Can Healthy Diets,Regular Exercise,and Better Lifestyle Delay the Progression of Dementia in Elderly Individuals?

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of total AD patients can be explained by genetic mutations in APP, PS1, and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state.

Keywords

Alzheimer’s disease amyloid-beta antioxidant enriched diet healthcare cost healthy diets mitochondria phosphorylated tau reactive oxygen species regular exercise

1 INTRODUCTION

In 1906, the German physician Alois Alzheimer discovered brain shrinkage and abnormal protein deposits surrounding nerve cells during his patient’s autopsy. His patient Auguste D., had profound memory loss, unfounded suspicions about her family, and other psychological changes. This initial description of Dr. Alzheimer’s abnormal protein deposits is now referred to as amyloid deposits.

By identifying the hallmarks of the patient’s condition, Alzheimer was given the honor of having Alzheimer’s disease (AD) named after him in 1910 [1]. In conducting biochemical analysis of AD brains in 1984, George Glenner and Caine Wong identified amyloid-β (Aβ) as a major hallmark of AD [2]. In 1986, Montejo de Garcini and colleagues identified an additional hallmark of AD, a phosphorylated form of the cytoskeletal protein tau [3, 4].

AD is characterized by cognitive impairment and age-dependent memory loss, and it is pathologically characterized by Aβ plaques and intracellular neurofibrillary tangles (NFTs). Only 1-2% of early-onset familial AD can be explained by gene mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) [5]. Risk factors for late-onset AD include the apolipoprotein E gene allele 4 (ApoE4) genotype and a variation in the sortilin-related receptor 1 gene [6]. Aging is the primary risk factor for AD; studies have shown diet and environmental factors play major factors in the progression of AD. By 2050, 50% of individuals 85 years or older will be afflicted by AD [5]. With this increase in incidence rates of AD, world-wide healthcare costs for individuals with AD were estimated to hit the trillion-dollar marker by 2018.

Many brain regions are implicated in AD, including the entorhinal cortex, the fronto-parietal cortex, the hippocampus, the temporal cortex, and sub-cortical nuclei. These sites are subjected to synaptic loss, synaptic damage, and mitochondrial dysfunctions during early stages of AD [5]. Other cellular changes include the formation and accumulation of Aβ peptides and Aβ plaques, hyperphosphorylation of the tau protein, and NFTs [7 –11]. Studies have found that the loss of synapses in the brain and corresponding damage in these brain regions are the best correlation of cognitive impairment in AD [10].

During early stages of disease progression, the patient with AD is still able to function independently and participate in social activities but may suffer from memory lapses [12]. In the middle stage of AD progression, symptoms become noticeable, affecting mood and increased memory impairment [12]. The middle stage of AD progression can last many years before a patient dies. During late stages of AD, affected individuals become less responsive to their environment and have increased cognitive impairment in speech and memory as well as increased motor impairment [12].

Statistics of AD show that women are at a higher lifetime risk for developing AD, making up to two-thirds of the afflicted population [12]. Studies of mouse models of AD show that this increased risk correlates with increased levels of Aβ in female mice brains [13]. Similarly, studies of postmortem brains of females with AD show increased levels of Aβ compared to males. However, some research suggests the AD risk increases in postmenopausal women due to dysfunctions in serotonin neurons from the absence of estradiol [14].

While the greatest risk of late-onset AD is aging, family history, and genetic susceptibility, these are non-modifiable. Many studies suggest that environmental factors play a role in the progression of AD. This article investigates various modifiable lifestyle factors and their roles in dementia and AD progression.

2 CAUSAL FACTORS OF ALZHEIMER’S DISEASE

Early-onset familial AD (FAD) accounts for about 1-2% of total AD cases, and mutations in APP, PS1, and PS2 loci cause AD in an autosomal dominant fashion. Causal factors of most late-onset AD are still unknown [5]. Mutations in APP are causal factors of FAD and are involved in the increased production of all types Aβ peptides [15]. PS1, when mutated, is involved in γ-secretase and the increased production of Aβ_1 - 42 [16]. Mutations in PS2 are causal factors of FAD and, like PS1, are shown to be involved in γ-secretase activity and the increased production of Aβ_1 - 42 [17].

