知表现较差以及痴呆风险增加有关。86在70岁及以上的男性中，睾酮水平的大幅下降与认知衰退增加有关。⁸⁷一些研究表明，睾酮疗法可以改善睾酮低水平男性的心理健康、生活质量和认知功能方面。^82,86然而，在女性中，老年时较高的睾酮水平似乎与认知能力更快下降有关，⁸⁸但这一发现因其他数据而变得复杂，这些数据表明，睾酮替代疗法可能在短期内对手术切除卵巢的女性的认知功能有好处。⁸⁹需要更多的研究来阐明睾酮替代对女性认知功能的潜在作用。

皮质醇。皮质醇是肾上腺对HPA轴激活反应而产生的一种糖皮质激素，是应激反应的关键调节因子。皮质醇还会影响情绪、注意力和记忆力，以及免疫、代谢和其他生理功能。⁸²HPA轴和由此产生的皮质醇释放通常受到生理节律信号的调节；在健康的情况下，皮质醇水平表现出明显的昼夜周期，早上达到峰值，晚上下降。⁹⁰

在老年人中，平均皮质醇水平更高，皮质醇释放的昼夜节律也变得迟钝。这可能与肾上腺刺激的负反馈控制减弱部分相关。^82,90慢性或重复的压力会增加HPA轴信号和皮质醇释放的持续失调，并与抑郁和焦虑、脑萎缩、认知障碍和痴呆有关。^82,90运动和正念训练可能有助于减少压力，修复皮质醇调节，减缓认知能力的下降。^90,91

脱氢表雄酮（DHEA）。DHEA是其他类固醇激素的前体，如雌激素、黄体酮和睾酮。此外，DHEA还具有一系列直接的激素作用。血液中的DHEA大多以硫酸脱氢表雄酮（DHEA-s）的形式存在。DHEA主要产生于肾上腺，但少量产生于卵巢和睾丸。DHEA和DHEA-s的水平都随着年龄的增长而下降，老年人的水平可能比年轻人低80-90%。^92,93一项大型研究总结称，男性和女性血液中DHEA-s水平越高，认知能力越强。⁹⁴脑内DHEA和DHEA-s浓度明显高于血液浓度，最近有人提出DHEA也可能在脑内合成。^93,95临床前证据表明，DHEA可能有助于皮质醇调节，减少神经炎症和大脑氧化应激，促进神经元生长。^93,95,96

术后认知功能障碍

术后认知功能障碍是指手术后持续性的认知障碍，经常影响定向、注意力、知觉、意识和判断。⁹⁷许多手术患者在手术后不久就会出现急性认知症状，称为术后谵妄，持续约4天。认知改变如意识混乱、注意力减少和对周围环境的意识减退是术后谵妄的特征。约10%的外科病人发生更持久的认知障碍。老年患者和已有认知障碍的患者术后出现慢性认知影响的风险更高。⁹⁸脑血管问题也与术后认知功能障碍的风险增加有关。⁹⁹术后认知功能下降会延长恢复时间和住院时间，并与较差的手术结果相关。⁹⁷

尽管病因尚不完全清楚，但有证据表明，外科创伤会引发炎症反应，通过系统免疫细胞和大脑免疫细胞之间的交流，引发神经炎症。系统验证和脑炎症也会引起血脑屏障功能障碍，导致脑组织更多的炎症活动。^100,101老年增加了术后认知功能障碍的风险，可能是由于免疫失调（免疫系统衰老的特征）。¹⁰²炎症还会增加氧化应激，消耗体内的抗氧化剂，这可能会进一步导致神经元损伤和功能障碍。¹⁰³麻醉对认知功能的潜在影响增加了复杂性，但观察性研究发现，术后认知功能障碍的风险可能与所使用的麻醉类型甚至手术类型无关。^101,103

通过一套循证的术前、术中和术后护理方案，可支持手术恢复，旨在减少压力，维持器官功能，加速肠道功能恢复。这些方案包括术前咨询、体育活动、心理训练和营养干预等措施；确保充足的营养，避免手术前不必要的长时间禁食；使用创伤最小的外科手术和麻醉技术；术后合理使用止痛药和其他药物；恢复健康饮食，促进日常节律和睡眠，术后早期活动。这些措施已被证明可以促进术后恢复，并有助于降低术后认知能力下降的风险。^97,104

五、益智药物和认知衰退的新疗法

虽然目前没有专门针对年龄相关的认知衰退的药物干预，但针对血管疾病和全身炎症等潜在问题的医学方法可能有助于防止渐进性认知能力下降。例如，使用某些抗高血压药物来降低高血压，可能会减缓认知能力下降和预防痴呆；然而，它们也有降低脑血管血流量和造成更多认知损害的风险。^105,106

一些观察性研究指出，使用他汀类降胆固醇药物（如辛伐他汀[Zocor]和阿托伐他汀[Lipitor]）的患者比不使用他汀类药物的患者发生轻度认知障碍和痴呆的风险更低¹⁰⁷；然而，其他研究和病例报告表明他汀类药物可能损害某些人的认知功能，108且其他研究也没有发现任何益处。¹⁰⁹大型随机对照试验发现他汀类药物对认知衰退或痴呆风险没有影响。^108,110-114

抗痴呆药物，如乙酰胆碱酯酶抑制剂多奈哌齐（Aricept）、加兰他明（Razadyne）、他林（Cognex）和利瓦斯汀（Exelon），虽然曾一度被认为对轻度认知障碍的患者有希望，但现在看来其在人群中既没有恢复认知功能，也没有防止痴呆。^115,116未来生物和基因标记的使用可能帮助研究人员识别那些最有可能从某些药物疗法中获益的人。¹¹⁵

其他几种具有潜在保护大脑作用的药物有：

1. 吡拉西坦（Notropil）和左乙拉西坦（Keppra）是抗癫痫药物，有时用作认知增强剂。这些以及一些相关的药物（“racetams”）通常被通俗地称为“益智药”。临床前证据表明，这些药物可能减少神经炎症，改善线粒体功能，并预防β-淀粉样蛋白诱导的神经元功能障碍。^117-119在早期研究中，左乙拉西坦在记忆测试中被发现可以改善认知表现。¹²⁰一项针对认知障碍和痴呆患者的临床试验结果表明，吡拉西坦可能对那些有抑郁症状的患者最有效。¹²¹这些药物对与年龄相关的认知衰退和轻度认知损害的患者是否有好处还没有确定。此外，吡拉西坦及其相关化合物的管制地位是模糊的，各国的法律地位也各不相同。

2. 齐留通 （Zyflo）是一种促炎酶5-脂氧合酶的抑制剂。虽然它的主要用途是作为一种抗哮喘药物，但已经在临床前试验中证明了它的一些有趣的脑功能影响。在动物研究中，齐留通被发现可以降低大脑中的β-淀粉样蛋白和tau蛋白水平，以及与淀粉样蛋白和tau蛋白相关的神经炎症、神经元功能障碍和认知障碍。^122-125其他动物研究表明齐留通可以减少中风后的脑损伤和认知能力丧失。^126-128齐留通在与年龄相关的认知衰退、轻度认知损害和痴呆方面的可能作用有待进一步研究。

3. 喜得镇（甲磺酸双氢麦角碱），一种麦角生物碱的混合物，已在初步试验中被发现能改善患与年龄相关的认知功能障碍的老年人的认知功能和情绪。^129,130其作用机制尚不完全清楚；然而，它似乎可以调节神经递质活性，改善大脑代谢，并增加大脑中的抗氧化酶活性。^131,132尽管有令人关注的发现，但几十年来没有临床试验来研究喜得镇在与年龄相关的认知衰退和轻度认知障碍方面的作用。

4. 司来吉林或咪多吡（Eldepryl）是一种单胺氧化酶b抑制剂，它能阻止某些神经递质的酶分解，如多巴胺和血清素。它被用于治疗帕金森病、阿尔茨海默病和重度抑郁症，并被认为有抗衰老的作用。¹³³在为期6个月的人类初步试验中，司来吉林被发现能改善轻度至中度脑萎缩患者的认知能力。¹³⁴对动物的研究表明，它可以减少氧化应激，保护由于血液流动损失而造成的大脑损伤，并保护神经传递和记忆。^135-138需要更多的临床试验来确定这种药物在与年龄相关的认知衰退方面的潜在益处。

5. 盐酸甲氯酚酯或甲氯芬酯 （Lucidril）能增强中枢神经系统中胆碱能通路的激活。对老年人的早期试验发现，盐酸甲氯酚酯改善了新记忆的形成，增加了对精神警觉性的主观报告。¹³⁹动物研究已经发现，这种药物可以防止由于铝中毒¹⁴⁰、药物毒性¹⁴¹、以及缺乏血流量而导致的认知能力丧失。¹⁴² 

六、注意饮食和生活方式对大脑健康的影响

一种包括健康的饮食、体育活动、充足的睡眠以及精神和社会刺激活动的方法，比任何个体干预对保持与年龄相关的认知健康都更为重要。^1,4,143

体育活动

终身保持身体活动对保持健康的认知功能至关重要。运动与认知衰退中大脑关键区域的年龄相关脑萎缩的减缓有关，在中年时积极锻炼与减缓认知衰退有关，并降低日后认知障碍和痴呆的风险。¹⁴⁴

临床前研究表明，运动可以刺激生长因子的产生，如脑源性神经营养因子（BDNF），它可以促进神经可塑性。运动还能改善脑血管功能，支持大脑新血管的形成，增加血液流动。¹⁴⁴

大量证据表明，就认知健康而言，任何类型和数量的体育活动都比不活动好。很明显，无论老年人目前的认知状况如何，有氧运动和力量训练都可以防止或延缓他们的认知能力下降。¹⁴⁵对于不能直立运动的老年患者，即使是坐着运动也有认知益处。¹⁴⁶

活跃小鼠的生长因子可以改善静息小鼠的大脑健康

有趣的是，临床前研究表明，运动的认知益处可能通过循环血液因子的管理而转移。在一项老龄小鼠的研究中，运动小鼠的血浆被注射到静息小鼠身上。运动后的小鼠神经发生增加，BDNF表达增加，学习和记忆能力提高，而静息的小鼠接受运动后小鼠的血浆也有同样的好处。研究人员发现，一种来自肝脏的特殊血液因子——糖基磷脂酰肌醇特异性磷脂酶D1 （Gpld1）在运动后增加，并与改善小鼠的认知功能有关。活跃、健康的老年人体内Gpld1的浓度也会增加。当Gpld1在衰老小鼠肝脏中过表达时，小鼠在神经发生和认知功能方面也有同样的改善。⁴⁸⁷这项研究给人们带来了希望：有一天，即使是那些不能锻炼的人也能从体育锻炼中获益。未来的研究可以探索是否可以通过将生长因子从年轻人、爱运动的人转移到老年人或久坐不动的人身上来获得类似的好处。

智力活动

许多研究表明，从事智力刺激的活动对生命各个阶段的认知健康都很重要。人们认为，教育和其他形式的智力刺激在人的一生中建立了认知储备（即大脑使用其他神经元途径来完成认知任务的能力）。拥有更大的认知储备可以延迟与大脑衰老或病理变化有关的症状的出现。^6,147

高等教育水平和终生使用双语对认知功能有保护作用，早期研究表明，在老年时接受教育和语言习得可能仍对认知的某些方面有好处。^6,148,149一项对研究的综合分析发现，音乐练习与保护认知功能的各个方面有关，包括那些受衰老影响的方面。长期接受音乐训练的人这种效果最强，但在晚年接受短期音乐训练后也能观察到这种效果。¹⁵⁰

多项研究表明，智力刺激的休闲活动与认知益处有关。例如，一项针对100名认知能力健康的老年人的研究发现，长期玩拼图的人在认知能力的各个方面都有更高的功能表现。¹⁵¹有证据表明，做数独和填字游戏对正在老化的大脑有好处。^152,153一项针对16572名年龄在65岁至100岁之间的参与者的研究发现，越频繁地玩文字或数字游戏，在基线测试和两年后的记忆、算术和语言流利度测试中都有更好的认知表现。即使是那些在研究开始后才开始玩文字或数字游戏的人，在研究结束时也比那些不经常玩文字或数字游戏的人表现出更好的认知功能。这种影响在所有年龄段的参与者中都同样强烈，在教育水平较低的参与者中更为明显。¹⁵⁴另一项研究发现，使用电脑、填字游戏、手工艺品和教育课程等活动都与延缓认知衰退一年以上有关。¹⁵⁵早期研究表明，智力刺激的计算机程序可能有助于改善轻度认知障碍和痴呆患者的认知表现。¹⁵⁶

减轻压力

慢性压力、焦虑、抑郁和睡眠障碍通常是相互关联的。这些疾病已经确定对大脑结构和功能有不利影响，并与痴呆风险的增加有关。¹⁵⁷减轻压力的技巧，如冥想和瑜伽，可能在减缓与年龄有关的认知衰退和预防认知障碍方面发挥作用。^157,158例如，正念冥想一直被发现对大脑结构、功能和可塑性有积极的影响，包括与认知功能障碍相关的大脑区域。⁶长期练瑜伽的人比不练瑜伽的人更不容易出现与年龄有关的脑萎缩，并且在一些认知测试中表现更好。^159,160其他研究也发现了类似的效果。¹⁶¹一项对于不同年龄受试者的认知功能研究发现，与没有练习的人相比，瑜伽长期练习者和冥想者的认知功能下降速度更慢，神经元网络更有弹性。¹⁶²

初步研究表明，冥想练习可以改善老年人的记忆、注意力和执行功能，^158,163还可能缓解与年龄有关的认知衰退。¹⁶⁴正念运动疗法，如太极、瑜伽和步行冥想对生活质量、情绪和认知功能也有积极的影响。¹⁶⁵在一项随机对照临床试验中，118名平均年龄62岁的参与者参加了一项为期8周的哈他瑜伽项目，该项目包括姿势、呼吸和冥想练习，提高了他们在注意力和信息处理速度测试中的表现。¹⁶⁶

社交活动

社交活动，就像身体和智力活动一样，可能是一生中大脑功能健康的重要中介。¹⁶⁷越来越多的研究表明，高社交参与度和强大的社交网络与减少与年龄相关的认知衰退、轻度认知障碍和痴呆有关。^167,168另一方面，认知功能和身体功能的渐进性丧失可能导致社交网络的强度减弱与孤独感增加，从而导致进一步的认知丧失。^169-171

强大的社交网络与老年人更好的认知功能相关，并降低了轻度认知障碍患者经历焦虑和抑郁症状的可能性。¹⁷²一项研究发现，在8年的时间里，无论研究开始时的认知状态如何，定期参加社会活动可以缓解老年男性和女性的认知衰退。¹⁷³类似地，对543名认知健康、67岁的参与者进行了8年的监测，发现社交参与与认知衰退速度较慢有关。¹⁷⁴在一项研究中，志愿服务被确定为一个特定的预测因子，可以预测随着年龄增长的认知弹性，这可能部分是由于许多志愿活动的社会和认知方面的结合。¹⁷⁵

参加群体社交活动对老年人的认知健康可能变得更加重要。¹⁷⁶即使是年纪很大的人，参加社交活动似乎也是有益的；在一项对256名85岁以上的人的研究中（这些人在研究开始时认知正常，并被监测了大约4年），参与艺术、手工艺和社会活动都被认为是对轻度认知损伤的保护。¹⁷⁷

睡眠

睡眠是大脑休息和修复的关键时间，急性和慢性睡眠障碍对身体、情绪和认知健康都有可衡量的负面影响。长期睡眠剥夺和慢性睡眠限制或碎片化会损害神经功能，并导致压力、情绪症状和认知功能障碍。¹⁷⁸在健康的老年人中，主观认知症状在那些也有睡眠障碍的人中更常见。¹⁷⁹

衰老与睡眠时间和质量的减少自然有关，^180,181其可能通过扰乱生理节律和应激激素信号，促进全身炎症、代谢紊乱和脂肪沉积来影响认知功能。^182,183此外，睡眠不良可能通过影响神经可塑性的表观遗传变化影响认知。¹⁸³

根据对这一关系的大型综合分析，维持健康认知功能的最佳睡眠时间似乎是每晚7-8小时，而较短或较长的睡眠时间都与认知能力下降、轻度认知障碍和痴呆的风险增加有关。^184,185

充足的日间活动和促进睡眠的夜间环境可以帮助患有睡眠障碍的老年人。已经证明了一些有效性的策略包括1^81,186,187：

1. 日间活动。因为白天过多或过少的活动都会导致晚上的睡眠问题，所以保持一个平衡的日常活动和活动计划有助于防止白天打盹，并促进更好的夜间睡眠。

2. 冥想。身心疗法和冥想可以促进放松，并可能增加睡眠时间。

3. 认知行为疗法。失眠症的认知行为干预主要是围绕睡眠对消极的思维模式进行重建。

4. 促进睡眠的设备。使用改善睡眠环境的设备（如耳塞、眼罩、白噪音机、加重毛毯和播放催眠音乐的设备）都证明了一些减少睡眠干扰的效果。

5. 白天亮光疗法。亮光疗法可以帮助增加白天的活动，减少白天的打盹，重置生物钟，从而帮助恢复正常的睡眠模式。

健康睡眠的各种其他重要考虑因素可在《失眠症》文章中获取。

阻塞性睡眠呼吸暂停和认知功能障碍

阻塞性睡眠呼吸暂停是一种常见的睡眠呼吸障碍，其特征是周期性的气道完全或部分关闭，导致睡眠过程中的呼吸暂停（缺少呼吸）或低呼吸（呼吸不足）。由于呼吸暂停和低呼吸，血液中的氧气水平下降，二氧化碳水平上升，导致大脑觉醒以触发恢复充分的呼吸。¹⁸⁸频繁的呼吸暂停和觉醒之间的循环会导致睡眠碎片化，如果是长期的，会导致生理节律信号中断、应激反应失调、全身炎症和氧化应激增加。^189,190阻塞性睡眠呼吸暂停可能是代谢和心血管疾病以及认知功能障碍的主要促成因素。^190,191

阻塞性睡眠呼吸暂停与认知衰退、轻度认知障碍和痴呆之间的关系已在众多研究中被观察到。^188,192一项包括14项超过400万参与者的研究的大型综合分析显示，睡眠呼吸障碍与认知障碍发生的可能性增加26%有关。26越来越多的证据表明，用持续正压通气（CPAP）治疗睡眠呼吸暂停可以减少睡眠呼吸暂停相关的认知能力下降。^193-195

更多信息可在《睡眠呼吸暂停》文章中获取。

饮食

以传统地中海饮食为基础的饮食模式已被证明对大脑、心血管、代谢功能和整体寿命有抗衰老作用。^143,196-198多项研究表明，地中海式饮食可以减缓认知能力下降，并可能降低患痴呆症的风险。¹⁹⁹

地中海式饮食。强调水果、蔬菜、未经提炼的全谷类，豆类和特级初榨橄榄油，以及适量的海鲜，发酵乳制品，和餐时红酒，200传统的地中海饮食提供了充足数量的关键营养物质如单不饱和脂肪酸和多不饱和脂肪酸，抗氧化剂，维生素，矿物质和植物营养素。它可以作为一个模板，以适应特定食品的当地性和季节性可获得性。^143,198

一项对832名参与者持续了18年的研究，每两到三年进行一次检查，发现那些饮食最符合地中海饮食的人的认知衰退明显低于那些饮食最不符合地中海饮食的人。201一项研究基于16年来27,842名参与健康专业人员随访研究的男性的数据，发现那些饮食最像地中海的人比那些饮食最不像地中海的人报告主观认知功能差的可能性低36%。202对认知能力正常的老年受试者的大脑检查表明，坚持地中海式饮食模式与β-淀粉样蛋白积累减少有关。与这种影响最密切相关的饮食成分是大量食用水果和蔬菜以及适量饮用葡萄酒。^203,204

表2：从西式饮食过渡到地中海饮食的策略²⁰⁰

特级初榨橄榄油。虽然地中海饮食习惯的结合是其功效的关键，但饮食中大量的特级初榨橄榄油被认为是其对认知的保护作用的重要原因。一些临床前研究表明，特级初榨橄榄油中的多酚可以减少β-淀粉样蛋白和tau蛋白的积累和毒性，并可能调节微小核糖核酸情况。^205-207一项在285名老年人中开展的临床试验比较了三种饮食：地中海式饮食，每周在其中补充多达1升（每天超过1-2杯）的特级初榨橄榄油；地中海式饮食，包括每天30克混合坚果；以及低脂饮食。6.5年后，橄榄油补充组的认知表现优于其他两组。²⁰⁸

咖啡

许多临床前和临床研究已经检验了喝咖啡有助于预防认知衰退的潜力。咖啡因和咖啡被认为可以改善短期记忆和认知能力，一些研究表明，长期饮用咖啡可以预防痴呆和认知衰退。此外，临床前模型已经证明了咖啡中的生物活性成分具有神经保护作用的生物学机制。²⁰⁹例如，在一项对145名认知健康的老年人进行的为期三年的研究中，中度至重度饮用咖啡的人认知能力下降程度较低，脑白质和脑血流的保护也较好。²¹⁰类似地，对11项前瞻性研究的分析发现，最高水平的咖啡消费量与降低27%的阿尔茨海默病风险有关。²¹¹然而，一些研究发现，少量的咖啡似乎也能保护认知功能。一项对9项前瞻性研究的分析得出结论，每天喝1-2杯咖啡能起到最佳保护作用，²¹²而其他研究表明，咖啡对认知和大脑的影响是复杂的，需要进一步研究。^213-215

热量限制

热量限制是一种减少热量摄入但保留足够营养摄入的饮食干预，已被证明可以延迟许多生物体中与年龄有关的疾病发生并延长寿命。²¹⁶这种效应被认为是因为其触发了恢复机制，增强了细胞对压力的抵抗力。^217,218这种效应被称为兴奋效应。

在啮齿动物模型中，热量限制与神经干细胞衰老减少、神经可塑性增强和更好的认知表现相关。²¹⁸具体来说，热量限制已经在动物模型中被发现可以刺激神经干细胞活动²¹⁹，促进髓磷脂生产所需的磷脂的正常代谢²²⁰，降低应激反应性和与应激相关的大脑结构变化²²¹，并诱导支持衰老大脑中年轻基因表达的表观遗传变化。²²²在动物身上与热量限制相关的一些代谢和分子变化以及健康益处，已在进行25%热量限制或间歇性禁食策略并结合体育运动的人身上得到证实。²¹⁶

更多信息可查阅《热量限制》文献。

乳糜泻，麸质敏感，认知衰退

乳糜泻是一种慢性疾病，是由对麸质（主要存在于小麦中的一种蛋白质）的自身免疫反应引起的。乳糜泻患者通常有高度的全身和胃肠道炎症，以及明显的肠道微生物失衡（失调）。²²³据估计，10%的乳糜泻患者还经历了与该疾病相关的神经系统症状，如头痛、肌肉协调性缺乏、四肢麻木或刺痛、抑郁以及从轻微的可逆认知症状（如“脑雾”）到永久性的神经损伤和痴呆的认知障碍。^223-225

非乳糜泻麸质敏感症是一种胃肠道疾病，是由对麸质的炎症反应引起的，似乎与自身抗体无关。它会导致与乳糜泻类似的后果，包括肠道和全身炎症和生态失调，可能会导致神经炎症和认知症状。²²⁶

在老年人中，乳糜泻和非乳糜泻麸质敏感性的神经表现通常归因于与年龄相关的认知衰退或被误诊为认知障碍甚至是阿尔茨海默症，但如果能准确诊断并实施无麸质饮食，这些症状通常就会消失。^223,227

七、健康的大脑：综合疗法

银杏

银杏 （Ginkgo biloba）也许是研究最广泛，使用最广泛的支持认知功能的综合疗法。银杏提取物已被证明可以减少氧化应激，减少神经炎症，改善微循环，调节神经递质活性，促进神经可塑性。^228,229动物实验表明银杏可以刺激神经干细胞的增殖和活性。²³⁰

大量随机对照试验、系统评价和综合分析得出结论，对于轻度认知障碍和痴呆患者，银杏（通常每天摄入120-240毫克）可以减缓认知能力下降，并减轻神经精神症状（如妄想、抑郁或焦虑情绪）。^228,231-2332019年的一篇专家共识论文发现，有证据证明标准化银杏提取物的有效性和安全性，可以单独使用或与传统疗法联合使用，用于治疗轻度认知障碍和痴呆症。²³⁴

假马齿苋

假马齿苋 （Bacopa monnieri）, 一种在印度具有宗教、文化和医学重要性的植物，几个世纪以来一直用于传统的阿育吠陀医学。²³⁵在临床前研究中，假马齿苋提取物已被证明具有诸如减少大脑氧化应激、调节神经递质活性、减少β-淀粉样蛋白沉积、加强神经元连接和增加脑血流等作用。^236,237人类研究表明，假马齿苋也可能改善应激反应。²³⁸此外，在小鼠中，假马齿苋提取物增加了脑源性神经营养因子（BDNF）的水平和新神经元的产生。²³⁹

一项包括9项随机对照试验518名受试者数据的综合分析得出结论，假马齿苋有可能改善认知能力的某些方面。²⁴⁰在一项随机对照试验中，54名年龄在65岁以上的参与者中，与接受无效对照剂的人相比，那些每天接受300毫克假马齿苋提取物的人在12周后有更好的认知表现，并减少了焦虑和抑郁的症状。²⁴¹两项临床试验使用不同的草药营养组合与假马齿苋补充剂，结论称这些补充剂对有轻度认知障碍的老年人有认知益处。^242,243

石杉碱甲

石杉碱甲是中草药蛇足石杉的一种生物活性化合物。石杉碱甲已被证明能抑制乙酰胆碱酯酶，这是一种分解乙酰胆碱的酶。乙酰胆碱是自主神经系统中的一种主要神经递质，乙酰胆碱酯酶加速了乙酰胆碱酯酶的分解，被认为是导致与年龄相关的认知衰退和痴呆的原因之一。²⁴⁴一些抗痴呆药物如多奈哌齐也通过抑制乙酰胆碱酯酶发挥作用，而石杉碱甲已被提出在阿尔茨海默病中具有疾病缓解作用。²⁴⁵此外，临床前证据表明石杉碱甲可能降低氧化应激，防止β-淀粉样蛋白和磷酸化tau蛋白积累，支持线粒体功能，并增加大脑神经生长因子的产生。²⁴⁶

大量的临床试验表明石杉碱甲可以改善痴呆患者的认知功能。一项综合分析包括10个随机对照试验，对总共825名阿尔茨海默氏症或血管性痴呆患者进行石杉碱甲的疗效评估，服用剂量从每天100到400微克不等。分析结果表明，石杉碱甲可以改善痴呆患者的认知功能，长时间使用可能会产生更大的益处。²⁴⁷另一项对阿尔茨海默病患者的20项随机对照试验的综合分析也指出石杉碱甲可能对认知功能有好处。²⁴⁸一项初步试验检查了石杉碱甲对阿尔茨海默病患者任务转换（一种高阶认知功能）的影响。经过8周0.2 毫克石杉碱治疗后，任务转换的认知功能和测试表现有所改善。²⁴⁹在另一项初步试验中，一种含有石杉碱甲和姜黄素的补充剂在6-12周和22-28周后改善了痴呆患者和轻度认知障碍患者的认知能力。²⁵⁰

需要注意的是，服用石杉碱甲的人有轻度的不良反应，如消化不良、便秘、头晕、心率减慢、口干等。^247,248

乙酰左旋肉碱

乙酰左旋肉碱是氨基酸的一种形式，属于肉碱，产生于线粒体，参与细胞能量生产。一项研究报告了从无认知问题到主观记忆障碍，到轻度认知障碍，再到痴呆的受试者，他们血液中的乙酰左旋肉碱水平逐渐下降。²⁵¹临床前研究表明，乙酰左旋肉碱可能保留脑线粒体功能，减少氧化应激，抑制小胶质细胞的炎症活动，并改善神经系统中的多巴胺信号。^252,253

一项随机对照试验的综合分析，包括21项研究超过1200名受试者的数据，发现补充乙酰左旋肉碱3个月或更长时间与轻度认知障碍和早期阿尔茨海默病患者的临床改善有关。²⁵⁴一项针对老年参与者的临床试验发现，使用乙酰左旋肉碱治疗可以减少身体和精神疲劳，改善认知和身体功能。²⁵⁵并且在改善老年人轻度抑郁症状方面具有相似的效果，这一效果可能与更好的认知功能有关。²⁵⁶与无效对照剂相比，服用6个月含有乙酰左旋肉碱和B族维生素、维生素E和其他氨基酸衍生物的复合补充剂，可改善轻度认知障碍参与者的认知功能。²⁵⁷

苏糖酸镁

苏糖酸镁是镁的一种形式，被发现对提高大脑镁水平特别有效。^258,259对于研究动物，增加脑镁水平可以增强其神经可塑性和认知功能。^258,260研究表明，在衰老和阿尔茨海默病的动物模型中，补充苏糖酸镁可以防止与年龄相关的特定神经递质受体（NMDA受体亚基NR2B）的丢失，抑制炎症信号，减少淀粉样斑块的形成，保护神经连接，并防止记忆丧失。^259,261-263其他动物研究表明，在有阿尔茨海默样大脑病理的小鼠中，苏糖酸镁可能增加精神和身体刺激活动的认知增强效果。²⁶⁴

多酚

多酚是一种存在于植物中的强氧化应激缓解化合物。人们认为，传统地中海饮食中的高多酚含量可能是其有益认知的一个重要原因。²⁶⁵在652名年龄在65岁及以上的无痴呆受试者中，那些尿中多酚含量较高（表明多酚摄入量较高）的受试者，在三年的监测中认知能力下降较少。²⁶⁶另一项针对447名心血管疾病风险增加的老年人的研究也发现，尿中多酚浓度较高的人认知能力更强。此外，摄入特定的富含多酚的食物（橄榄油、咖啡、核桃和葡萄酒）与在认知功能某些方面的测试中表现更好独立相关。²⁶⁵

有证据表明，多酚可以减少大脑氧化应激和神经炎症，并改善脑血管功能。²⁶⁷除了抑制多余的自由基外，多酚还可能影响与衰老相关的信号传导，保护神经干细胞活性，促进神经可塑性，减少蛋白质积累，诱导参与突触可塑性的基因发生表观遗传变化，并促进肠道微生物组健康。^267-270

莓多酚。蓝莓及其多酚，尤其是赋予蓝莓颜色的花青素，可能对包括认知障碍在内的慢性疾病有预防作用。²⁷¹对老年人的研究表明，蓝莓可以增强大脑血流量，并且增加与年龄相关的认知衰退相关区域的大脑活动。^272,273在一项随机对照试验中，37名年龄在60岁到75岁之间的人每天服用24克冷冻蓝莓干（相当于一杯新鲜蓝莓）90天，与无效对照剂相比，他们的认知表现更好。²⁷⁴另一项对照试验发现，用全果蓝莓粉治疗24周可以改善老年人的认知功能。²⁷⁵在一项对26名患者进行的安慰剂对照试验中，手术前至少14天每天服用500毫升蓝莓汁可减少与麻醉相关的认知缺陷。²⁷⁶在一项对40名年龄在50-70岁的健康受试者进行的对照试验中，与无效对照剂相比，饮用混合浆果饮料五周可以改善心血管风险指标和记忆测试表现。²⁷⁷

葡萄多酚。葡萄多酚，如槲皮素，番茄红素，白藜芦醇和花青素，已经证明有神经保护作用。²⁷⁸一项对111名健康老年人进行的随机对照试验发现，持续12周每天摄入250毫克的葡萄提取物可以提高认知测试的分数。²⁷⁹在小型对照试验中，患有认知能力下降和轻度认知障碍的老年人在每天饮用15-20盎司（取决于体重）的康科德葡萄汁12-16周后，认知能力得到了改善。^280,281一项针对10名患有轻度认知衰退的参与者的小规模安慰剂对照试验发现，服用无效对照剂的人在与痴呆有关的大脑区域的代谢活动显著减少，而服用葡萄提取物的人则没有出现这种下降。²⁸²一项随机对照试验在215名健康的老年人中发现，持续6个月每天服用600毫克一种高多酚葡萄加蓝莓提取物，只有那些在基线认知测试中得分最低的人才具有显著效果。²⁸³

白藜芦醇。白藜芦醇是一种葡萄多酚，尤其在红葡萄酒中发现，许多研究表明它具有强大的自由基猝灭能力。284白藜芦醇似乎可以通过调节年龄相关信号、改善脑血流和增强神经可塑性来减缓认知能力下降。²⁸⁵临床试验的结果好坏参半；然而，一项包括10个随机对照试验的综合分析发现，白藜芦醇可能改善老年人认知功能和情绪的某些方面。²⁸⁶

在一项随机安慰剂对照试验中，46名年龄在50-75岁的健康个体接受了26周的每日200毫克白藜芦醇摄入，他们在记忆任务中表现更好，同时改善了糖代谢（表现为HgbA1c降低），增加了神经元连接，并减少了体脂。²⁸⁷另一项对40名患有轻度认知障碍的患者进行的试验发现，每天服用200毫克白藜芦醇26周后，葡萄糖代谢更好，大脑结构保护更好，但与无效对照剂相比，认知功能没有差异。²⁸⁸在一项针对久坐不动、超重的老年人的对照试验中，每天摄入1,000毫克白藜芦醇90天，能改善精神运动速度，但不能改善认知功能的其他方面，而每天300毫克则没有效果。²⁸⁹在一项对绝经后女性的对照试验中，每天服用150毫克白藜芦醇14周后可以改善脑血管功能和认知能力；研究人员提出，白藜芦醇在这一人群中的一些作用是由于它的植物雌激素作用。²⁹⁰

绿茶儿茶素。绿茶是多酚儿茶素的来源。越来越多的证据表明，绿茶儿茶素可能通过调节神经生长因子、调节参与炎症和神经元存活的细胞信号，以及减少异常蛋白的积累来减缓大脑衰老。^291,292一项对21项研究的综述发现，绿茶可能会减轻焦虑，改善记忆力和注意力，增强大脑功能。²⁹³

绿原酸。绿原酸是在咖啡中发现的多酚，许多研究表明绿原酸的摄入与更好的认知功能和情绪有关。294一项针对38名年龄在50-69岁、有主观记忆力问题的健康成年人的研究发现，连续16周在睡前饮用含有300毫克绿原酸的饮料，可以改善认知能力，提高血液蛋白质水平，这被认为是早期阿尔茨海默病的标志物。²⁹⁵

褪黑素

褪黑素有助于调节大脑的生理节律控制中心，促进睡眠。随着年龄的增长，生理节律模式和夜间褪黑素的分泌会减少，导致睡眠质量差和随之而来的神经退化。^296,297在老年人中，夜间褪黑素水平较低与轻度认知障碍和痴呆有关。298-300动物研究表明褪黑素可以修复昼夜节律和睡眠障碍，减少相关的认知问题。^301-303在阿尔茨海默病和血管性痴呆的动物模型中也发现了褪黑素降低神经炎症和神经退化的潜力。^304-306

在一项对轻度认知障碍患者的回顾性分析中，报道了褪黑素对睡眠、情绪和几项认知功能测试的影响。该分析比较了在睡前服用加或不加3-24毫克褪黑素的标准药物对96名门诊病人的效果。研究人员对参与者进行了15至60个月的监测，结果显示，接受褪黑素治疗的一组人睡眠和情绪都有所改善，认知功能的各项测试都表现得更好。³⁰⁷在这些研究人员先前进行的一项设计类似的回顾性分析中，每晚服用3-9毫克褪黑素9-18个月的治疗改善了轻度认知障碍患者除一项认知测试外的所有认知测试的表现。³⁰⁸

一项在139名接受髋关节手术的老年参与者中进行的随机对照试验发现，在手术前一天开始的6天睡前服用1毫克褪黑素可预防术后认知能力下降；与无效对照剂相比，在睡眠质量、疲劳和总体幸福感方面也有改善。³¹⁰对阿尔茨海默病患者的临床试验表明，褪黑素可能改善睡眠，减轻行为症状，并增强认知功能的某些方面。^311,312

在一项无前例的研究中，研究人员将褪黑素与其两种代谢物对记忆的影响进行了比较。³⁰⁹这项研究通过一项新的物体识别任务和一项对涉及认知记忆的特定大脑区域的褪黑素及其代谢产物的分析，在小鼠身上测试了干预措施。值得注意的是，新的物体识别任务是用在小鼠身上的，因为小鼠有检查陌生物体的本能倾向。如果有选择，健康的年轻小鼠通常会花更多时间检查陌生的物体，而不是熟悉的物体。结果显示褪黑素及其代谢产物在物体识别方面与对照组相比有显著改善。在接受代谢物AMK的老年小鼠中观察到最有效的效果，因为这些小鼠能识别物体长达4天。研究还表明褪黑素及其代谢产物可以在海马体和鼻周皮层中积累。

Omega-3脂肪酸和鱼油

长链Omega-3脂肪酸二十二碳六烯酸（DHA）是大脑健康的关键营养物质，DHA缺乏会导致情绪不佳和认知功能障碍等症状。神经元细胞膜中DHA浓度较高，DHA在此处在维持细胞膜流动性方面起着重要的结构作用。^313,314临床前研究表明，DHA加上来自鱼类的另一种Omega-3脂肪酸——二十碳五烯酸（EPA），可以防止淀粉样斑块和神经纤维缠结³¹⁵，还可以防止堵塞并可改善大脑小血管的血液流动。³¹⁶大脑中适当使用B族维生素也需要充足的Omega-3脂肪酸。^314,317此外，DHA具有抗炎作用，是神经保护素D1的前体，这是一种参与神经元生长和生存的信号分子。³¹³

许多研究已经指出，较高的海产品摄入量、血液或膳食中Omega-3脂肪酸水平与较好的认知功能之间存在很强的联系。^318-320一项针对2622名老年人的研究发现，血液中长链Omega-3脂肪酸（包括EPA和DHA）含量最高的人在13年的时间里，出现不健康衰老的风险降低18%。不健康衰老的定义是慢性疾病、身体或认知功能障碍，或因任何原因死亡。321其他研究的结果表明Omega-6和Omega-3脂肪酸的比例可能是影响大脑结构和认知功能的一个重要因素。^322,323

一项对6项随机对照试验进行的综合分析发现，补充Omega-3脂肪酸可以减缓老年人认知能力下降的速度，这些试验每天服用的剂量从400毫克到1800毫克不等，持续时间为3-40个月。³²⁴类似地，一项对24项研究的大型综述发现，有证据表明摄入Omega-3脂肪酸对改善认知老化有有益作用。³²⁵然而，研究结果并不一致。例如，连续18个月每天摄入1720毫克DHA和600毫克EPA对390名健康的老年人的认知衰退没有影响³²⁶；并且，在99名认知功能正常或轻度受损的参与者中，持续一年每天750毫克DHA加120毫克EPA也没有显示出显著的影响。³²⁷

在一项随机安慰剂对照试验中，1680名70岁及以上有主观记忆障碍的参与者每天接受800毫克DHA加225毫克EPA或无效对照剂治疗3年。虽然在最初的分析中补充DHA和EPA并没有影响认知功能，³²⁸仅对那些基线Omega-3指数（红细胞中Omega-3脂肪酸的测量）较低的人进行二次分析，结果显示补剂能改善这组人的执行功能。³²⁹同一研究的数据表明，Omega-3指数≤5%的人认知能力下降的几率增加，可能从补充剂中获益最多。³³⁰

另一个可能影响临床试验结果的因素是ApoE4基因变异的存在，这与DHA代谢紊乱有关。³³¹一项针对915名老年参与者的研究仅指出了较高的海鲜摄入量与ApoE4携带者认知衰退的减少之间的联系。³³²另一项研究发现，食用海鲜对淀粉样蛋白斑和神经纤维缠结可观察到的预防效果仅仅是由于ApoE4载体的作用。³¹⁵由于这些发现，有人提出补充DHA可能对ApoE4携带者更重要。³³³

B族维生素

B族维生素是同型半胱氨酸代谢所必需的，而较低水平的B族维生素，特别是叶酸、B12和B6，与老年人同型半胱氨酸水平高和认知能力下降更严重有关。^334-337虽然补充B族维生素已被证明能有效降低高同型半胱氨酸水平，但到目前为止，有关认知益处的临床试验结果好忧参半。^338-341

研究人员一直在调查那些最有可能从B族维生素治疗中获益的因素，如Omega-3脂肪酸状态、同型半胱氨酸水平或认知障碍程度。一项随机试验发现，补充B族维生素对认知功能的积极影响取决于足够的Omega-3脂肪酸状态。³¹⁷一项为期2年的随机对照试验发现，只有那些基线同型半胱氨酸水平为11.3微克/升或更高的人，补充B6、B12和叶酸才能减缓认知能力的下降。³⁴²在对有轻度认知障碍的老年人进行为期五年的监测期间，补充叶酸和B12与降低痴呆风险有关。³⁴³在被诊断患有轻度认知障碍的老年人中，每天摄入400微克叶酸可在6个月³⁴⁴和1年后降低认知衰退和血液中炎症细胞因子水平。³⁴⁵在一项针对轻度认知障碍患者的试验中，即使仅12周后，服用B6、叶酸和B12补充剂也能降低同型半胱氨酸水平，改善认知功能和抑郁症。³⁴⁶