Genes involved in late sporadic onset of AD are the ApoE4 genotype, sortilin related receptor, clusterin, and complement component receptor 1. The apolipoprotein E allele 4, a E4 polymorphism, is a risk factor for late-onset AD and is involved in the increased production of Aβ [18]. Mutation of the sortilin-related receptor is also involved in the increased production of Aβ [19]. Clusterin, a protein expressed abundantly in the brain, is involved in the clearing of Aβ from brain to plasma. However, in patients with late-onset AD, clusterin re-enters the brain and dysfunctionally cause a decrease in Aβ clearance [19, 20]. Complement component receptor 1 is involved in the clearance of Aβ, but variants of the protein can interfere with the clearance of Aβ [20, 21].

2.1 Aβ production and its toxicity in AD

Amyloid plaques are primarily comprised of Aβ. Aβ is produced from the faulty processing of amyloid-β protein precursor (AβPP) in AD neurons. There are two pathways in which this occurs: amyloidogenic and non-amyloidogenic. In the amyloidogenic pathway, AβPP undergoes processing by β- and γ-secretase, resulting in Aβ. In the non-amyloidogenic pathway, cleavage occurs by a secretase within in Aβ domain, preventing it from forming the full Aβ [22]. Mutations in APP, PS1, and PS2 genes activate β- and γ-secretase and cause the production of Aβ in early-onset AD [5, 8]. In late-onset AD, oxidative stress is suggested to activate β-secretase and to cause abnormal processing of Aβ [5]. Studies using transgenic AD mouse lines have found that over time, Aβ production and deposits increase age-dependently. Similarly, studies of postmortem brains of elderly patients with AD and patients with mild cognitive impairment (MCI) have found an age-dependent increase in Aβ levels [23]. Strong evidence suggests that aging has a role in the production and deposit of Aβ in the brains of AD patients and in transgenic AD mice.

While it is generally accepted that extracellular Aβ deposits are byproducts of AD pathology, recent research has focused on Aβ toxicity operating intracellularly. Studies show that intracellular Aβ is present in AD-affected brain regions and contribute to fibrillogenesis and Aβ deposit formation [23 –25].

Intracellular sites—including the Golgi apparatus, endoplasmic reticulum, endosomal–lysosomal systems, and multi-vesicular bodies—contain Aβ in AD progression, wherever AβPP β- and γ-secretases are present [7]. A large body of research shows that Aβ accumulates in cellular compartments at toxic levels and interfere with normal cell functioning [7]. These findings suggest that Aβ plays a critical role in the disease progression of AD.

2.2 Phosphorylated tau toxicity

Tau was found to be a microtubule-associated protein (MAP) [26] that stimulates tubulin assembly into microtubules in the brain. Subsequent research implicated tau in the formation of paired helical filaments (PHFs) and NFTs in the AD brain [27 –29]. The tau gene encodes six tau isoforms in the adult human brain; each isoform has a specific physiological role as a result of being differentially expressed during development and activation of the microtubule assembly [30 –32].

Tau may owe its differential consequences to its ability to readily bind microtubules. This ability likely results in microtubule instability [25 –35]. However, tau can negatively compete with the motor protein kinesin to bind to microtubules, leading to reduced axonal transport [33 –35]. Tau undergoes many post-translational modifications, including phosphorylation, glycosylation, ubiquitination, glycation, poly-amination, nitration, truncation, and aggregation. In 1977, tau has been found to be a phosphoprotein and its phosphorylation has been found to negatively promote the assembly of microtubules [36, 37]. Hyperphosphorylation of tau has been found to play a large role in AD progression.

Tau phosphorylation has different biological and pathological roles, depending on its site. Phosphorylated tau at Ser262, Thr231, and Ser235 inhibits its binding to microtubules by ∼35%, ∼25%, and ∼10%, respectively, according to a quantitative in vitro study [38]. Kinetic studies in vitro suggest that binding between hyperphosphorylated tau and normal tau suggest that Ser199/Ser202/Thr205, Thr212, Thr231/Ser235, Ser262/Ser356, and Ser422 are critical phosphorylation sites that convert tau to an inhibitory molecule that isolates normal microtubule-associated proteins from microtubules [39]. Phosphorylation at Thr231, Ser396, and Ser422 promotes self-aggregation of tau into microfilaments. When Ser422 is mutated into Glu, it increases its tendency to aggregate [40]. These findings show that tau phosphorylation at various sites impacts its activity and aggregation.