另一个潜在的重要因素是亚甲基四氢叶酸还原酶（MTHFR）基因的影响；特定MTHFR变体的携带者会有异常的叶酸代谢，并需要更多的叶酸摄入以避免叶酸缺乏。³⁴⁷普通的叶酸补充剂对他们的益处也更少。为了克服这一障碍，一项初步研究对高同型半胱氨酸水平的患者补充了L-甲基叶酸（活性形式的叶酸）和B12（甲基钴胺素），发现这种治疗可以减少认知衰退，并且对轻度认知功能障碍患者更有效。³⁴⁸

α-甘油磷酰胆碱（Alphoscerate胆碱）

α-甘油磷酰胆碱（α-GPC）（也称为alphoscerate胆碱）是营养物质卵磷脂和神经递质乙酰胆碱前体的半合成衍生物。349乙酰胆碱是自主神经系统中的一种主要神经递质，其加速分解被认为有助于与年龄相关的认知衰退和痴呆。事实上，可降低乙酰胆碱代谢酶浓度的乙酰胆碱酯酶，已经在“超级老年者”（即具有异常年轻的认知功能的老年人）的大脑中被观察到。²⁴⁴

乙酰胆碱前体，单独或联合乙酰胆碱酯酶抑制剂药物使用，是一种很有前途的治疗痴呆的方法。^349-351一项随机对照试验比较了261名轻度至中度阿尔茨海默病患者每日服用1200毫克α-GPC与无效对照剂180天的效果。接受α-GPC的患者在认知功能和行为评估方面有改善，而接受无效对照剂的患者在临床措施方面没有变化，或恶化。³⁵²在一项对50名有轻度认知障碍的受试者进行的初步试验中，每天服用1200毫克α-GPC，持续3个月，可改善认知功能。在治疗结束后7到9个月进行的随访评估发现，认知功能仍然高于治疗前的水平。³⁵³另一项初步试验发现，经历过中风的患者在接受15天治疗后，α-GPC对认知功能有有益影响。³⁵⁴

一项随机对照试验的报告显示，多奈哌齐（乙酰胆碱酯酶抑制剂）联合α-GPC治疗，与多奈哌齐加无效对照剂相比，在一年³⁵⁵及两年³⁵⁶后，更有效保护阿尔茨海默病患者的认知和行为功能以及脑血管受损，并在三年后减少情感淡漠和与渐进性痴呆有关的动机损失。³⁵⁷这项试验的最新报告显示，联合使用这两种药物可以减少阿尔茨海默病相关的行为和情绪障碍。³⁵⁸

磷脂酰丝氨酸

大脑含有高浓度的磷脂酰丝氨酸，这种磷脂包含两种脂肪酸，是细胞膜和髓磷脂的一部分。磷脂酰丝氨酸对于认知功能的各个方面以及神经系统控制运动功能都是必需的。衰老与大脑结构和化学物质的退化有关，这可能受到补充磷脂酰丝氨酸的影响。^359,360

早期的临床试验使用从牛脑组织中提取的磷脂酰丝氨酸，显示出对老年人的认知能力有很大的益处^361,362；然而，有关磷脂酰丝氨酸来源的安全问题导致其被撤出市场。磷脂酰丝氨酸也可从大豆中提取。在无对照的试验中显示，每天300毫克剂量的大豆磷脂酰丝氨酸，可改善一些存在记忆障碍的老年人的认知性能。^363,364

牛磷脂酰丝氨酸与大豆磷脂酰丝氨酸在脂肪酸结构上有所不同：来源于牛的磷脂酰丝氨酸包含Omega-3脂肪酸DHA，而来源于大豆的则不含有。海洋磷脂酰丝氨酸与Omega-3脂肪酸EPA和DHA的络合已经被证明是安全的，并且可能对老年人的认知有积极的影响。³⁶⁵在一项公开试验中，8名60岁以上的患有主观记忆障碍的志愿者，每天摄入300毫克伴EPA和DHA的磷脂酰丝氨酸，持续6周后在短期记忆测试中表现有所改善。³⁶⁶在一项随机对照试验中，157名有主观记忆障碍的参与者比较了每天300毫克海洋磷脂酰丝氨酸和无效对照剂的效果。15周结束时，接受磷脂酰丝氨酸的受试者在短期记忆测试中表现得更好，基线认知功能最好的受试者效果最强。³⁶⁷试验继续进行了15周，所有参与者每天服用100毫克磷脂酰丝氨酸补充剂；那些之前已经服用补充剂的人保持了他们的认知能力，而那些之前服用无效对照剂的人表现出了认知功能的改善。³⁶⁰

初乳素（富含脯氨酸的多肽复合物）

初乳素是分娩后乳房分泌的第一种乳汁，以其高水平的抗体和其他具有免疫激活作用的因素而闻名。^368,369临床前和临床研究的发现表明初乳素，一种在初乳中发现的富含脯氨酸的多肽复合物，可能有助于防止认知衰退的进展，特别是对阿尔茨海默症患者。^370,371许多研究已经发现了初乳素发挥有益作用的一系列可能机制，包括调节免疫活性，防止氧化应激和DNA的氧化损伤，减少炎症，抑制一氧化氮的过量产生，以及减少与年龄相关的线粒体功能障碍。^372-376

一项随机对照试验在105名轻度至中度阿尔茨海默病患者中比较了初乳素和无效对照剂。初乳素组每隔一天摄入100微克初乳素，连续3周，之后2周不治疗，进行3个五周周期。在第一个15周后，所有的受试者在第二个15周摄入初乳素。初乳素治疗对认知功能和日常生活活动的能力有稳定作用，轻度认知丧失的参与者对治疗的反应比重度认知丧失的参与者更好。377在另一项试验中，33名阿尔茨海默病患者使用了相同的剂量计划，为期16至28个月，结果发现它能稳定或改善健康状况。³⁷⁸一项早期的临床试验包括46名轻度至中度阿尔茨海默病患者。他们被分成以下几组，分别摄入100 微克初乳素，100 微克硒，或无效对照剂，连续3周，随后2周不治疗，进行为期一年的五周周期。在接受初乳素治疗的15名患者中，有8名患者病情有所改善，其他7名患者病情没有变化；相比之下，服用硒组和无效对照剂组的患者病情都没有好转，有些甚至恶化。³⁷⁹研究报告了一些用初乳素治疗的病人的轻微副作用很快会消失。^378,379

长春西汀

长春西汀，也被称为Cavinton，是一种从小长春花（Vinca minor）中合成的生物碱衍生物。长春西汀已被证明具有神经保护的作用，如改变炎症信号，减少氧化应激，提高细胞能量的产生，抑制血管壁增厚，扩张大脑血管，并可能防止动脉粥样硬化斑块的形成。^380-383

在一项针对26名多次中风患者的安慰剂对照试验中，长春西汀在三个月后阻止了一项认知功能测试的恶化。³⁸⁴其他使用长春西汀的研究也指出，它能改善轻度认知障碍和脑血管功能不全患者的认知能力。^385,386注意：孕妇或可能怀孕的女性不应使用长春西汀。

锂

锂是一种高剂量用作情绪稳定剂的矿物质，主要用于双相情感障碍患者。^387,388饮用水中自然存在微量的锂，在人群研究中，饮用水中锂的高发生率与痴呆和精神疾病的低发生率相关。^389,390越来越多的临床前证据表明，锂可能通过其预防氧化和炎症性神经元损伤、增强神经可塑性、调节蛋白质代谢、调节生理节律和下丘脑-垂体-肾上腺（HPA）轴活动的能力而保护神经。^{387,388,391-393}此外，动物和实验室研究表明，长期低剂量锂治疗可以增加BDNF的神经元产生。^394-396

一项共222名受试者的三项临床试验的综合分析得出结论，锂疗法可能对轻度认知障碍和阿尔茨海默病患者有益。³⁹⁷由于锂在高剂量下具有巨大的毒性潜力，388微剂量治疗更好。在一项试验中，每日服用微量（300微克）锂的阿尔茨海默病患者，其认知能力下降的情况比未接受治疗的患者要少。认知功能的差异在3个月后变显著，并在15个月的试验过程中逐渐扩大。³⁹⁸研究表明，在易于患阿尔茨海默样病变的大鼠中，微量锂可减少氧化应激、神经炎症和异常蛋白积累，并促进神经元再生及防止记忆丧失。^399,400

可可

可可是由可可树（Theobroma cacao）的种子制成的。可可含有高浓度的抗自由基多酚——黄烷醇。越来越多的证据表明，可可及其黄烷醇可以改善血管功能，促进脑血管血液流动，并增强认知功能。^401,402一项实验室研究的结果表明，可可也可能抑制β-淀粉样蛋白的聚集。⁴⁰³此外，可可中的咖啡因、儿茶素和其他成分可能有助于大脑健康。⁴⁰⁴

基于针对2056名参与者的西班牙老年人营养和心血管风险研究的分析数据，研究人员指出，比起前一年不吃黑巧克力的人，前一年日常食用10克（0.35克，大约一英寸方片）或更多的黑巧克力的人认知能力更好且患轻度认知障碍的风险更低。⁴⁰⁵另一项针对531名年龄在65岁及以上的受试者的研究发现，那些低咖啡因摄入量 （每天少于75毫克；大约相当于一杯6盎司的咖啡或两杯茶的量） 的受试者在大约四年的监测中，食用巧克力与降低认知衰退风险有关。⁴⁰⁶

在一项针对40名健康老年人的随机对照试验中，每天饮用一次含494毫克黄烷醇的可可饮料，持续12周，可提高BDNF的血液水平，改善认知功能。407一项为期8周的随机对照试验比较了补充含不同剂量可可黄烷醇的饮料对90名认知正常的老年受试者的影响。在试验结束时，每天摄入993毫克可可黄烷醇的人与摄入量较少的人相比在某些测试中的认知能力有所改善。此外，与每天服用48毫克的患者相比，每天服用993毫克和520 毫克的患者在胰岛素抵抗、血压和脂质过氧化（氧化应激的一种测量方法）方面都有改善。⁴⁰⁸在一项对健康老年人进行的为期三个月的随机对照试验中，高可可饮食改善了局部脑功能和认知能力。⁴⁰⁹

绿薄荷提取物

绿薄荷（Mentha spicata）是一种芳香草本植物，富含水溶性多酚，其中许多具有抗炎和减少自由基的特性。迷迭香酸及其衍生物通常是绿薄荷多酚的主要成分。⁴¹⁰

迷迭香酸在实验室模型中显示出了神经保护作用，如减少神经炎症和大脑氧化应激，防止β-淀粉样蛋白诱导的认知衰退。^411,412迷迭香酸似乎也抑制涉及tau蛋白病理的酶。⁴¹³此外，绿薄荷提取物被发现能抑制乙酰胆碱酯酶，这一作用可能会增加乙酰胆碱水平，从而支持学习、记忆和情绪。⁴¹⁰

在一项随机的安慰剂对照试验中，90名年龄相关记忆损伤的个体每天分别接受900 毫克，600 毫克，或0毫克（无效对照剂）高迷迭香酸绿薄荷提取物90天。与服用无效对照剂的人相比，那些服用900毫克的人在记忆测试中表现更好，并且报告称他们的入睡能力有所提高。⁴¹⁴在一项试验性试验中，11名自述有轻度记忆障碍的受试者接受了30天的治疗，每天服用900毫克的高迷迭香酸的绿薄荷提取物，结果在推理、注意力和注意力测试中表现有所改善。即使是短期用药，也能在2-4小时内改善注意力和注意力。⁴¹⁵

绿色燕麦提取物

燕麦（Avena sativa）是一种含有许多活性化合物的谷物。^416,417从野生绿色燕麦中提取的一种物质被证明可以抑制一种叫做单胺氧化酶-B（MAO-B）的酶。⁴¹⁶代谢多巴胺的MAO-B活性在老年时增加，降低多巴胺水平，可能导致氧化应激和线粒体功能障碍，加速组织衰老。^418,419阻断MAO-B有助于使多巴胺水平正常化，这可能会减少氧化应激，改善认知和记忆方面。^419,420野生绿色燕麦提取物还被发现能扩张脑血管，抑制另一种叫做磷酸二酯酶-4的酶，⁴²¹这种作用可能会减缓与年龄相关的认知衰退。^422,423

在健康成年人中，1500毫克野生绿色燕麦提取物与无效对照剂相比，使动脉血流量增加了40%多一点。⁴²⁴在健康的中年人中，一次800毫克剂量的野生绿色燕麦提取物可以改善他们在注意力、延迟回忆、记忆和执行功能测试中的表现。⁴²⁵在患有轻度年龄相关认知问题的患者中，1600毫克的野生绿燕麦提取物可以改善他们在一项测试中注意力、专注力和任务专注能力的表现。⁴²⁶

狮鬃菇

狮鬃菇 （猴头菇）是一种来自亚洲的烹饪和药用蘑菇。狮鬃菇提取物已被证明具有抗炎和减少氧化应激的作用，据报道，食用狮鬃菇具有神经保护、促进认知、抗衰老和抗抑郁的特性，以及其他健康益处。⁴²⁷在一项随机对照试验中，30名患有轻度认知障碍的老年人每天服用3000毫克狮鬃菇，持续16周，与无效对照剂相比，其认知功能得到改善。⁴²⁸在动物研究中，狮鬃菇增强了健康野生型小鼠的神经功能，改善了记忆性能。⁴²⁹在阿尔茨海默病小鼠模型中，狮鬃菇提取物也被发现可以刺激神经元生长因子和新神经元的形成，并减少β-淀粉样斑块和淀粉样蛋白诱导的炎症。^430,431

吡咯并喹啉醌

吡咯并喹啉醌（PQQ）是一种支持生长发育的重要化合物。⁴³²PQQ在氧化还原（redox）生化反应中起着关键作用，在这种反应中电子由供体分子给予，被受体分子吸收。氧化还原反应是几乎所有细胞过程的基础。^432,433临床前研究表明，提高PQQ水平可能会改善线粒体数量和功能，减少全身和大脑炎症，延长细胞寿命，防止神经毒素，并可能改善神经系统和心血管健康。^{433,434,435-439}一些研究也表明PQQ可能阻止β-淀粉样蛋白的积累。^440-443此外，PQQ已经被发现可以刺激一种叫做神经生长因子的蛋白质的产生，^444-446促进神经细胞的再生，^447,448并保护实验动物的认知功能。⁴⁴⁹

研究结果表明PQQ可能通过增加局部脑血流和氧气使用来改善认知功能。在一项对41名健康老年受试者的对照试验中，与无效对照剂相比，持续12周每天摄入20毫克PQQ可导致脑血流量增加和认知性能下降减缓。此外，在试验开始时认知功能最低的参与者在试验结束时表现出认知功能某一方面的改善。⁴⁵⁰另一项研究同样指出，健康受试者每天服用20毫克PQQ，连续服用12周，可增加局部脑血流量和氧利用。⁴⁵¹

烟酰胺核糖

烟酰胺核糖是维生素B3的一种形式。与其他形式的B3（烟酰胺和烟酸）一样，烟酰胺核糖在人体内是烟酰胺腺嘌呤二核苷酸（NAD+）的前体。^452,453NAD+是一种普遍的辅助因子，在氧化还原（redox）生化反应中起着至关重要的作用，通过氧化还原转化为其还原性形式NADH。氧化还原反应是线粒体细胞能量产生的重要过程。此外，NAD+似乎参与调节控制一系列细胞功能的酶，这些细胞功能包括基因表达、代谢、DNA修复、细胞凋亡（程序性细胞死亡）和衰老。^454-456

衰老与NAD+的产生减少有关，NAD+/NADH比值的降低与线粒体功能障碍和年龄相关的代谢紊乱有关，如认知衰退和痴呆、糖尿病、肥胖、非酒精性脂肪肝、心血管疾病和一些癌症。^452,457-459据认为，提高NAD+的可用性可能有助于减缓衰老过程和预防年龄相关疾病。^457,460

在健康的老年志愿者中，每天250毫克和500毫克的NAD+前体烟酰胺核糖在4周后安全剂量依赖地提高了血液NAD+水平。⁴⁶¹在小鼠中，口服烟酰胺核糖可增加脑NAD+水平，改善认知功能，⁴⁶²增强神经可塑性，并减少tau蛋白诱导的神经元损伤。⁴⁶³动物研究的进一步证据表明，NAD+疗法可能刺激线粒体活动，维持干细胞的再生潜能，延长寿命。^464,465

辅酶Q10

辅酶Q10 （CoQ10）在线粒体能量产生中起着重要作用。CoQ10已被证明具有神经保护作用，可能是通过增强线粒体功能和调节小胶质细胞介导的，小胶质细胞是介导神经炎症的大脑免疫细胞。^466,467较低的血液CoQ10水平与老年人失能性痴呆的风险增加⁴⁶⁸和心力衰竭患者的认知功能恶化相关。⁴⁶⁹临床前证据表明，CoQ10可能减缓神经退行性疾病如亨廷顿病、帕金森病和阿尔茨海默病患者的认知衰退。^470-472

印度人参

南非醉茄，通常也称为印度人参（Ashwagandha），是一种在阿育吠陀医学中使用了几个世纪的植物。印度人参的植物和根提取物含有几种具有抗氧化、抗炎和免疫刺激功能的生物活性化合物。⁴⁷³细胞和动物模型显示，印度人参提取物和相关化合物通过多种信号通路拯救神经元细胞免受化学损伤和炎症，保护神经元免受典型的神经退化过程，包括阿尔茨海默病、帕金森病和亨廷顿病。⁴⁷⁴

在人体研究中，印度人参提取物也被证明可以改善记忆和认知功能。在一项双盲安慰剂对照研究中，50名成年人被随机分配接受印度人参根提取物（300毫克，每日两次）或无效对照剂，为期8周。据统计，印度人参与短期和一般记忆、执行功能、持续注意力和信息处理速度的显著改善有关。⁴⁷⁵此外，在53名双相情感障碍患者的随机对照试验中，每天辅助使用500毫克的印度人参提取物可改善听-语工作记忆、反应时间和社会认知。⁴⁷⁶

各种模型的大量研究表明，印度人参具有神经保护作用。⁴⁷⁴例如，在暴露于神经毒性物质的小鼠中，印度人参逆转了NMDA神经递质受体的损伤，而NMDA神经递质受体对学习和记忆非常重要。⁴⁷⁷在大鼠体内注射印度人参提取物可以防止神经毒素引起的认知能力下降。⁴⁷⁸可能有助于印度人参的神经保护活性的一种机制是增强对氧化应激的防御能力。

Withanone是在印度人参的提取物中发现的一种活性化合物。对大鼠进行三周的withanone注射可以通过降低炎症分子水平来显著改善认知能力。在同一项研究中，研究人员发现，withanone可以抑制β-淀粉样蛋白，这种蛋白与阿尔茨海默病的发展有关。⁴⁷⁹

孕烯醇酮

孕烯醇酮是一种类固醇激素，由大脑、肾上腺和其他器官中的胆固醇合成。孕烯醇酮既可以调节信号通路本身，也可以通过进一步的代谢形成其他类固醇激素，包括孕酮、醛固酮、皮质醇和睾酮。⁴⁸⁰在大脑中，孕烯醇酮被证明可以调节NMDA受体介导的神经传递，支持学习和记忆。⁴⁸¹此外，孕烯醇酮具有抗炎特性。⁴⁸²

在有学习和记忆障碍的大鼠中，鼻内给药孕烯醇酮可改善学习、长期记忆并抵抗记忆消退。⁴⁸³在一项初步研究中，年老的大鼠在海马体和其他大脑区域中的孕烯醇酮含量显著降低，记忆力问题较少的动物体内的孕烯醇酮含量较高。通过注射孕烯醇酮，这些动物的记忆缺陷得到了暂时的纠正。⁴⁸⁴

大多数关于孕烯醇酮对认知衰退影响的人类研究都是在精神障碍（如精神分裂症和双相情感障碍）的背景下进行的。在一项为期8周的随机、安慰剂对照试验中，在新近发病的精神分裂症或相关疾病患者中，使用50毫克/天的辅助孕烯醇酮可显著改善执行功能、视觉和持续注意力。⁴⁸⁵另一项针对精神分裂症患者的安慰剂对照研究发现，每天服用30毫克孕烯醇酮可以改善注意力和工作记忆表现。⁴⁸⁶

积雪草

积雪草（Centella asiatica），是东南亚传统医药中常用的一种绿叶植物，因其富含多种有益营养素而颇具价值，包括三萜、类胡萝卜素、维生素B和C、矿物质和其他植物营养素。⁴⁸⁸在积雪草中发现的一种关键活性成分是亚细亚酸，一种三萜烯，临床前研究表明，它可以防止某些药物引起的认知能力下降，还可以调节神经传递，并具有其他对认知和神经的有益作用。^489-492许多积雪草制剂被标准化为积雪草皂苷，在体内被代谢为亚细亚酸。⁴⁹³

临床前研究表明，积雪草可以减少氧化应激的标记物，从而改善神经元的健康。^494-496此外，积雪草可降低大鼠海马体和大脑皮层中的乙酰胆碱酯酶水平，其速率与多奈哌齐（一种乙酰胆碱酯酶抑制剂）相当。^495,497乙酰胆碱酯酶是一种分解乙酰胆碱的酶，乙酰胆碱是一种重要的神经递质。乙酰胆碱水平降低与年龄相关的认知衰退和阿尔茨海默病有关。⁴⁹⁵

在阿尔茨海默病小鼠模型中，积雪草水提取物被证明以剂量依赖的方式改善记忆。此外，影响信息处理的大脑区域（如海马体和前额叶皮层）的神经密度标记物也增加了。⁴⁹⁴在年龄较大的小鼠中，积雪草水提取物可以提高测量空间学习和记忆的测试表现。⁴⁹⁸

在一项对28名健康的老年志愿者的研究中，连续两个月，每天250-750毫克的积雪草提取物可以改善工作记忆和自我评估情绪。⁴⁹⁹在一项人体随机对照试验的系统回顾和综合分析中，研究人员报告称，与无效对照剂相比，积雪草产品并没有显著改善认知功能领域；然而，积雪草确实改善了情绪和警觉性，且没有不良事件的报道。⁵⁰⁰还需要对人体内的积雪草进行进一步的调查。

类胡萝卜素

类胡萝卜素是有机的、色素强烈的化合物，存在于藻类、植物、真菌和许多细菌中。类胡萝卜素可分为叶黄素（如叶黄素和玉米黄质）和胡萝卜素（如β-胡萝卜素和番茄红素）。在人类食用的水果和蔬菜中发现了大约50种不同类型的类胡萝卜素，在人体组织和血液中发现了大约20种类胡萝卜素。⁵⁰¹

血清和视网膜中叶黄素和玉米黄质浓度的升高与几个炎症生物标志物及认知和神经传递评估的改善有关。⁵⁰¹神经影像研究显示，拥有较高浓度叶黄素和玉米黄质的老年人，白质完整性增强，特别是在易受年龄相关变化影响的大脑区域。⁵⁰²类胡萝卜素也被证明通过降低细胞因子和其他促炎分子的循环水平来减少炎症信号。此外，类胡萝卜素可以保护细胞免受氧化应激，从而可能通过防止神经元细胞损伤来减缓认知衰退。⁵⁰¹

有大量证据支持类胡萝卜素在认知表现中的作用。根据2011-2014年美国全国健康和营养检查调查（NHANES）的结果，在60岁及以上的参与者中，叶黄素和玉米黄质的饮食摄入越多，他们在学习和记忆测试中的得分就越高，这表明叶黄素和玉米黄质可能有助于防止或减缓年龄相关的认知衰退。⁵⁰³相比之下，在其他营养物质中，低胡萝卜素摄入量与老年人认知衰退的风险显著相关。⁵⁰⁴此外，血清和视网膜中较高的叶黄素和玉米黄质浓度与视觉空间处理和决策能力的改善有关。在加工和决策任务中，功能核磁共振成像（fMRI）显示，在任务中表现更好和叶黄素和玉米黄质水平较高的参与者的神经效率有所提高。⁵⁰⁵最后，在近5万名女性护士中评估了类胡萝卜素膳食的影响。在2012年至2014年期间评估了自报告的主观认知功能，其在过去的30年（1984年至2006年）中与类胡萝卜素膳食消耗量显著相关。摄入类胡萝卜素最低量的护士比摄入类胡萝卜素最高量的护士患认知功能不良的风险高33%。⁵⁰⁶

在一项随机对照试验中，80名年龄在65至92岁之间的成年人接受12毫克叶黄素和玉米黄质或无效对照剂治疗12个月。叶黄素和玉米黄质含量高的参与者大脑皮层中的神经元，对视觉刺激的反应明显比含量低的参与者的大脑皮层神经元更敏感，这表明视觉记忆和处理速度得到了改善。⁵⁰⁷此外，在一项有91名黄斑色素水平较低的参与者（平均年龄45岁）的安慰剂对照试验中，每天补充10毫克叶黄素、10毫克内消旋玉米黄质和2毫克玉米黄质12个月，显著改善了记忆。⁵⁰⁸最后，在一项有62名老年人（平均年龄73.7岁）参加的安慰剂对照研究中，持续12个月补充12毫克叶黄素和玉米黄质与复杂注意力和认知灵活性的显著增加相关。⁵⁰⁹

本文提出了许多问题，这些问题可能会随着新数据的出现而发生变化。我们建议的营养或治疗方案均不用于确保治愈或预防任何疾病。Piping Rock健康研究院没有对参考资料中包含的数据进行独立验证，并明确声明对文献中的任何错误不承担任何责任。

八、参考文献

1.Miquel S, Champ C, Day J, et al. Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions.Ageing Res Rev.2018;42:40-55.

2.Knight JN, Y. . Anatomy and physiology of ageing 5: the nervous system.Nursing Times [online].2017;113(6):55-58.

3.Park DC, Festini SB. Theories of Memory and Aging: A Look at the Past and a Glimpse of the Future.The journals of gerontology Series B, Psychological sciences and social sciences.2017;72(1):82-90.

4.Anastasiou CA, Yannakoulia M, Kontogianni MD, et al. Mediterranean Lifestyle in Relation to Cognitive Health: Results from the HELIAD Study.Nutrients.2018;10(10).

5.Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation.Nature.2016;539(7628):180-186.

6.Phillips C. Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging.Neural plasticity.2017;2017:3589271.

7.Steindler DA, Reynolds BA. Perspective: Neuroregenerative Nutrition.Adv Nutr.2017;8(4):546-557.

8.Poulose SM, Miller MG, Scott T, Shukitt-Hale B. Nutritional Factors Affecting Adult Neurogenesis and Cognitive Function.Adv Nutr.2017;8(6):804-811.

9.Palmer AL, Ousman SS. Astrocytes and Aging.Frontiers in aging neuroscience.2018;10:337.

10.Liu H, Yang Y, Xia Y, et al. Aging of cerebral white matter.Ageing Res Rev.2017;34:64-76.

11.Lopez-Valdes HE, Martinez-Coria H. The Role of Neuroinflammation in Age-Related Dementias.Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion.2016;68(1):40-48.

12.Smith LK, White CW, 3rd, Villeda SA. The systemic environment: at the interface of aging and adult neurogenesis.Cell and tissue research.2018;371(1):105-113.

13.Raz N, Daugherty AM. Pathways to Brain Aging and Their Modifiers: Free-Radical-Induced Energetic and Neural Decline in Senescence (FRIENDS) Model - A Mini-Review.Gerontology.2018;64(1):49-57.

14.Yang T, Sun Y, Lu Z, Leak RK, Zhang F. The impact of cerebrovascular aging on vascular cognitive impairment and dementia.Ageing Res Rev.2017;34:15-29.

15.Safaiyan S, Kannaiyan N, Snaidero N, et al. Age-related myelin degradation burdens the clearance function of microglia during aging.Nat Neurosci.2016;19(8):995-998.

16.Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review.Jama.2014;312(23):2551-2561.

17.Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, diagnosis, and treatment.Clin Geriatr Med.2014;30(3):421-442.

18.Allan CL, Behrman S, Ebmeier KP, Valkanova V. Diagnosing early cognitive decline-When, how and for whomMaturitas.2017;96:103-108.

19.Langa KM, Larson EB, Crimmins EM, et al. A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012.JAMA internal medicine.2017;177(1):51-58.

20.Cheng YW, Chen TF, Chiu MJ. From mild cognitive impairment to subjective cognitive decline: conceptual and methodological evolution.Neuropsychiatr Dis Treat.2017;13:491-498.

21.Michel JP. Is It Possible to Delay or Prevent Age-Related Cognitive DeclineKorean journal of family medicine.2016;37(5):263-266.

22.Vicario A, Cerezo GH. At the Heart of Brain Disorders - Preventing Cognitive Decline and Dementia.European cardiology.2015;10(1):60-63.

23.Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective.Alzheimer's & Dementia.2015;11(6):718-726.

24.Deckers K, Schievink SHJ, Rodriquez MMF, et al. Coronary heart disease and risk for cognitive impairment or dementia: Systematic review and meta-analysis.PLoS One.2017;12(9):e0184244.

25.Zhao C, Noble JM, Marder K, Hartman JS, Gu Y, Scarmeas N. Dietary Patterns, Physical Activity, Sleep, and Risk for Dementia and Cognitive Decline.Current nutrition reports.2018;7(4):335-345.

26.Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis.JAMA Neurol.2017;74(10):1237-1245.

27.Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and Dementia: An International Consensus Statement.J Alzheimers Dis.2018;62(2):561-570.

28.Karri V, Schuhmacher M, Kumar V. Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain.Environmental toxicology and pharmacology.2016;48:203-213.

29.Brandt J, Leong C. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research.Drugs in R&D.2017;17(4):493-507.

30.Picton JD, Marino AB, Nealy KL. Benzodiazepine use and cognitive decline in the elderly.American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.2018;75(1):e6-e12.

31.Gray SL, Hanlon JT. Anticholinergic medication use and dementia: latest evidence and clinical implications.Therapeutic advances in drug safety.2016;7(5):217-224.

32.Colangelo A, Cirillo G, Alberghina L, Papa M, Westerhoff H. Neural plasticity and adult neurogenesis: the deep biology perspective.Neural Regeneration Research.2019;14(2):201-205.

33.de Lucia C, Murphy T, Thuret S. Emerging Molecular Pathways Governing Dietary Regulation of Neural Stem Cells during Aging.Front Physiol.2017;8:17.

34.Numakawa T, Odaka H, Adachi N. Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases.International journal of molecular sciences.2018;19(11).

35.Rivera A, Vanzuli I, Arellano JJ, Butt A. Decreased Regenerative Capacity of Oligodendrocyte Progenitor Cells (NG2-Glia) in the Ageing Brain: A Vicious Cycle of Synaptic Dysfunction, Myelin Loss and Neuronal DisruptionCurrent Alzheimer research.2016;13(4):413-418.

36.Apple DM, Solano-Fonseca R, Kokovay E. Neurogenesis in the aging brain.Biochemical pharmacology.2017;141:77-85.

37.Wang Y, Ji X, Leak RK, Chen F, Cao G. Stem cell therapies in age-related neurodegenerative diseases and stroke.Ageing Res Rev.2017;34:39-50.

38.Nivet E. Modifiers of Neural Stem Cells and Aging: Pulling the Trigger of a Neurogenic Decline.Current Stem Cell Reports.2016;2(3):273-281.

39.Brainard J, Gobel M, Bartels K, Scott B, Koeppen M, Eckle T. Circadian rhythms in anesthesia and critical care medicine: potential importance of circadian disruptions.Seminars in cardiothoracic and vascular anesthesia.2015;19(1):49-60.

40.Krishnan HC, Lyons LC. Synchrony and desynchrony in circadian clocks: impacts on learning and memory.Learning & memory (Cold Spring Harbor, NY).2015;22(9):426-437.

41.Pace-Schott EF, Spencer RM. Sleep-dependent memory consolidation in healthy aging and mild cognitive impairment.Curr Top Behav Neurosci.2015;25:307-330.

42.Terzibasi-Tozzini E, Martinez-Nicolas A, Lucas-Sanchez A. The clock is ticking. Ageing of the circadian system: From physiology to cell cycle.Seminars in cell & developmental biology.2017;70:164-176.

43.Toth P, Tarantini S, Csiszar A, Ungvari Z. Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging.American journal of physiology Heart and circulatory physiology.2017;312(1):H1-h20.

44.Tarantini S, Tran CHT, Gordon GR, Ungvari Z, Csiszar A. Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline.Exp Gerontol.2017;94:52-58.

45.Martinez-Ramirez S, Greenberg SM, Viswanathan A. Cerebral microbleeds: overview and implications in cognitive impairment.Alzheimer's Research & Therapy.2014;6(3):33.

46.De Luca C, Colangelo AM, Alberghina L, Papa M. Neuro-Immune Hemostasis: Homeostasis and Diseases in the Central Nervous System.Frontiers in cellular neuroscience.2018;12:459.

47.Yin F, Sancheti H, Patil I, Cadenas E. Energy metabolism and inflammation in brain aging and Alzheimer's disease.Free radical biology & medicine.2016;100:108-122.

48.Grizzanti J, Lee HG, Camins A, Pallas M, Casadesus G. The therapeutic potential of metabolic hormones in the treatment of age-related cognitive decline and Alzheimer's disease.Nutr Res.2016;36(12):1305-1315.

49.Noble EE, Hsu TM, Kanoski SE. Gut to Brain Dysbiosis: Mechanisms Linking Western Diet Consumption, the Microbiome, and Cognitive Impairment.Frontiers in behavioral neuroscience.2017;11:9.

50.Grimm A, Eckert A. Brain aging and neurodegeneration: from a mitochondrial point of view.Journal of neurochemistry.2017;143(4):418-431.

51.Khacho M, Clark A, Svoboda DS, et al. Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis.Human molecular genetics.2017;26(17):3327-3341.

52.Sripetchwandee J, Chattipakorn N, Chattipakorn SC. Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia.Frontiers in endocrinology.2018;9:496.

53.Salameh TS, Rhea EM, Banks WA, Hanson AJ. Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease.Experimental biology and medicine (Maywood, NJ).2016;241(15):1676-1683.

54.Assuncao N, Sudo FK, Drummond C, de Felice FG, Mattos P. Metabolic Syndrome and cognitive decline in the elderly: A systematic review.PLoS One.2018;13(3):e0194990.

55.Moon JH. Endocrine Risk Factors for Cognitive Impairment.Endocrinology and metabolism (Seoul, Korea).2016;31(2):185-192.

56.Walker JM, Harrison FE. Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer's Disease: Impacts on Cognitive Decline.Nutrients.2015;7(9):7332-7357.

57.Bae CS, Song J. The Role of Glucagon-Like Peptide 1 (GLP1) in Type 3 Diabetes: GLP-1 Controls Insulin Resistance, Neuroinflammation and Neurogenesis in the Brain.International journal of molecular sciences.2017;18(11).

58.McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild Traumatic Brain Injury (mTBI) and chronic cognitive impairment: A scoping review.PLoS One.2017;12(4):e0174847.

59.McAllister T, McCrea M. Long-Term Cognitive and Neuropsychiatric Consequences of Repetitive Concussion and Head-Impact Exposure.Journal of athletic training.2017;52(3):309-317.

60.Fehily B, Fitzgerald M. Repeated Mild Traumatic Brain Injury: Potential Mechanisms of Damage.Cell transplantation.2017;26(7):1131-1155.

61.Giza CC, Hovda DA. The new neurometabolic cascade of concussion.Neurosurgery.2014;75 Suppl 4:S24-33.

62.Oehr L, Anderson J. Diffusion-Tensor Imaging Findings and Cognitive Function Following Hospitalized Mixed-Mechanism Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis.Archives of physical medicine and rehabilitation.2017;98(11):2308-2319.

63.Broglio SP, Eckner JT, Paulson HL, Kutcher JS. Cognitive decline and aging: the role of concussive and subconcussive impacts.Exercise and sport sciences reviews.2012;40(3):138-144.

64.NIH. National Institues of Health: National Institute on Aging: What happens to the brain in Alzheimer's disease Available at https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease. Last updated 05/16/2017. Accessed 01/09/2019. 2017.

65.Laurent C, Buee L, Blum D. Tau and neuroinflammation: What impact for Alzheimer's Disease and TauopathiesBiomedical journal.2018;41(1):21-33.

66.Chalermpalanupap T, Weinshenker D, Rorabaugh JM. Down but Not Out: The Consequences of Pretangle Tau in the Locus Coeruleus.Neural plasticity.2017;2017:7829507.

67.Mufson EJ, Ikonomovic MD, Counts SE, et al. Molecular and cellular pathophysiology of preclinical Alzheimer's disease.Behavioural brain research.2016;311:54-69.

68.Colijn MA, Grossberg GT. Amyloid and Tau Biomarkers in Subjective Cognitive Impairment.J Alzheimers Dis.2015;47(1):1-8.

69.Villemagne VL, Dore V, Bourgeat P, et al. Abeta-amyloid and Tau Imaging in Dementia.Seminars in nuclear medicine.2017;47(1):75-88.

70.Mielke MM, Hagen CE, Wennberg AMV, et al. Association of Plasma Total Tau Level With Cognitive Decline and Risk of Mild Cognitive Impairment or Dementia in the Mayo Clinic Study on Aging.JAMA Neurol.2017;74(9):1073-1080.

71.Guerrero-Munoz MJ, Gerson J, Castillo-Carranza DL. Tau Oligomers: The Toxic Player at Synapses in Alzheimer's Disease.Frontiers in cellular neuroscience.2015;9:464.

72.Cui D, Xu X. DNA Methyltransferases, DNA Methylation, and Age-Associated Cognitive Function.International journal of molecular sciences.2018;19(5).

73.Deibel SH, Zelinski EL, Keeley RJ, Kovalchuk O, McDonald RJ. Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline.Oncotarget.2015;6(27):23181-23203.

74.Daulatzai MA. "Boomerang Neuropathology" of Late-Onset Alzheimer's Disease is Shrouded in Harmful "BDDS": Breathing, Diet, Drinking, and Sleep During Aging.Neurotoxicity research.2015;28(1):55-93.

75.Moretti R, Caruso P. The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice.International journal of molecular sciences.2019;20(1).

76.Price BR, Wilcock DM, Weekman EM. Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia.Frontiers in aging neuroscience.2018;10:350.

77.Mikkelsen K, Stojanovska L, Tangalakis K, Bosevski M, Apostolopoulos V. Cognitive decline: A vitamin B perspective.Maturitas.2016;93:108-113.

78.Merlini M, Rafalski VA, Rios Coronado PE, et al. Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model.Neuron.2019.

79.Marioni RE, Stewart MC, Murray GD, et al. Peripheral levels of fibrinogen, C-reactive protein, and plasma viscosity predict future cognitive decline in individuals without dementia.Psychosomatic medicine.2009;71(8):901-906.

80.Marioni RE, Deary IJ, Murray GD, et al. Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts.Behav Genet.2011;41(5):691-699.

81.Pedersen A, Stanne TM, Redfors P, et al. Fibrinogen concentrations predict long-term cognitive outcome in young ischemic stroke patients.Research and practice in thrombosis and haemostasis.2018;2(2):339-346.

82.Ebner NC, Kamin H, Diaz V, Cohen RA, MacDonald K. Hormones as "difference makers" in cognitive and socioemotional aging processes.Frontiers in psychology.2014;5:1595.

83.Lejri I, Grimm A, Eckert A. Mitochondria, Estrogen and Female Brain Aging.Frontiers in aging neuroscience.2018;10:124.

84.Hara Y, Waters EM, McEwen BS, Morrison JH. Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse.Physiol Rev.2015;95(3):785-807.

85.Dumas JA. Strategies for Preventing Cognitive Decline in Healthy Older Adults.Can J Psychiatry.2017;62(11):754-760.

86.Yeap BB. Hormonal changes and their impact on cognition and mental health of ageing men.Maturitas.2014;79(2):227-235.

87.Hsu B, Cumming RG, Waite LM, et al. Longitudinal Relationships between Reproductive Hormones and Cognitive Decline in Older Men: The Concord Health and Ageing in Men Project.J Clin Endocrinol Metab.2015;100(6):2223-2230.

88.Hogervorst E. Effects of gonadal hormones on cognitive behaviour in elderly men and women.J Neuroendocrinol.2013;25(11):1182-1195.

89.Hogervorst E. Prevention of dementia with sex hormones: a focus on testosterone and cognition in women.Minerva Med.2012;103(5):353-359.

90.Tortosa-Martinez J, Manchado C, Cortell-Tormo JM, Chulvi-Medrano I. Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults.Neurobiology of stress.2018;9:40-47.

91.Russell-Williams J, Jaroudi W, Perich T, Hoscheidt S, El Haj M, Moustafa AA. Mindfulness and meditation: treating cognitive impairment and reducing stress in dementia.Rev Neurosci.2018;29(7):791-804.

92.Samaras N, Papadopoulou MA, Samaras D, Ongaro F. Off-label use of hormones as an antiaging strategy: a review.Clinical interventions in aging.2014;9:1175-1186.

93.Maggio M, De Vita F, Fisichella A, et al. DHEA and cognitive function in the elderly.J Steroid Biochem Mol Biol.2015;145:281-292.

94.de Menezes KJ, Peixoto C, Nardi AE, Carta MG, Machado S, Veras AB. Dehydroepiandrosterone, Its Sulfate and Cognitive Functions.Clinical practice and epidemiology in mental health : CP & EMH.2016;12:24-37.

95.Powrie YSL, Smith C. Central intracrine DHEA synthesis in ageing-related neuroinflammation and neurodegeneration: therapeutic potentialJournal of neuroinflammation.2018;15(1):289.

96.Jimenez-Rubio G, Herrera-Perez JJ, Hernandez-Hernandez OT, Martinez-Mota L. Relationship between androgen deficiency and memory impairment in aging and Alzheimer’s disease.Actas espanolas de psiquiatria.2017;45(5):227-247.

97.Kotekar N, Shenkar A, Nagaraj R. Postoperative cognitive dysfunction - current preventive strategies.Clin Interv Aging.2018;13:2267-2273.

98.Needham MJ, Webb CE, Bryden DC. Postoperative cognitive dysfunction and dementia: what we need to know and do.British journal of anaesthesia.2017;119(suppl_1):i115-i125.

99.Kant IMJ, de Bresser J, van Montfort SJT, Slooter AJC, Hendrikse J. MRI Markers of Neurodegenerative and Neurovascular Changes in Relation to Postoperative Delirium and Postoperative Cognitive Decline.Am J Geriatr Psychiatry.2017;25(10):1048-1061.

100.Liu Y, Yin Y. Emerging Roles of Immune Cells in Postoperative Cognitive Dysfunction.Mediators of inflammation.2018;2018:6215350.

101.Cascella M, Bimonte S. The role of general anesthetics and the mechanisms of hippocampal and extra-hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction.Neural Regen Res.2017;12(11):1780-1785.

102.Luo A, Yan J, Tang X, Zhao Y, Zhou B, Li S. Postoperative cognitive dysfunction in the aged: the collision of neuroinflammaging with perioperative neuroinflammation.Inflammopharmacol.2019.

103.Safavynia SA, Goldstein PA. The Role of Neuroinflammation in Postoperative Cognitive Dysfunction: Moving From Hypothesis to Treatment.Frontiers in psychiatry.2018;9:752.

104.Brown Ct, Deiner S. Perioperative cognitive protection.British journal of anaesthesia.2016;117(suppl 3):iii52-iii61.

105.Hernandorena I, Duron E, Vidal JS, Hanon O. Treatment options and considerations for hypertensive patients to prevent dementia.Expert opinion on pharmacotherapy.2017;18(10):989-1000.

106.Tadic M, Cuspidi C, Hering D. Hypertension and cognitive dysfunction in elderly: blood pressure management for this global burden.BMC cardiovascular disorders.2016;16(1):208.

107.Chu CS, Tseng PT, Stubbs B, et al. Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis.Sci Rep.2018;8(1):5804.

108.Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms.Translational neurodegeneration.2018;7:5.

109.Bosch J, O'Donnell M, Swaminathan B, et al. Effects of blood pressure and lipid lowering on cognition.Results from the HOPE-3 study.2019:10.1212/WNL.0000000000007174.

110.Ong KL, Morris MJ, McClelland RL, et al. Relationship of Lipids and Lipid-Lowering Medications With Cognitive Function: The Multi-Ethnic Study of Atherosclerosis.American journal of epidemiology.2018;187(4):767-776.

111.McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia.The Cochrane database of systematic reviews.2016(1):Cd003160.

112.Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet.2002;360(9346):1623-1630.

113.Group HPSC. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet.2002;360(9326):7-22.

114.Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)--can C-reactive protein be used to target statin therapy in primary preventionThe American journal of cardiology.2006;97(2a):33a-41a.

115.Karakaya T, Fuer F, Schrder J, Pantel J. Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer′s Disease.Curr Neuropharmacol.2013;11(1):102-108.

116.Farlow MR. Treatment of mild cognitive impairment (MCI).Current Alzheimer research.2009;6(4):362-367.

117.Tripathi A, Paliwal P, Krishnamurthy S. Piracetam Attenuates LPS-Induced Neuroinflammation and Cognitive Impairment in Rats.Cellular and molecular neurobiology.2017;37(8):1373-1386.

118.Sanchez PE, Zhu L, Verret L, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model.Proc Natl Acad Sci U S A.2012;109(42):E2895-2903.

119.Stockburger C, Kurz C, Koch KA, Eckert SH, Leuner K, Muller WE. Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam.Biochem Soc Trans.2013;41(5):1331-1334.

120.Bakker A, Krauss GL, Albert MS, et al. Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment.Neuron.2012;74(3):467-474.

121.Tariska P, Paksy A. [Cognitive enhancement effect of piracetam in patients with mild cognitive impairment and dementia].Orvosi hetilap.2000;141(22):1189-1193.

122.Giannopoulos PF, Chiu J, Pratico D. Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway.Molecular neurobiology.2018.

123.Giannopoulos PF, Chiu J, Pratico D. Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice.Aging Cell.2018;17(3):e12759.

124.Chu J, Li JG, Pratico D. Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.PLoS One.2013;8(8):e70991.

125.Di Meco A, Lauretti E, Vagnozzi AN, Pratico D. Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice.Neurobiol Aging.2014;35(11):2458-2464.

126.Shi SS, Yang WZ, Tu XK, Wang CH, Chen CM, Chen Y. 5-Lipoxygenase inhibitor zileuton inhibits neuronal apoptosis following focal cerebral ischemia.Inflammation.2013;36(6):1209-1217.

127.Silva BC, de Miranda AS, Rodrigues FG, et al. The 5-lipoxygenase (5-LOX) Inhibitor Zileuton Reduces Inflammation and Infarct Size with Improvement in Neurological Outcome Following Cerebral Ischemia.Curr Neurovasc Res.2015;12(4):398-403.

128.Tu XK, Zhang HB, Shi SS, et al. 5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway.Neurochem Res.2016;41(10):2779-2787.

129.Rouy JM, Douillon AM, Compan B, Wolmark Y. Ergoloid mesylates ('Hydergine') in the treatment of mental deterioration in the elderly: a 6-month double-blind, placebo-controlled trial.Current medical research and opinion.1989;11(6):380-389.

130.van Loveren-Huyben CM, Engelaar HF, Hermans MB, van der Bom JA, Leering C, Munnichs JM. Double-blind clinical and psychologic study of ergoloid mesylates (Hydergine) in subjects with senile mental deterioration.J Am Geriatr Soc.1984;32(8):584-588.

131.Wadworth AN, Chrisp P. Co-dergocrine mesylate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in age-related cognitive decline.Drugs Aging.1992;2(3):153-173.

132.Sozmen EY, Kanit L, Kutay FZ, Hariri NI. Possible supportive effects of co-dergocrine mesylate on antioxidant enzyme systems in aged rat brain.European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology.1998;8(1):13-16.

133.Miklya I. The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015).Molecular psychiatry.2016;21(11):1499-1503.

134.Bettini R, Gorini M. [Effectiveness and tolerability of selegiline in the treatment of pathological cerebral involutions].Clin Ter.2002;153(6):377-380.

135.Goverdhan P, Sravanthi A, Mamatha T. Neuroprotective effects of meloxicam and selegiline in scopolamine-induced cognitive impairment and oxidative stress.International journal of Alzheimer's disease.2012;2012:974013.

136.Unal I, Gursoy-Ozdemir Y, Bolay H, Soylemezoglu F, Saribas O, Dalkara T. Chronic daily administration of selegiline and EGb 761 increases brain's resistance to ischemia in mice.Brain research.2001;917(2):174-181.

137.Kiray M, Bagriyanik HA, Pekcetin C, Ergur BU, Uysal N. Protective effects of deprenyl in transient cerebral ischemia in rats.The Chinese journal of physiology.2008;51(5):275-281.

138.Kiray M, Bagriyanik HA, Pekcetin C, et al. Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats.Physiological research / Academia Scientiarum Bohemoslovaca.2006;55(2):205-212.

139.Marcer D, Hopkins SM. The differential effects of meclofenoxate on memory loss in the elderly.Age Ageing.1977;6(2):123-131.

140.Nehru B, Bhalla P, Garg A. Evidence for centrophenoxine as a protective drug in aluminium induced behavioral and biochemical alteration in rat brain.Molecular and cellular biochemistry.2006;290(1-2):33-42.

141.Voronina TA, Garibova TL, Trofimov SS, Sopyev Zh A, Petkov VD, Lazarova MB. Comparative studies on the influence of ONK (N(5-hydroxynicotinoil) glutamic acid), piracetam and meclofenoxate on the learning- and memory-impairing effect of scopolamine, clonidine, and methergoline.Acta physiologica et pharmacologica Bulgarica.1991;17(4):8-16.

142.Liao Y, Wang R, Tang XC. Centrophenoxine improves chronic cerebral ischemia induced cognitive deficit and neuronal degeneration in rats.Acta Pharmacol Sin.2004;25(12):1590-1596.

143.Klimova B, Valis M. Nutritional Interventions as Beneficial Strategies to Delay Cognitive Decline in Healthy Older Individuals.Nutrients.2018;10(7).

144.Chieffi S, Messina G, Villano I, et al. Neuroprotective Effects of Physical Activity: Evidence from Human and Animal Studies.Frontiers in neurology.2017;8:188.

145.Northey JM, Cherbuin N, Pumpa KL, Smee DJ, Rattray B. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis.British journal of sports medicine.2018;52(3):154-160.

146.Sexton BP, Taylor NF. To sit or not to sit A systematic review and meta-analysis of seated exercise for older adults.Australasian journal on ageing.2018.

147.Cheng ST. Cognitive Reserve and the Prevention of Dementia: the Role of Physical and Cognitive Activities.Curr Psychiatry Rep.2016;18(9):85.

148.Thow ME, Summers MJ, Saunders NL, Summers JJ, Ritchie K, Vickers JC. Further education improves cognitive reserve and triggers improvement in selective cognitive functions in older adults: The Tasmanian Healthy Brain Project.Alzheimer's & dementia (Amsterdam, Netherlands).2018;10:22-30.

149.Antoniou M, Wright SM. Uncovering the Mechanisms Responsible for Why Language Learning May Promote Healthy Cognitive Aging.Frontiers in psychology.2017;8:2217.

150.Roman-Caballero R, Arnedo M, Trivino M, Lupianez J. Musical practice as an enhancer of cognitive function in healthy aging - A systematic review and meta-analysis.PLoS One.2018;13(11):e0207957.

151.Fissler P, Kuster OC, Laptinskaya D, Loy LS, von Arnim CAF, Kolassa IT. Jigsaw Puzzling Taps Multiple Cognitive Abilities and Is a Potential Protective Factor for Cognitive Aging.Frontiers in aging neuroscience.2018;10:299.

152.Pillai JA, Hall CB, Dickson DW, Buschke H, Lipton RB, Verghese J. Association of crossword puzzle participation with memory decline in persons who develop dementia.Journal of the International Neuropsychological Society : JINS.2011;17(6):1006-1013.

153.Ferreira N, Owen A, Mohan A, Corbett A, Ballard C. Associations between cognitively stimulating leisure activities, cognitive function and age-related cognitive decline.International journal of geriatric psychiatry.2015;30(4):422-430.

154.Litwin H, Schwartz E, Damri N. Cognitively Stimulating Leisure Activity and Subsequent Cognitive Function: A SHARE-based Analysis.The Gerontologist.2017;57(5):940-948.

155.Howard EP, Morris JN, Steel K, et al. Short-Term Lifestyle Strategies for Sustaining Cognitive Status.Biomed Res Int.2016;2016:7405748.

156.Lee GJ, Bang HJ, Lee KM, et al. A comparison of the effects between 2 computerized cognitive training programs, Bettercog and COMCOG, on elderly patients with MCI and mild dementia: A single-blind randomized controlled study.Medicine.2018;97(45):e13007.

157.Chetelat G, Lutz A, Arenaza-Urquijo E, Collette F, Klimecki O, Marchant N. Why could meditation practice help promote mental health and well-being in agingAlzheimers Res Ther.2018;10(1):57.

158.Sperduti M, Makowski D, Blonde P, Piolino P. Meditation and successful aging: can meditative practices counteract age-related cognitive declineGeriatrie et psychologie neuropsychiatrie du vieillissement.2017;15(2):205-213.

159.Villemure C, Ceko M, Cotton VA, Bushnell MC. Neuroprotective effects of yoga practice: age-, experience-, and frequency-dependent plasticity.Frontiers in human neuroscience.2015;9:281.

160.Prakash R, Rastogi P, Dubey I, Abhishek P, Chaudhury S, Small BJ. Long-term concentrative meditation and cognitive performance among older adults.Neuropsychology, development, and cognition Section B, Aging, neuropsychology and cognition.2012;19(4):479-494.

161.Luders E, Cherbuin N, Kurth F. Forever Young(er): potential age-defying effects of long-term meditation on gray matter atrophy.Frontiers in psychology.2014;5:1551.

162.Gard T, Taquet M, Dixit R, et al. Fluid intelligence and brain functional organization in aging yoga and meditation practitioners.Frontiers in aging neuroscience.2014;6:76.

163.Berk L, van Boxtel M, van Os J. Can mindfulness-based interventions influence cognitive functioning in older adults A review and considerations for future research.Aging & mental health.2017;21(11):1113-1120.

164.Gard T, Holzel BK, Lazar SW. The potential effects of meditation on age-related cognitive decline: a systematic review.Ann N Y Acad Sci.2014;1307:89-103.

165.Laird KT, Paholpak P, Roman M, Rahi B, Lavretsky H. Mind-Body Therapies for Late-Life Mental and Cognitive Health.Curr Psychiatry Rep.2018;20(1):2.

166.Gothe NP, Kramer AF, McAuley E. Hatha Yoga Practice Improves Attention and Processing Speed in Older Adults: Results from an 8-Week Randomized Control Trial.Journal of alternative and complementary medicine (New York, NY).2017;23(1):35-40.

167.Dause TJ, Kirby ED. Aging gracefully: social engagement joins exercise and enrichment as a key lifestyle factor in resistance to age-related cognitive decline.Neural Regen Res.2019;14(1):39-42.

168.Pillemer SC, Holtzer R. The differential relationships of dimensions of perceived social support with cognitive function among older adults.Aging & mental health.2016;20(7):727-735.

169.Parisi JM, Roberts L, Szanton SL, Hodgson NA, Gitlin LN. Valued Activities among Individuals with and without Cognitive Impairments: Findings from the National Health and Aging Trends Study.The Gerontologist.2017;57(2):309-318.

170.Hughes TF, Flatt JD, Fu B, Chang CC, Ganguli M. Engagement in social activities and progression from mild to severe cognitive impairment: the MYHAT study.International psychogeriatrics.2013;25(4):587-595.

171.Small BJ, Dixon RA, McArdle JJ, Grimm KJ. Do changes in lifestyle engagement moderate cognitive decline in normal aging Evidence from the Victoria Longitudinal Study.Neuropsychology.2012;26(2):144-155.

172.Yates JA, Clare L, Woods RT. "You've got a friend in me": can social networks mediate the relationship between mood and MCIBMC geriatrics.2017;17(1):144.

173.Lee Y, Jean Yeung WJ. Gender matters: Productive social engagement and the subsequent cognitive changes among older adults.Social science & medicine (1982).2018.

174.Saint Martin M, Sforza E, Barthelemy JC, et al. Long-lasting active lifestyle and successful cognitive aging in a healthy elderly population: The PROOF cohort.Revue neurologique.2017;173(10):637-644.

175.Park S, Kwon E, Lee H. Life Course Trajectories of Later-Life Cognitive Functions: Does Social Engagement in Old Age MatterInternational journal of environmental research and public health.2017;14(4).

176.Haslam C, Cruwys T, Haslam SA. "The we's have it": evidence for the distinctive benefits of group engagement in enhancing cognitive health in aging.Social science & medicine (1982).2014;120:57-66.

177.Roberts RO, Cha RH, Mielke MM, et al. Risk and protective factors for cognitive impairment in persons aged 85 years and older.Neurology.2015;84(18):1854-1861.

178.Trost Bobic T, Secic A, Zavoreo I, et al. The Impact of Sleep Deprivation on the Brain.Acta Clin Croat.2016;55(3):469-473.

179.Tsapanou A, Vlachos GS, Cosentino S, et al. Sleep and subjective cognitive decline in cognitively healthy elderly: Results from two cohorts.J Sleep Res.2018.

180.Dzierzewski JM, Dautovich N, Ravyts S. Sleep and Cognition in Older Adults.Sleep medicine clinics.2018;13(1):93-106.

181.Wennberg AMV, Wu MN, Rosenberg PB, Spira AP. Sleep Disturbance, Cognitive Decline, and Dementia: A Review.Seminars in neurology.2017;37(4):395-406.

182.Atienza M, Ziontz J, Cantero JL. Low-grade inflammation in the relationship between sleep disruption, dysfunctional adiposity, and cognitive decline in aging.Sleep medicine reviews.2018;42:171-183.

183.Akers KG, Cherasse Y, Fujita Y, Srinivasan S, Sakurai T, Sakaguchi M. Concise Review: Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function.Stem cells (Dayton, Ohio).2018;36(7):969-976.

184.Wu L, Sun D, Tan Y. A systematic review and dose-response meta-analysis of sleep duration and the occurrence of cognitive disorders.Sleep & breathing = Schlaf & Atmung.2018;22(3):805-814.

185.Liang Y, Qu LB, Liu H. Non-linear associations between sleep duration and the risks of mild cognitive impairment/dementia and cognitive decline: a dose-response meta-analysis of observational studies.Aging clinical and experimental research.2018.

186.Ho ECM, Siu AMH. Occupational Therapy Practice in Sleep Management: A Review of Conceptual Models and Research Evidence.Occupational therapy international.2018;2018:8637498.

187.Gutman SA, Gregory KA, Sadlier-Brown MM, et al. Comparative Effectiveness of Three Occupational Therapy Sleep Interventions: A Randomized Controlled Study.OTJR : occupation, participation and health.2017;37(1):5-13.

188.Bucks RS, Olaithe M, Rosenzweig I, Morrell MJ. Reviewing the relationship between OSA and cognition: Where do we go from hereRespirology (Carlton, Vic).2017;22(7):1253-1261.

189.Ayas NT, Taylor CM, Laher I. Cardiovascular consequences of obstructive sleep apnea.Current opinion in cardiology.2016;31(6):599-605.

190.Floras JS. Sleep Apnea and Cardiovascular Disease: An Enigmatic Risk Factor.Circ Res.2018;122(12):1741-1764.

191.Chowdhuri S, Patel P, Badr MS. Apnea in Older Adults.Sleep medicine clinics.2018;13(1):21-37.

192.Zhu X, Zhao Y. Sleep-disordered breathing and the risk of cognitive decline: a meta-analysis of 19,940 participants.Sleep & breathing = Schlaf & Atmung.2018;22(1):165-173.

193.Hobzova M, Hubackova L, Vanek J, et al. Cognitive function and depressivity before and after cpap treatment in obstructive sleep apnea patients.Neuro endocrinology letters.2017;38(3):145-153.

194.Yan B, Jin Y, Hu Y, Li S. Effects of continuous positive airway pressure on elderly patients with obstructive sleep apnea: a meta-analysis.Medecine sciences : M/S.2018;34 Focus issue F1:66-73.

195.Devita M, Zangrossi A, Marvisi M, Merlo P, Rusconi ML, Mondini S. Global cognitive profile and different components of reaction times in obstructive sleep apnea syndrome: Effects of continuous positive airway pressure over time.International journal of psychophysiology : official journal of the International Organization of Psychophysiology.2018;123:121-126.

196.Eleftheriou D, Benetou V, Trichopoulou A, La Vecchia C, Bamia C. Mediterranean diet and its components in relation to all-cause mortality: meta-analysis.The British journal of nutrition.2018;120(10):1081-1097.

197.Carlos S, De La Fuente-Arrillaga C, Bes-Rastrollo M, et al. Mediterranean Diet and Health Outcomes in the SUN Cohort.Nutrients.2018;10(4).

198.Romagnolo DF, Selmin OI. Mediterranean Diet and Prevention of Chronic Diseases.Nutrition today.2017;52(5):208-222.

199.Aridi YS, Walker JL, Wright ORL. The Association between the Mediterranean Dietary Pattern and Cognitive Health: A Systematic Review.Nutrients.2017;9(7).

200.Martinez-Gonzalez MA, Hershey MS, Zazpe I, Trichopoulou A. Transferability of the Mediterranean Diet to Non-Mediterranean Countries. What Is and What Is Not the Mediterranean Diet.Nutrients.2017;9(11).

201.Tanaka T, Talegawkar SA, Jin Y, Colpo M, Ferrucci L, Bandinelli S. Adherence to a Mediterranean Diet Protects from Cognitive Decline in the Invecchiare in Chianti Study of Aging.Nutrients.2018;10(12).

202.Bhushan A, Fondell E, Ascherio A, Yuan C, Grodstein F, Willett W. Adherence to Mediterranean diet and subjective cognitive function in men.European journal of epidemiology.2018;33(2):223-234.

203.Vassilaki M, Aakre JA, Syrjanen JA, et al. Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers.J Alzheimers Dis.2018;64(1):281-290.

204.Rainey-Smith SR, Gu Y, Gardener SL, et al. Mediterranean diet adherence and rate of cerebral Abeta-amyloid accumulation: Data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.Translational psychiatry.2018;8(1):238.

205.Qosa H, Mohamed LA, Batarseh YS, et al. Extra-virgin olive oil attenuates amyloid-beta and tau pathologies in the brains of TgSwDI mice.J Nutr Biochem.2015;26(12):1479-1490.

206.Batarseh YS, Mohamed LA, Al Rihani SB, et al. Oleocanthal ameliorates amyloid-beta oligomers' toxicity on astrocytes and neuronal cells: In vitro studies.Neuroscience.2017;352:204-215.

207.Luceri C, Bigagli E, Pitozzi V, Giovannelli L. A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain.European journal of nutrition.2017;56(2):865-877.

208.Martinez-Lapiscina EH, Clavero P, Toledo E, et al. Virgin olive oil supplementation and long-term cognition: the PREDIMED-NAVARRA randomized, trial.The journal of nutrition, health & aging.2013;17(6):544-552.

209.Carman AJ, Dacks PA, Lane RF, Shineman DW, Fillit HM. Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.The journal of nutrition, health & aging.2014;18(4):383-392.

210.Haller S, Montandon ML, Rodriguez C, Herrmann FR, Giannakopoulos P. Impact of Coffee, Wine, and Chocolate Consumption on Cognitive Outcome and MRI Parameters in Old Age.Nutrients.2018;10(10).

211.Liu QP, Wu YF, Cheng HY, et al. Habitual coffee consumption and risk of cognitive decline/dementia: A systematic review and meta-analysis of prospective cohort studies.Nutrition (Burbank, Los Angeles County, Calif).2016;32(6):628-636.

212.Wu L, Sun D, He Y. Coffee intake and the incident risk of cognitive disorders: A dose-response meta-analysis of nine prospective cohort studies.Clin Nutr.2017;36(3):730-736.

213.Solfrizzi V, Panza F, Imbimbo BP, et al. Coffee Consumption Habits and the Risk of Mild Cognitive Impairment: The Italian Longitudinal Study on Aging.J Alzheimers Dis.2015;47(4):889-899.

214.Araujo LF, Giatti L, Reis RC, et al. Inconsistency of Association between Coffee Consumption and Cognitive Function in Adults and Elderly in a Cross-Sectional Study (ELSA-Brasil).Nutrients.2015;7(11):9590-9601.

215.Araujo LF, Mirza SS, Bos D, et al. Association of Coffee Consumption with MRI Markers and Cognitive Function: A Population-Based Study.J Alzheimers Dis.2016;53(2):451-461.

216.Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: An update.Ageing research reviews.2017;39:36-45.

217.Mattson MP. The impact of dietary energy intake on cognitive aging.Frontiers in aging neuroscience.2010;2:5.

218.Fusco S, Pani G. Brain response to calorie restriction.Cellular and molecular life sciences : CMLS.2013;70(17):3157-3170.

219.Park JH, Glass Z, Sayed K, et al. Calorie restriction alleviates the age-related decrease in neural progenitor cell division in the aging brain.Eur J Neurosci.2013;37(12):1987-1993.

220.Babenko NA, Shakhova EG. Long-term food restriction prevents aging-associated sphingolipid turnover dysregulation in the brain.Arch Gerontol Geriatr.2014;58(3):420-426.

221.Willette AA, Coe CL, Colman RJ, et al. Calorie restriction reduces psychological stress reactivity and its association with brain volume and microstructure in aged rhesus monkeys.Psychoneuroendocrinology.2012;37(7):903-916.

222.Hadad N, Unnikrishnan A, Jackson JA, et al. Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation.Neurobiol Aging.2018;67:53-66.

223.Campagna G, Pesce M, Tatangelo R, Rizzuto A, La Fratta I, Grilli A. The progression of coeliac disease: its neurological and psychiatric implications.Nutr Res Rev.2017;30(1):25-35.

224.Casella G, Bordo BM, Schalling R, et al. Neurological disorders and celiac disease.Minerva gastroenterologica e dietologica.2016;62(2):197-206.

225.Makhlouf S, Messelmani M, Zaouali J, Mrissa R. Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet.Acta neurologica Belgica.2018;118(1):21-27.

226.Daulatzai MA. Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia.CNS & neurological disorders drug targets.2015;14(1):110-131.

227.Lurie Y, Landau DA, Pfeffer J, Oren R. Celiac disease diagnosed in the elderly.Journal of clinical gastroenterology.2008;42(1):59-61.

228.Zhang HF, Huang LB, Zhong YB, et al. An Overview of Systematic Reviews of Ginkgo biloba Extracts for Mild Cognitive Impairment and Dementia.Frontiers in aging neuroscience.2016;8:276.

229.Gargouri B, Carstensen J, Bhatia HS, Huell M, Dietz GPH, Fiebich BL. Anti-neuroinflammatory effects of Ginkgo biloba extract EGb761 in LPS-activated primary microglial cells.Phytomedicine.2018;44:45-55.

230.Osman NM, Amer AS, Abdelwahab S. Effects of Ginko biloba leaf extract on the neurogenesis of the hippocampal dentate gyrus in the elderly mice.Anatomical science international.2016;91(3):280-289.

231.Tan MS, Yu JT, Tan CC, et al. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis.J Alzheimers Dis.2015;43(2):589-603.

232.Hashiguchi M, Ohta Y, Shimizu M, Maruyama J, Mochizuki M. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia.Journal of pharmaceutical health care and sciences.2015;1:14.

233.Gauthier S, Schlaefke S. Efficacy and tolerability of Ginkgo biloba extract EGb 761(R) in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials.Clin Interv Aging.2014;9:2065-2077.

234.Kandiah N, Ong PA, Yuda T, et al. Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761((R)).CNS neuroscience & therapeutics.2019;25(2):288-298.

235.Stough C, Singh H, Zangara A. Mechanisms, Efficacy, and Safety of Bacopa monnieri (Brahmi) for Cognitive and Brain Enhancement.Evidence-based complementary and alternative medicine : eCAM.2015;2015:717605.

236.Chaudhari KS, Tiwari NR, Tiwari RR, Sharma RS. Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease.Annals of neurosciences.2017;24(2):111-122.

237.Aguiar S, Borowski T. Neuropharmacological review of the nootropic herb Bacopa monnieri.Rejuvenation Res.2013;16(4):313-326.

238.Benson S, Downey LA, Stough C, Wetherell M, Zangara A, Scholey A. An acute, double-blind, placebo-controlled cross-over study of 320 mg and 640 mg doses of Bacopa monnieri (CDRI 08) on multitasking stress reactivity and mood.Phytotherapy research : PTR.2014;28(4):551-559.

239.Kwon HJ, Jung HY, Hahn KR, et al. Bacopa monnieri extract improves novel object recognition, cell proliferation, neuroblast differentiation, brain-derived neurotrophic factor, and phosphorylation of cAMP response element-binding protein in the dentate gyrus.Laboratory animal research.2018;34(4):239-247.

240.Kongkeaw C, Dilokthornsakul P, Thanarangsarit P, Limpeanchob N, Norman Scholfield C. Meta-analysis of randomized controlled trials on cognitive effects of Bacopa monnieri extract.Journal of ethnopharmacology.2014;151(1):528-535.

241.Calabrese C, Gregory WL, Leo M, Kraemer D, Bone K, Oken B. Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial.Journal of alternative and complementary medicine (New York, NY).2008;14(6):707-713.

242.Zanotta D, Puricelli S, Bonoldi G. Cognitive effects of a dietary supplement made from extract of Bacopa monnieri, astaxanthin, phosphatidylserine, and vitamin E in subjects with mild cognitive impairment: a noncomparative, exploratory clinical study.Neuropsychiatric disease and treatment.2014;10:225-230.

243.Cicero AF, Bove M, Colletti A, et al. Short-Term Impact of a Combined Nutraceutical on Cognitive Function, Perceived Stress and Depression in Young Elderly with Cognitive Impairment: A Pilot, Double-Blind, Randomized Clinical Trial.The journal of prevention of Alzheimer's disease.2017;4(1):12-15.

244.Janeczek M, Gefen T, Samimi M, et al. Variations in Acetylcholinesterase Activity within Human Cortical Pyramidal Neurons Across Age and Cognitive Trajectories.Cerebral cortex (New York, NY : 1991).2018;28(4):1329-1337.

245.Damar U, Gersner R, Johnstone JT, Schachter S, Rotenberg A. Huperzine A: A promising anticonvulsant, disease modifying, and memory enhancing treatment option in Alzheimer's disease.Med Hypotheses.2017;99:57-62.

246.Qian ZM, Ke Y. Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's DiseaseFrontiers in aging neuroscience.2014;6:216.

247.Xing SH, Zhu CX, Zhang R, An L. Huperzine a in the treatment of Alzheimer's disease and vascular dementia: a meta-analysis.Evidence-based complementary and alternative medicine : eCAM.2014;2014:363985.

248.Yang G, Wang Y, Tian J, Liu JP. Huperzine A for Alzheimer's disease: a systematic review and meta-analysis of randomized clinical trials.PLoS One.2013;8(9):e74916.

249.Gul A, Bakht J, Mehmood F. Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer's disease.Journal of the Chinese Medical Association : JCMA.2018.

250.Tabira T, Kawamura N. A Study of a Supplement Containing Huperzine A and Curcumin in Dementia Patients and Individuals with Mild Cognitive Impairment.J Alzheimers Dis.2018;63(1):75-78.

251.Cristofano A, Sapere N, La Marca G, et al. Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia.PLoS One.2016;11(5):e0155694.

252.Mehrotra A, Kanwal A, Banerjee SK, Sandhir R. Mitochondrial modulators in experimental Huntington's disease: reversal of mitochondrial dysfunctions and cognitive deficits.Neurobiol Aging.2015;36(6):2186-2200.

253.Singh S, Mishra A, Srivastava N, Shukla R, Shukla S. Acetyl-L-Carnitine via Upegulating Dopamine D1 Receptor and Attenuating Microglial Activation Prevents Neuronal Loss and Improves Memory Functions in Parkinsonian Rats.Molecular neurobiology.2018;55(1):583-602.

254.Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease.International clinical psychopharmacology.2003;18(2):61-71.

255.Malaguarnera M, Gargante MP, Cristaldi E, et al. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.Archives of gerontology and geriatrics.2008;46(2):181-190.

256.Bersani G, Meco G, Denaro A, et al. L-Acetylcarnitine in dysthymic disorder in elderly patients: a double-blind, multicenter, controlled randomized study vs. fluoxetine.European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology.2013;23(10):1219-1225.

257.Remington R, Lortie JJ, Hoffmann H, Page R, Morrell C, Shea TB. A Nutritional Formulation for Cognitive Performance in Mild Cognitive Impairment: A Placebo-Controlled Trial with an Open-Label Extension.J Alzheimers Dis.2015;48(3):591-595.

258.Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium.Neuron.2010;65(2):165-177.

259.Wang D, Jacobs SA, Tsien JZ. Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline.Expert opinion on therapeutic targets.2014;18(10):1121-1130.

260.Abumaria N, Yin B, Zhang L, et al. Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala.J Neurosci.2011;31(42):14871-14881.

261.Yu X, Guan PP, Zhu D, et al. Magnesium Ions Inhibit the Expression of Tumor Necrosis Factor alpha and the Activity of gamma-Secretase in a beta-Amyloid Protein-Dependent Mechanism in APP/PS1 Transgenic Mice.Frontiers in molecular neuroscience.2018;11:172.

262.Yu X, Guan PP, Guo JW, et al. By suppressing the expression of anterior pharynx-defective-1alpha and -1beta and inhibiting the aggregation of beta-amyloid protein, magnesium ions inhibit the cognitive decline of amyloid precursor protein/presenilin 1 transgenic mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology.2015;29(12):5044-5058.

263.Li W, Yu J, Liu Y, et al. Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer's disease mouse model.Molecular brain.2014;7:65.

264.Huang Y, Huang X, Zhang L, et al. Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice.CNS neuroscience & therapeutics.2018;24(1):70-79.

265.Valls-Pedret C, Lamuela-Raventos RM, Medina-Remon A, et al. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk.J Alzheimers Dis.2012;29(4):773-782.

266.Rabassa M, Cherubini A, Zamora-Ros R, et al. Low Levels of a Urinary Biomarker of Dietary Polyphenol Are Associated with Substantial Cognitive Decline over a 3-Year Period in Older Adults: The Invecchiare in Chianti Study.J Am Geriatr Soc.2015;63(5):938-946.

267.Flanagan E, Muller M, Hornberger M, Vauzour D. Impact of Flavonoids on Cellular and Molecular Mechanisms Underlying Age-Related Cognitive Decline and Neurodegeneration.Current nutrition reports.2018;7(2):49-57.

268.Sarubbo F, Moranta D, Pani G. Dietary polyphenols and neurogenesis: Molecular interactions and implication for brain ageing and cognition.Neuroscience and biobehavioral reviews.2018;90:456-470.

269.Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gut-brain interactions.Mech Ageing Dev.2014;136-137:59-69.

270.Frolinger T, Herman F, Sharma A, Sims S, Wang J, Pasinetti GM. Epigenetic modifications by polyphenolic compounds alter gene expression in the hippocampus.Biology open.2018;7(10).

271.Ma L, Sun Z, Zeng Y, Luo M, Yang J. Molecular Mechanism and Health Role of Functional Ingredients in Blueberry for Chronic Disease in Human Beings.International journal of molecular sciences.2018;19(9).

272.Boespflug EL, Eliassen JC, Dudley JA, et al. Enhanced neural activation with blueberry supplementation in mild cognitive impairment.Nutritional neuroscience.2018;21(4):297-305.

273.Bowtell JL, Aboo-Bakkar Z, Conway ME, Adlam AR, Fulford J. Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation.Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.2017;42(7):773-779.

274.Miller MG, Hamilton DA, Joseph JA, Shukitt-Hale B. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial.European journal of nutrition.2018;57(3):1169-1180.

275.McNamara RK, Kalt W, Shidler MD, et al. Cognitive response to fish oil, blueberry, and combined supplementation in older adults with subjective cognitive impairment.Neurobiol Aging.2018;64:147-156.

276.Traupe I, Giacalone M, Agrimi J, et al. Postoperative cognitive dysfunction and short-term neuroprotection from blueberries: a pilot study.Minerva Anestesiol.2018;84(12):1352-1360.

277.Nilsson A, Salo I, Plaza M, Bjorck I. Effects of a mixed berry beverage on cognitive functions and cardiometabolic risk markers; A randomized cross-over study in healthy older adults.PloS one.2017;12(11):e0188173.

278.Herman F, Westfall S, Brathwaite J, Pasinetti GM. Suppression of Presymptomatic Oxidative Stress and Inflammation in Neurodegeneration by Grape-Derived Polyphenols.Frontiers in pharmacology.2018;9:867.

279.Calapai G, Bonina F, Bonina A, et al. A Randomized, Double-Blinded, Clinical Trial on Effects of a Vitis vinifera Extract on Cognitive Function in Healthy Older Adults.Frontiers in pharmacology.2017;8:776.

280.Krikorian R, Boespflug EL, Fleck DE, et al. Concord grape juice supplementation and neurocognitive function in human aging.J Agric Food Chem.2012;60(23):5736-5742.

281.Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment.The British journal of nutrition.2010;103(5):730-734.

282.Lee J, Torosyan N, Silverman DH. Examining the impact of grape consumption on brain metabolism and cognitive function in patients with mild decline in cognition: A double-blinded placebo controlled pilot study.Exp Gerontol.2017;87(Pt A):121-128.

283.Bensalem J, Dudonne S, Etchamendy N, et al. Polyphenols from grape and blueberry improve episodic memory in healthy elderly with lower level of memory performance: a bicentric double-blind, randomized, placebo-controlled clinical study.The journals of gerontology Series A, Biological sciences and medical sciences.2018.

284.Ramirez-Garza SL, Laveriano-Santos EP, Marhuenda-Munoz M, et al. Health Effects of Resveratrol: Results from Human Intervention Trials.Nutrients.2018;10(12).

285.Cao W, Dou Y, Li A. Resveratrol Boosts Cognitive Function by Targeting SIRT1.Neurochem Res.2018;43(9):1705-1713.

286.Marx W, Kelly JT, Marshall S, et al. Effect of resveratrol supplementation on cognitive performance and mood in adults: a systematic literature review and meta-analysis of randomized controlled trials.Nutrition reviews.2018;76(6):432-443.

287.Witte AV, Kerti L, Margulies DS, Floel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults.J Neurosci.2014;34(23):7862-7870.

288.Kobe T, Witte AV, Schnelle A, et al. Impact of Resveratrol on Glucose Control, Hippocampal Structure and Connectivity, and Memory Performance in Patients with Mild Cognitive Impairment.Front Neurosci.2017;11:105.

289.Anton SD, Ebner N, Dzierzewski JM, et al. Effects of 90 Days of Resveratrol Supplementation on Cognitive Function in Elders: A Pilot Study.Journal of alternative and complementary medicine (New York, NY).2018;24(7):725-732.

290.Evans HM, Howe PR, Wong RH. Effects of Resveratrol on Cognitive Performance, Mood and Cerebrovascular Function in Post-Menopausal Women; A 14-Week Randomised Placebo-Controlled Intervention Trial.Nutrients.2017;9(1).

291.Farzaei MH, Bahramsoltani R, Abbasabadi Z, Braidy N, Nabavi SM. Role of green tea catechins in prevention of age-related cognitive decline: Pharmacological targets and clinical perspective.Journal of cellular physiology.2019;234(3):2447-2459.

292.Pervin M, Unno K, Ohishi T, Tanabe H, Miyoshi N, Nakamura Y. Beneficial Effects of Green Tea Catechins on Neurodegenerative Diseases.Molecules (Basel, Switzerland).2018;23(6).

293.Mancini E, Beglinger C, Drewe J, Zanchi D, Lang UE, Borgwardt S. Green tea effects on cognition, mood and human brain function: A systematic review.Phytomedicine : international journal of phytotherapy and phytopharmacology.2017;34:26-37.

294.Heitman E, Ingram DK. Cognitive and neuroprotective effects of chlorogenic acid.Nutritional neuroscience.2017;20(1):32-39.

295.Saitou K, Ochiai R, Kozuma K, et al. Effect of Chlorogenic Acids on Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Trial.Nutrients.2018;10(10).

296.Spinedi E, Cardinali DP. Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer s Disease and Melatonin. <br>.Neuroendocrinology.2018.

297.Sarlak G, Jenwitheesuk A, Chetsawang B, Govitrapong P. Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration.Journal of pharmacological sciences.2013;123(1):9-24.

298.Waller KL, Mortensen EL, Avlund K, et al. Melatonin and cortisol profiles in late midlife and their association with age-related changes in cognition.Nature and science of sleep.2016;8:47-53.

299.Sirin FB, Kumbul Doguc D, Vural H, et al. Plasma 8-isoPGF2alpha and serum melatonin levels in patients with minimal cognitive impairment and Alzheimer disease.Turkish journal of medical sciences.2015;45(5):1073-1077.

300.Obayashi K, Saeki K, Iwamoto J, et al. Physiological Levels of Melatonin Relate to Cognitive Function and Depressive Symptoms: The HEIJO-KYO Cohort.J Clin Endocrinol Metab.2015;100(8):3090-3096.

301.Xia T, Cui Y, Chu S, et al. Melatonin pretreatment prevents isoflurane-induced cognitive dysfunction by modulating sleep-wake rhythm in mice.Brain research.2016;1634:12-20.

302.Kwon KJ, Lee EJ, Kim MK, et al. The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function.Neuroscience.2015;301:403-414.

303.Song J, Chu S, Cui Y, et al. Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice.Experimental neurology.2018;306:45-54.

304.Shen D, Tian X, Sang W, Song R. Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia.Neuroimmunomodulation.2016;23(5-6):318-331.

305.Corpas R, Grinan-Ferre C, Palomera-Avalos V, et al. Melatonin induces mechanisms of brain resilience against neurodegeneration.Journal of pineal research.2018;65(4):e12515.

306.Permpoonputtana K, Tangweerasing P, Mukda S, Boontem P, Nopparat C, Govitrapong P. Long-term administration of melatonin attenuates neuroinflammation in the aged mouse brain.EXCLI journal.2018;17:634-646.

307.Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI. Therapeutic application of melatonin in mild cognitive impairment.American journal of neurodegenerative disease.2012;1(3):280-291.

308.Furio AM, Brusco LI, Cardinali DP. Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study.Journal of pineal research.2007;43(4):404-409.

309.Iwashita H, Matsumoto Y, Maruyama Y, Watanabe K, Chiba A, Hattori A. The melatonin metabolite N1-acetyl-5-methoxykynuramine facilitates long-term object memory in young and aging mice.Journal of pineal research.2021;70(1):e12703.

310.Fan Y, Yuan L, Ji M, Yang J, Gao D. The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial.Journal of clinical anesthesia.2017;39:77-81.

311.Srinivasan V, Pandi-Perumal SR, Cardinali DP, Poeggeler B, Hardeland R. Melatonin in Alzheimer's disease and other neurodegenerative disorders.Behavioral and brain functions : BBF.2006;2:15.

312.Cardinali DP, Vigo DE, Olivar N, Vidal MF, Brusco LI. Melatonin Therapy in Patients with Alzheimer's Disease.Antioxidants (Basel, Switzerland).2014;3(2):245-277.

313.Cardoso C, Afonso C, Bandarra NM. Dietary DHA and health: cognitive function ageing.Nutrition research reviews.2016;29(2):281-294.

314.Rathod R, Kale A, Joshi S. Novel insights into the effect of vitamin B(1)(2) and omega-3 fatty acids on brain function.J Biomed Sci.2016;23:17.

315.Morris MC, Brockman J, Schneider JA, et al. Association of Seafood Consumption, Brain Mercury Level, and APOE epsilon4 Status With Brain Neuropathology in Older Adults.Jama.2016;315(5):489-497.

316.Luo C, Ren H, Yao X, et al. Enriched Brain Omega-3 Polyunsaturated Fatty Acids Confer Neuroprotection against Microinfarction.EBioMedicine.2018;32:50-61.

317.Oulhaj A, Jerneren F, Refsum H, Smith AD, de Jager CA. Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment.J Alzheimers Dis.2016;50(2):547-557.

318.Nishihira J, Tokashiki T, Higashiuesato Y, et al. Associations between Serum Omega-3 Fatty Acid Levels and Cognitive Functions among Community-Dwelling Octogenarians in Okinawa, Japan: The KOCOA Study.J Alzheimers Dis.2016;51(3):857-866.

319.Lukaschek K, von Schacky C, Kruse J, Ladwig KH. Cognitive Impairment Is Associated with a Low Omega-3 Index in the Elderly: Results from the KORA-Age Study.Dement Geriatr Cogn Disord.2016;42(3-4):236-245.

320.D'Ascoli TA, Mursu J, Voutilainen S, Kauhanen J, Tuomainen TP, Virtanen JK. Association between serum long-chain omega-3 polyunsaturated fatty acids and cognitive performance in elderly men and women: The Kuopio Ischaemic Heart Disease Risk Factor Study.European journal of clinical nutrition.2016;70(8):970-975.

321.Lai HT, de Oliveira Otto MC, Lemaitre RN, et al. Serial circulating omega 3 polyunsaturated fatty acids and healthy ageing among older adults in the Cardiovascular Health Study: prospective cohort study.BMJ (Clinical research ed).2018;363:k4067.

322.Zamroziewicz MK, Paul EJ, Zwilling CE, Barbey AK. Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity.Aging Dis.2017;8(4):372-383.

323.Andruchow ND, Konishi K, Shatenstein B, Bohbot VD. A lower ratio of omega-6 to omega-3 fatty acids predicts better hippocampus-dependent spatial memory and cognitive status in older adults.Neuropsychology.2017;31(7):724-734.

324.Zhang XW, Hou WS, Li M, Tang ZY. Omega-3 fatty acids and risk of cognitive decline in the elderly: a meta-analysis of randomized controlled trials.Aging clinical and experimental research.2016;28(1):165-166.

325.Masana MF, Koyanagi A, Haro JM, Tyrovolas S. n-3 Fatty acids, Mediterranean diet and cognitive function in normal aging: A systematic review.Exp Gerontol.2017;91:39-50.

326.Danthiir V, Hosking DE, Nettelbeck T, et al. An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults.Am J Clin Nutr.2018;107(5):754-762.

327.Baleztena J, Ruiz-Canela M, Sayon-Orea C, et al. Association between cognitive function and supplementation with omega-3 PUFAs and other nutrients in >/= 75 years old patients: A randomized multicenter study.PLoS One.2018;13(3):e0193568.

328.Andrieu S, Guyonnet S, Coley N, et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial.Lancet Neurol.2017;16(5):377-389.

329.Hooper C, De Souto Barreto P, Coley N, et al. Cognitive Changes with Omega-3 Polyunsaturated Fatty Acids in Non-Demented Older Adults with Low Omega-3 Index.The journal of nutrition, health & aging.2017;21(9):988-993.

330.Coley N, Raman R, Donohue MC, Aisen PS, Vellas B, Andrieu S. Defining the Optimal Target Population for Trials of Polyunsaturated Fatty Acid Supplementation Using the Erythrocyte Omega-3 Index: A Step Towards Personalized Prevention of Cognitive DeclineThe journal of nutrition, health & aging.2018;22(8):982-998.

331.Yassine HN, Croteau E, Rawat V, et al. DHA brain uptake and APOE4 status: a PET study with [1-(11)C]-DHA.Alzheimers Res Ther.2017;9(1):23.

332.van de Rest O, Wang Y, Barnes LL, Tangney C, Bennett DA, Morris MC. APOE epsilon4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline.Neurology.2016;86(22):2063-2070.

333.Nock TG, Chouinard-Watkins R, Plourde M. Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline.Biochimica et biophysica acta Molecular and cell biology of lipids.2017;1862(10 Pt A):1068-1078.

334.Porter K, Hoey L, Hughes CF, Ward M, McNulty H. Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing.Nutrients.2016;8(11).

335.Mendonca N, Granic A, Mathers JC, et al. One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study.Journal of the American Medical Directors Association.2017;18(9):806.e819-806.e827.

336.Mizrahi EH, Lubart E, Leibovitz A. Low Borderline Levels of Serum Vitamin B12 May Predict Cognitive Decline in Elderly Hip Fracture Patients.The Israel Medical Association journal : IMAJ.2017;19(5):305-308.

337.Hughes CF, Ward M, Tracey F, et al. B-Vitamin Intake and Biomarker Status in Relation to Cognitive Decline in Healthy Older Adults in a 4-Year Follow-Up Study.Nutrients.2017;9(1).

338.Zhang DM, Ye JX, Mu JS, Cui XP. Efficacy of Vitamin B Supplementation on Cognition in Elderly Patients With Cognitive-Related Diseases.Journal of geriatric psychiatry and neurology.2017;30(1):50-59.

339.Rutjes AW, Denton DA, Di Nisio M, et al. Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life.The Cochrane database of systematic reviews.2018;12:Cd011906.

340.D'Cunha NM, Georgousopoulou EN, Dadigamuwage L, et al. Effect of long-term nutraceutical and dietary supplement use on cognition in the elderly: a 10-year systematic review of randomised controlled trials.The British journal of nutrition.2018;119(3):280-298.

341.Butler M, Nelson VA, Davila H, et al. Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review.Ann Intern Med.2018;168(1):52-62.

342.de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.International journal of geriatric psychiatry.2012;27(6):592-600.

343.Blasko I, Hinterberger M, Kemmler G, et al. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort.The journal of nutrition, health & aging.2012;16(8):687-694.

344.Ma F, Wu T, Zhao J, et al. Effects of 6-Month Folic Acid Supplementation on Cognitive Function and Blood Biomarkers in Mild Cognitive Impairment: A Randomized Controlled Trial in China.The journals of gerontology Series A, Biological sciences and medical sciences.2016;71(10):1376-1383.

345.Ma F, Wu T, Zhao J, et al. Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI.Sci Rep.2016;6:37486.

346.Lee HK, Kim SY, Sok SR. Effects of Multivitamin Supplements on Cognitive Function, Serum Homocysteine Level, and Depression of Korean Older Adults With Mild Cognitive Impairment in Care Facilities.Journal of nursing scholarship : an official publication of Sigma Theta Tau International Honor Society of Nursing.2016;48(3):223-231.

347.Mitchell ES, Conus N, Kaput J. B vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline.Neuroscience and biobehavioral reviews.2014;47:307-320.

348.Hara J, Shankle WR, Barrentine LW, Curole MV. Novel Therapy of Hyperhomocysteinemia in Mild Cognitive Impairment, Alzheimer's Disease, and Other Dementing Disorders.The journal of nutrition, health & aging.2016;20(8):825-834.

349.Scapicchio PL. Revisiting choline alphoscerate profile: a new, perspective, role in dementiaInt J Neurosci.2013;123(7):444-449.

350.Traini E, Bramanti V, Amenta F. Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent.Current Alzheimer research.2013;10(10):1070-1079.

351.Tayebati SK, Amenta F. Choline-containing phospholipids: relevance to brain functional pathways.Clinical chemistry and laboratory medicine : CCLM / FESCC.2013;51(3):513-521.

352.De Jesus Moreno Moreno M. Cognitive improvement in mild to moderate Alzheimer's dementia after treatment with the acetylcholine precursor choline alfoscerate: a multicenter, double-blind, randomized, placebo-controlled trial.Clinical therapeutics.2003;25(1):178-193.

353.Gavrilova SI, Kolykhalov IV, Ponomareva EV, Fedorova YB, Selezneva ND. [Clinical efficacy and safety of choline alfoscerate in the treatment of late-onset cognitive impairment].Zh Nevrol Psikhiatr Im S S Korsakova.2018;118(5):45-53.

354.Pizova NV. [The use of cereton in patients with chronic brain ischemia and moderate cognitive impairment].Zh Nevrol Psikhiatr Im S S Korsakova.2014;114(12):78-83.

355.Amenta F, Carotenuto A, Fasanaro AM, Rea R, Traini E. The ASCOMALVA trial: association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in Alzheimer's disease with cerebrovascular injury: interim results.J Neurol Sci.2012;322(1-2):96-101.

356.Amenta F, Carotenuto A, Fasanaro AM, Rea R, Traini E. The ASCOMALVA (Association between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in Alzheimer's Disease) Trial: interim results after two years of treatment.J Alzheimers Dis.2014;42 Suppl 3:S281-288.

357.Rea R, Carotenuto A, Traini E, Fasanaro AM, Manzo V, Amenta F. Apathy Treatment in Alzheimer's Disease: Interim Results of the ASCOMALVA Trial.J Alzheimers Dis.2015;48(2):377-383.

358.Carotenuto A, Rea R, Traini E, et al. The Effect of the Association between Donepezil and Choline Alphoscerate on Behavioral Disturbances in Alzheimer's Disease: Interim Results of the ASCOMALVA Trial.J Alzheimers Dis.2017;56(2):805-815.

359.Glade MJ, Smith K. Phosphatidylserine and the human brain.Nutrition (Burbank, Los Angeles County, Calif).2015;31(6):781-786.

360.Vakhapova V, Cohen T, Richter Y, Herzog Y, Kam Y, Korczyn AD. Phosphatidylserine containing omega-3 Fatty acids may improve memory abilities in nondemented elderly individuals with memory complaints: results from an open-label extension study.Dementia and geriatric cognitive disorders.2014;38(1-2):39-45.

361.Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders.Acta psychiatrica Scandinavica.1990;81(3):265-270.

362.Cenacchi T, Bertoldin T, Farina C, Fiori MG, Crepaldi G. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration.Aging (Milan, Italy).1993;5(2):123-133.

363.Kato-Kataoka A, Sakai M, Ebina R, Nonaka C, Asano T, Miyamori T. Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints.Journal of clinical biochemistry and nutrition.2010;47(3):246-255.

364.Richter Y, Herzog Y, Lifshitz Y, Hayun R, Zchut S. The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints: a pilot study.Clin Interv Aging.2013;8:557-563.

365.Vakhapova V, Richter Y, Cohen T, Herzog Y, Korczyn AD. Safety of phosphatidylserine containing omega-3 fatty acids in non-demented elderly: a double-blind placebo-controlled trial followed by an open-label extension.BMC Neurol.2011;11:79.

366.Richter Y, Herzog Y, Cohen T, Steinhart Y. The effect of phosphatidylserine-containing omega-3 fatty acids on memory abilities in subjects with subjective memory complaints: a pilot study.Clinical interventions in aging.2010;5:313-316.

367.Vakhapova V, Cohen T, Richter Y, Herzog Y, Korczyn AD. Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: a double-blind placebo-controlled trial.Dement Geriatr Cogn Disord.2010;29(5):467-474.

368.Rathe M, Muller K, Sangild PT, Husby S. Clinical applications of bovine colostrum therapy: a systematic review.Nutrition reviews.2014;72(4):237-254.

369.Bagwe S, Tharappel LJ, Kaur G, Buttar HS. Bovine colostrum: an emerging nutraceutical.Journal of complementary & integrative medicine.2015;12(3):175-185.

370.Camfield DA, Owen L, Scholey AB, Pipingas A, Stough C. Dairy constituents and neurocognitive health in ageing.The British journal of nutrition.2011;106(2):159-174.

371.Janusz M, Zablocka A. Colostrinin: a proline-rich polypeptide complex of potential therapeutic interest.Cellular and molecular biology (Noisy-le-Grand, France).2013;59(1):4-11.

372.Bacsi A, Aguilera-Aguirre L, German P, Kruzel ML, Boldogh I. Colostrinin decreases spontaneous and induced mutation frequencies at the hprt locus in Chinese hamster V79 cells.Journal of experimental therapeutics & oncology.2006;5(4):249-259.

373.Bacsi A, Woodberry M, Kruzel ML, Boldogh I. Colostrinin delays the onset of proliferative senescence of diploid murine fibroblast cells.Neuropeptides.2007;41(2):93-101.

374.Zablocka A, Ogorzalek A, Macala J, Janusz M. A proline-rich polypeptide complex (PRP) influences inducible nitric oxide synthase in mice at the protein level.Nitric oxide : biology and chemistry.2010;23(1):20-25.

375.Zablocka A, Janusz M. Effect of the proline-rich polypeptide complex/colostrinin on the enzymatic antioxidant system.Arch Immunol Ther Exp (Warsz).2012;60(5):383-390.

376.Janusz M, Zablocka A. Colostral proline-rich polypeptides--immunoregulatory properties and prospects of therapeutic use in Alzheimer's disease.Current Alzheimer research.2010;7(4):323-333.

377.Bilikiewicz A, Gaus W. Colostrinin (a naturally occurring, proline-rich, polypeptide mixture) in the treatment of Alzheimer's disease.Journal of Alzheimer's disease : JAD.2004;6(1):17-26.

378.Leszek J, Inglot AD, Janusz M, et al. Colostrinin proline-rich polypeptide complex from ovine colostrum--a long-term study of its efficacy in Alzheimer's disease.Medical science monitor : international medical journal of experimental and clinical research.2002;8(10):Pi93-96.

379.Leszek J, Inglot AD, Janusz M, Lisowski J, Krukowska K, Georgiades JA. Colostrinin: a proline-rich polypeptide (PRP) complex isolated from ovine colostrum for treatment of Alzheimer's disease. A double-blind, placebo-controlled study.Archivum immunologiae et therapiae experimentalis.1999;47(6):377-385.

380.Jeon KI, Xu X, Aizawa T, et al. Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism.Proceedings of the National Academy of Sciences of the United States of America.2010;107(21):9795-9800.

381.Hadjiev D. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine.Ideggyogyaszati szemle.2003;56(5-6):166-172.

382.Bagoly E, Feher G, Szapary L. [The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies].Orvosi hetilap.2007;148(29):1353-1358.

383.Cai Y, Li JD, Yan C. Vinpocetine attenuates lipid accumulation and atherosclerosis formation.Biochemical and biophysical research communications.2013;434(3):439-443.

384.Kemeny V, Molnar S, Andrejkovics M, Makai A, Csiba L. Acute and chronic effects of vinpocetine on cerebral hemodynamics and neuropsychological performance in multi-infarct patients.J Clin Pharmacol.2005;45(9):1048-1054.

385.Valikovics A, Csanyi A, Nemeth L. [Study of the effects of vinpocetin on cognitive functions].Ideggyogyaszati szemle.2012;65(3-4):115-120.

386.Valikovics A. [Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions].Ideggyogyaszati szemle.2007;60(7-8):301-310.

387.Rybakowski JK. Challenging the Negative Perception of Lithium and Optimizing Its Long-Term Administration.Frontiers in molecular neuroscience.2018;11:349.

388.Won E, Kim YK. An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms.International journal of molecular sciences.2017;18(12).

389.Kessing LV, Gerds TA, Knudsen NN, et al. Association of Lithium in Drinking Water With the Incidence of DementiaAssociation of Lithium in Drinking Water With Dementia IncidenceAssociation of Lithium in Drinking Water With Dementia Incidence.JAMA Psychiatry.2017;74(10):1005-1010.

390.Brown EE, Gerretsen P, Pollock B, Graff-Guerrero A. Psychiatric benefits of lithium in water supplies may be due to protection from the neurotoxicity of lead exposure.Med Hypotheses.2018;115:94-102.

391.Morris G, Berk M. The Putative Use of Lithium in Alzheimer's Disease.Current Alzheimer research.2016;13(8):853-861.

392.Brzozka MM, Havemann-Reinecke U, Wichert SP, Falkai P, Rossner MJ. Molecular Signatures of Psychosocial Stress and Cognition Are Modulated by Chronic Lithium Treatment.Schizophrenia bulletin.2016;42 Suppl 1:S22-33.

393.Kerr F, Bjedov I, Sofola-Adesakin O. Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models.Frontiers in molecular neuroscience.2018;11:297.

394.De-Paula VJ, Gattaz WF, Forlenza OV. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.Bipolar disorders.2016;18(8):692-695.

395.Gideons ES, Lin PY, Mahgoub M, Kavalali ET, Monteggia LM. Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling.Elife.2017;6.

396.Valvassori SS, Borges CP, Varela RB, et al. The different effects of lithium and tamoxifen on memory formation and the levels of neurotrophic factors in the brain of male and female rats.Brain research bulletin.2017;134:228-235.

397.Matsunaga S, Kishi T, Annas P, Basun H, Hampel H, Iwata N. Lithium as a Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis.J Alzheimers Dis.2015;48(2):403-410.

398.Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease.Current Alzheimer research.2013;10(1):104-107.

399.Wilson EN, Do Carmo S, Iulita MF, et al. Microdose Lithium NP03 Diminishes Pre-Plaque Oxidative Damage and Neuroinflammation in a Rat Model of Alzheimer's-like Amyloidosis.Current Alzheimer research.2018;15(13):1220-1230.

400.Wilson EN, Do Carmo S, Iulita MF, et al. BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology.Translational psychiatry.2017;7(8):e1190.

401.Rees A, Dodd GF, Spencer JPE. The Effects of Flavonoids on Cardiovascular Health: A Review of Human Intervention Trials and Implications for Cerebrovascular Function.Nutrients.2018;10(12).

402.Grassi D, Ferri C, Desideri G. Brain Protection and Cognitive Function: Cocoa Flavonoids as Nutraceuticals.Curr Pharm Des.2016;22(2):145-151.

403.Wang J, Varghese M, Ono K, et al. Cocoa extracts reduce oligomerization of amyloid-beta: implications for cognitive improvement in Alzheimer's disease.J Alzheimers Dis.2014;41(2):643-650.

404.Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance.Br J Clin Pharmacol.2013;75(3):716-727.

405.Orozco Arbelaez E, Banegas JR, Rodriguez Artalejo F, Lopez Garcia E. [Influence of habitual chocolate consumption over the Mini-Mental State Examination in Spanish older adults].Nutr Hosp.2017;34(4):841-846.

406.Moreira A, Diogenes MJ, de Mendonca A, Lunet N, Barros H. Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline.J Alzheimers Dis.2016;53(1):85-93.

407.Neshatdoust S, Saunders C, Castle SM, et al. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: Two randomised, controlled trials.Nutr Healthy Aging.2016;4(1):81-93.

408.Mastroiacovo D, Kwik-Uribe C, Grassi D, et al. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study--a randomized controlled trial.Am J Clin Nutr.2015;101(3):538-548.

409.Brickman AM, Khan UA, Provenzano FA, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults.Nat Neurosci.2014;17(12):1798-1803.

410.Goncalves S, Moreira E, Grosso C, Andrade PB, Valentao P, Romano A. Phenolic profile, antioxidant activity and enzyme inhibitory activities of extracts from aromatic plants used in Mediterranean diet.J Food Sci Technol.2017;54(1):219-227.

411.Nabavi SF, Tenore GC, Daglia M, Tundis R, Loizzo MR, Nabavi SM. The cellular protective effects of rosmarinic acid: from bench to bedside.Curr Neurovasc Res.2015;12(1):98-105.

412.Lee AY, Hwang BR, Lee MH, Lee S, Cho EJ. Perilla frutescens var. japonica and rosmarinic acid improve amyloid-beta25-35 induced impairment of cognition and memory function.Nutrition research and practice.2016;10(3):274-281.

413.Paudel P, Seong SH, Zhou Y, et al. Rosmarinic Acid Derivatives' Inhibition of Glycogen Synthase Kinase-3beta Is the Pharmacological Basis of Kangen-Karyu in Alzheimer's Disease.Molecules (Basel, Switzerland).2018;23(11).

414.Herrlinger KA, Nieman KM, Sanoshy KD, et al. Spearmint Extract Improves Working Memory in Men and Women with Age-Associated Memory Impairment.Journal of alternative and complementary medicine (New York, NY).2018;24(1):37-47.

415.Nieman KM. Tolerance, bioavailability, and potential cognitive health implications of a distinct aqueous spearmint extract.Functional Foods in Health and Disease.2015;5(5):165–187.

416.Wong RH, Howe PR, Bryan J, Coates AM, Buckley JD, Berry NM. Chronic effects of a wild green oat extract supplementation on cognitive performance in older adults: a randomised, double-blind, placebo-controlled, crossover trial.Nutrients.2012;4(5):331-342.

417.Dimpfel W, Storni C, Verbruggen M. Ingested oat herb extract (Avena sativa) changes EEG spectral frequencies in healthy subjects.Journal of alternative and complementary medicine (New York, NY).2011;17(5):427-434.

418.Maggiorani D, Manzella N, Edmondson DE, et al. Monoamine Oxidases, Oxidative Stress, and Altered Mitochondrial Dynamics in Cardiac Ageing.Oxid Med Cell Longev.2017;2017:3017947.

419.Weinreb O, Amit T, Bar-Am O, Youdim MB. Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and beta-amyloid in ageing and Alzheimer's disease.Br J Pharmacol.2016;173(13):2080-2094.

420.Riederer P, Muller T. Use of monoamine oxidase inhibitors in chronic neurodegeneration.Expert opinion on drug metabolism & toxicology.2017;13(2):233-240.

421.Perrinjaquet-Moccetti T, Wullschleger C, Schmidt A, Aydogan C, Kreuter M.Bioactivity-based development of a wild green oat (Avena sativa L.) extract in support of mental health disorders.Vol 272006.

422.Garcia AM, Martinez A, Gil C. Enhancing cAMP Levels as Strategy for the Treatment of Neuropsychiatric Disorders.Current topics in medicinal chemistry.2016;16(29):3527-3535.

423.Heckman PRA, Blokland A, Prickaerts J. From Age-Related Cognitive Decline to Alzheimer's Disease: A Translational Overview of the Potential Role for Phosphodiesterases.Advances in neurobiology.2017;17:135-168.

424.Wong RH, Howe PR, Coates AM, Buckley JD, Berry NM. Chronic consumption of a wild green oat extract (Neuravena) improves brachial flow-mediated dilatation and cerebrovascular responsiveness in older adults.Journal of hypertension.2013;31(1):192-200.

425.Kennedy DO, Jackson PA, Forster J, et al. Acute effects of a wild green-oat (Avena sativa) extract on cognitive function in middle-aged adults: A double-blind, placebo-controlled, within-subjects trial.Nutritional neuroscience.2017;20(2):135-151.

426.Berry NM, Robinson MJ, Bryan J, Buckley JD, Murphy KJ, Howe PR. Acute effects of an Avena sativa herb extract on responses to the Stroop Color-Word test.Journal of alternative and complementary medicine (New York, NY).2011;17(7):635-637.

427.Friedman M. Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion's Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compounds.J Agric Food Chem.2015;63(32):7108-7123.

428.Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial.Phytother Res.2009;23(3):367-372.

429.Brandalise F, Cesaroni V, Gregori A, et al. Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice.Evidence-based complementary and alternative medicine : eCAM.2017;2017:3864340.

430.Tsai-Teng T, Chin-Chu C, Li-Ya L, et al. Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe/PS1dE9 transgenic mice.J Biomed Sci.2016;23(1):49.

431.Mori K, Obara Y, Moriya T, Inatomi S, Nakahata N. Effects of Hericium erinaceus on amyloid beta(25-35) peptide-induced learning and memory deficits in mice.Biomedical research (Tokyo, Japan).2011;32(1):67-72.

432.Misra HS, Rajpurohit YS, Khairnar NP. Pyrroloquinoline-quinone and its versatile roles in biological processes.Journal of biosciences.2012;37(2):313-325.

433.Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone.Alternative medicine review : a journal of clinical therapeutic.2009;14(3):268-277.

434.Harris CB, Chowanadisai W, Mishchuk DO, Satre MA, Slupsky CM, Rucker RB. Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects.J Nutr Biochem.2013;24(12):2076-2084.

435.Zhou XQ, Yao ZW, Peng Y, et al. PQQ ameliorates D-galactose induced cognitive impairments by reducing glutamate neurotoxicity via the GSK-3beta/Akt signaling pathway in mouse.Sci Rep.2018;8(1):8894.

436.Qin J, Wu M, Yu S, et al. Pyrroloquinoline quinone-conferred neuroprotection in rotenone models of Parkinson's disease.Toxicol Lett.2015;238(3):70-82.

437.Yang C, Yu L, Kong L, et al. Pyrroloquinoline quinone (PQQ) inhibits lipopolysaccharide induced inflammation in part via downregulated NF-kappaB and p38/JNK activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice.PLoS One.2014;9(10):e109502.

438.Guan S, Xu J, Guo Y, et al. Pyrroloquinoline quinone against glutamate-induced neurotoxicity in cultured neural stem and progenitor cells.International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience.2015;42:37-45.

439.Zhang Q, Chen S, Yu S, et al. Neuroprotective effects of pyrroloquinoline quinone against rotenone injury in primary cultured midbrain neurons and in a rat model of Parkinson's disease.Neuropharmacology.2016;108:238-251.

440.Kim J, Harada R, Kobayashi M, Kobayashi N, Sode K. The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein.Molecular neurodegeneration.2010;5:20.

441.Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins.Prion.2010;4(1):26-31.

442.Kobayashi M, Kim J, Kobayashi N, et al. Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein.Biochemical and biophysical research communications.2006;349(3):1139-1144.

443.Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells.Neurosci Lett.2009;464(3):165-169.

444.Yamaguchi K, Sasano A, Urakami T, Tsuji T, Kondo K. Stimulation of nerve growth factor production by pyrroloquinoline quinone and its derivatives in vitro and in vivo.Bioscience, biotechnology, and biochemistry.1993;57(7):1231-1233.

445.Urakami T, Tanaka A, Yamaguchi K, Tsuji T, Niki E. Synthesis of esters of coenzyme PQQ and IPQ, and stimulation of nerve growth factor production.BioFactors (Oxford, England).1995;5(3):139-146.

446.Murase K, Hattori A, Kohno M, Hayashi K. Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes.Biochemistry and molecular biology international.1993;30(4):615-621.

447.Liu S, Li H, Ou Yang J, et al. Enhanced rat sciatic nerve regeneration through silicon tubes filled with pyrroloquinoline quinone.Microsurgery.2005;25(4):329-337.

448.Li HH, Liu SQ, Peng H, Zhang N. Pyrroloquinoline quinone enhances regeneration of transected sciatic nerve in rats.Chinese journal of traumatology = Zhonghua chuang shang za zhi / Chinese Medical Association.2005;8(4):225-229.

449.Ohwada K, Takeda H, Yamazaki M, et al. Pyrroloquinoline Quinone (PQQ) Prevents Cognitive Deficit Caused by Oxidative Stress in Rats.Journal of clinical biochemistry and nutrition.2008;42:29-34.

450.Itoh Y, Hine K, Miura H, et al. Effect of the Antioxidant Supplement Pyrroloquinoline Quinone Disodium Salt (BioPQQ) on Cognitive Functions.Adv Exp Med Biol.2016;876:319-325.

451.Nakano M, Murayama Y, Hu L, Ikemoto K, Uetake T, Sakatani K. Effects of Antioxidant Supplements (BioPQQ) on Cerebral Blood Flow and Oxygen Metabolism in the Prefrontal Cortex.Adv Exp Med Biol.2016;923:215-222.

452.Srivastava S. Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders.Clinical and translational medicine.2016;5(1):25.

453.Stein LR, Imai S. The dynamic regulation of NAD metabolism in mitochondria.Trends in endocrinology and metabolism: TEM.2012;23(9):420-428.

454.Mendelsohn AR, Larrick JW. The NAD+/PARP1/SIRT1 Axis in Aging.Rejuvenation research.2017;20(3):244-247.

455.Imai S, Guarente L. NAD+ and sirtuins in aging and disease.Trends Cell Biol.2014;24(8):464-471.

456.Kulikova V, Shabalin K, Nerinovski K, et al. Generation, Release, and Uptake of the NAD Precursor Nicotinic Acid Riboside by Human Cells.The Journal of biological chemistry.2015;290(45):27124-27137.

457.Yang Y, Sauve AA. NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy.Biochim Biophys Acta.2016;1864(12):1787-1800.

458.Elhassan YS, Philp AA, Lavery GG. Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule.Journal of the Endocrine Society.2017;1(7):816-835.

459.Matasic DS, Brenner C, London B. Emerging potential benefits of modulating NAD(+) metabolism in cardiovascular disease.American journal of physiology Heart and circulatory physiology.2018;314(4):H839-h852.

460.Yoshino J, Baur JA, Imai SI. NAD(+) Intermediates: The Biology and Therapeutic Potential of NMN and NR.Cell metabolism.2018;27(3):513-528.

461.Dellinger RW, Santos SR, Morris M, et al. Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD(+) levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.NPJ aging and mechanisms of disease.2017;3:17.

462.Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models.Neurobiol Aging.2013;34(6):1581-1588.

463.Hou Y, Lautrup S, Cordonnier S, et al. NAD(+) supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency.Proceedings of the National Academy of Sciences of the United States of America.2018;115(8):E1876-e1885.

464.Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice.Science (New York, NY).2016;352(6292):1436-1443.

465.Khan NA, Auranen M, Paetau I, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.EMBO molecular medicine.2014;6(6):721-731.

466.Singh A, Kumar A. Microglial Inhibitory Mechanism of Coenzyme Q10 Against Abeta (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations.Frontiers in pharmacology.2015;6:268.

467.Bhardwaj M, Kumar A. Neuroprotective mechanism of Coenzyme Q10 (CoQ10) against PTZ induced kindling and associated cognitive dysfunction: Possible role of microglia inhibition.Pharmacological reports : PR.2016;68(6):1301-1311.

468.Yamagishi K, Ikeda A, Moriyama Y, et al. Serum coenzyme Q10 and risk of disabling dementia: the Circulatory Risk in Communities Study (CIRCS).Atherosclerosis.2014;237(2):400-403.

469.Kure CE, Rosenfeldt FL, Scholey AB, et al. Relationships Among Cognitive Function and Cerebral Blood Flow, Oxidative Stress, and Inflammation in Older Heart Failure Patients.Journal of cardiac failure.2016;22(7):548-559.

470.Li Z, Wang P, Yu Z, et al. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson's disease.European neurology.2015;73(3-4):205-211.

471.Dumont M, Kipiani K, Yu F, et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease.J Alzheimers Dis.2011;27(1):211-223.

472.Hickey MA, Zhu C, Medvedeva V, Franich NR, Levine MS, Chesselet MF. Evidence for behavioral benefits of early dietary supplementation with CoEnzymeQ10 in a slowly progressing mouse model of Huntington's disease.Molecular and cellular neurosciences.2012;49(2):149-157.

473.Bharti VK, Malik JK, Gupta RC. Chapter 52 - Ashwagandha: Multiple Health Benefits. In: Gupta RC, ed.Nutraceuticals.Boston: Academic Press; 2016:717-733.

474.Dar NJ, MuzamilAhmad. Neurodegenerative diseases and Withania somnifera (L.): An update.Journal of ethnopharmacology.2020;256:112769.

475.Choudhary D, Bhattacharyya S, Bose S. Efficacy and Safety of Ashwagandha (Withania somnifera (L.) Dunal) Root Extract in Improving Memory and Cognitive Functions.Journal of dietary supplements.2017;14(6):599-612.

476.Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, Jindal R. Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder.The Journal of clinical psychiatry.2013;74(11):1076-1083.

477.Birla H, Keswani C, Rai SN, et al. Neuroprotective effects of Withania somnifera in BPA induced-cognitive dysfunction and oxidative stress in mice.Behavioral and brain functions : BBF.2019;15(1):9.

478.Ahmed ME, Javed H, Khan MM, et al. Attenuation of oxidative damage-associated cognitive decline by Withania somnifera in rat model of streptozotocin-induced cognitive impairment.Protoplasma.2013;250(5):1067-1078.

479.Pandey A, Bani S, Dutt P, Kumar Satti N, Avtar Suri K, Nabi Qazi G. Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction.Cytokine.2018;102:211-221.

480.Vallée M. Neurosteroids and potential therapeutics: Focus on pregnenolone.J Steroid Biochem Mol Biol.2016;160:78-87.

481.Smith CC, Gibbs TT, Farb DH. Pregnenolone sulfate as a modulator of synaptic plasticity.Psychopharmacology.2014;231(17):3537-3556.

482.Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G. The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation.J Biol Chem.2019;294(12):4596-4607.

483.Abdel-Hafiz L, Chao OY, Huston JP, et al. Promnestic effects of intranasally applied pregnenolone in rats.Neurobiology of learning and memory.2016;133:185-195.

484.Vallée M, Mayo W, Darnaudéry M, et al. Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus.Proc Natl Acad Sci U S A.1997;94(26):14865-14870.

485.Kreinin A, Bawakny N, Ritsner MS. Adjunctive Pregnenolone Ameliorates the Cognitive Deficits in Recent-Onset Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Trial.Clin Schizophr Relat Psychoses.2017;10(4):201-210.

486.Ritsner MS, Gibel A, Shleifer T, et al. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial.The Journal of clinical psychiatry.2010;71(10):1351-1362.

487.Horowitz AM, Fan X, Bieri G, et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain.Science (New York, NY). 2020;369(6500):167-173.

488.Chandrika UG, Prasad Kumarab PA. Gotu Kola (Centella asiatica): Nutritional Properties and Plausible Health Benefits.Advances in food and nutrition research.2015;76:125-157.

489.Chaisawang P, Sirichoat A, Chaijaroonkhanarak W, et al. Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy.PLoS One.2017;12(7):e0180650.

490.Umka Welbat J, Sirichoat A, Chaijaroonkhanarak W, et al. Asiatic Acid Prevents the Deleterious Effects of Valproic Acid on Cognition and Hippocampal Cell Proliferation and Survival.Nutrients.2016;8(5).

491.Hamid K, Ng I, Tallapragada VJ, et al. An Investigation of the Differential Effects of Ursane Triterpenoids from Centella asiatica, and Their Semisynthetic Analogues, on GABAA Receptors.Chem Biol Drug Des.2016;88(3):386-397.

492.Xu MF, Xiong YY, Liu JK, Qian JJ, Zhu L, Gao J. Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells.Acta Pharmacol Sin.2012;33(5):578-587.

493.Nagoor Meeran MF, Goyal SN, Suchal K, Sharma C, Patil CR, Ojha SK. Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise.Frontiers in pharmacology.2018;9(892).

494.Matthews DG, Caruso M, Murchison CF, et al. Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice.Antioxidants (Basel, Switzerland).2019;8(12).

495.Chiroma SM, Baharuldin MTH, Mat Taib CN, et al. Protective Effects of Centella asiatica on Cognitive Deficits Induced by D-gal/AlCl(3) via Inhibition of Oxidative Stress and Attenuation of Acetylcholinesterase Level.Toxics.2019;7(2).

496.Veerendra Kumar MH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats.Journal of ethnopharmacology.2002;79(2):253-260.

497.Chiroma SM, Hidayat Baharuldin MT, Mat Taib CN, et al. Protective effect of Centella asiatica against D-galactose and aluminium chloride induced rats: Behavioral and ultrastructural approaches.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.2019;109:853-864.

498.Gray NE, Harris CJ, Quinn JF, Soumyanath A. Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice.Journal of ethnopharmacology.2016;180:78-86.

499.Wattanathorn J, Mator L, Muchimapura S, et al. Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica.Journal of ethnopharmacology.2008;116(2):325-332.

500.Puttarak P, Dilokthornsakul P, Saokaew S, et al. Effects of Centella asiatica (L.) Urb. on cognitive function and mood related outcomes: A Systematic Review and Meta-analysis.Sci Rep.2017;7(1):10646.

501.Tan BL, Norhaizan ME. Carotenoids: How Effective Are They to Prevent Age-Related DiseasesMolecules (Basel, Switzerland).2019;24(9):1801.

502.Mewborn CM, Terry DP, Renzi-Hammond LM, Hammond BR, Miller LS. Relation of Retinal and Serum Lutein and Zeaxanthin to White Matter Integrity in Older Adults: A Diffusion Tensor Imaging Study.Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.2018;33(7):861-874.

503.Christensen K, Gleason CE, Mares JA. Dietary carotenoids and cognitive function among US adults, NHANES 2011-2014.Nutritional neuroscience.2020;23(7):554-562.

504.Araki A, Yoshimura Y, Sakurai T, et al. Low intakes of carotene, vitamin B2 , pantothenate and calcium predict cognitive decline among elderly patients with diabetes mellitus: The Japanese Elderly Diabetes Intervention Trial.Geriatrics & gerontology international.2017;17(8):1168-1175.

505.Mewborn CM, Lindbergh CA, Robinson TL, et al. Lutein and Zeaxanthin Are Positively Associated with Visual-Spatial Functioning in Older Adults: An fMRI Study.Nutrients.2018;10(4).

506.Yuan C, Fondell E, Ascherio A, et al. Long-Term Intake of Dietary Carotenoids Is Positively Associated with Late-Life Subjective Cognitive Function in a Prospective Study in US Women.J Nutr.2020;150(7):1871-1879.

507.Ceravolo SA, Hammond BR, Oliver W, Clementz B, Miller LS, Renzi-Hammond LM. Dietary Carotenoids Lutein and Zeaxanthin Change Brain Activation in Older Adult Participants: A Randomized, Double-Masked, Placebo-Controlled Trial.Mol Nutr Food Res.2019;63(15):1801051.

508.Power R, Coen RF, Beatty S, et al. Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.J Alzheimers Dis.2018;61(3):947-961.

509.Hammond BR, Jr., Miller LS, Bello MO, Lindbergh CA, Mewborn C, Renzi-Hammond LM. Effects of Lutein/Zeaxanthin Supplementation on the Cognitive Function of Community Dwelling Older Adults: A Randomized, Double-Masked, Placebo-Controlled Trial.Frontiers in aging neuroscience.2017;9:254.

510.Ghossein N, Kang M, Lakhkar A. Anticholinergic Medications. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK555893/. Accessed October 19, 2020.

511.Weigand AJ, Bondi MW, Thomas KR, et al. Association of anticholinergic medications and AD biomarkers with incidence of MCI among cognitively normal older adults.Neurology. 2020;95(16):e2295.