While PHF tau inhibits the stimulation of microtubules, the absence of the overt phenotype of tau in knockout transgenic mice suggests that dysfunctions from tau hyperphosphorylation may not be sufficient to lead to neurodegeneration [41 –43]. Rather, both the abnormally hyperphosphorylated tau isolated from the AD brain and the in vitro hyperphosphorylated tau gain a toxic ability to sequester normal tau and other MAPs, such as MAP1 and MAP2, resulting in microtubule disassembly [44].

When tau is phosphorylated, lose its ability to bind to microtubules and not able to support axonal transport effectively, leading to synaptic starvation, synaptic damage, and neuronal dysfunction. On the other hand, when tau is dephosphorylated, it maintains normal functions [44 –47].

The specific molecular basis of hyperphosphorylated tau toxicity is yet to be thoroughly researched. While early studies show a correlation across the number of NFTs in the brain, the severity of dementia, and the extent of neurodegeneration due to tau aggregation [48 –50], studies suggest that unpolymerized abnormal tau, rather than highly polymerized PHFs, are toxic. A correlational study conducted on biopsied human brain tissue showed no relationship between microtubule attenuation in AD/aging and tau filament formation [51].

In an in vitro study of phosphorylated tau, polymerization of hyperphosphorylated tau into PHFs was found to eliminate its toxic activity to sequester other MAPs [52]. Therefore, NFTs may be viewed as a marker of AD rather than a main cause of neurodegeneration, just as Aβ plaques have been viewed recently as byproduct of disease process rather than causing disease. Polymerization of toxic abnormal tau into PHFs and NFTs could even be regarded as a neuronal defense mechanism to decrease the toxicity of the abnormally hyperphosphorylated tau. This phenomenon has been found to occur in other diseases characterized by abnormal protein aggregates, such as Huntington disease and cardiomyopathy. In these cases, the abnormal non-fibrillar protein oligomers, instead of the protein aggregates themselves, appear to be pathogenic [53 –55].

While tau is well researched in AD pathology, small amounts of tau exist in normal physiological conditions in dendrites and dendritic spines yet its functions are not extensively studied [56]. Tau is shown to interact with several cellular proteins such as tubulin, F-actin, and Src family kinases as well play a major role in mediating alterations in the cytoskeletal structure of dendrites and spines as well as synaptic scaffold and signaling [57]. Further, synaptic plasticity is impaired in Tau-KO animals while tau phosphorylation in specific epitopes is shown to play a major role in synaptic plasticity [58, 59]. Analysis shows that the phosphorylation of tau is modulated through NMDA receptor activation and is suggested to oscillate between phosphorylated and non-phosphorylated states in dendritic sites [60]. A recent study provides evidence that physiological neuronal activity activates local translation and phosphorylation of tau [61]. Overall the data suggest that tau in dendritic compartments is involved in normal physiological synaptic functions.

2.3 Synaptic damage

Healthy synapse terminals transmit signals between cells to process information. However, during aging, the number of synapses and their transmission of signals decrease significantly [62 –64]. This phenomenon has been documented in different brain regions of elderly individuals and signs of an aging brain.

In a study of synaptic loss, postmortem brain samples were taken from the cerebellum (unaffected in AD) and the hippocampus (affected in AD) of adult and elderly patients with and without AD. The synapse-to-neurons ratio varied in the samples taken from the cerebellum of the adult and elderly persons without AD and of elderly AD patients. There were no significant differences in the synapse-to-neuron ratio in the samples taken from the cerebellum of AD and non-AD persons, but there was more than a 50% decrease in the synapse-to-neuron ratio in the sample from the hippocampus of persons with AD and without AD [64]. In several studies that investigated the extent that synaptic loss correlates with cognitive decline in elderly persons with AD, researchers found a 25–30% decrease in cortical synapses and a 15–35% decrease in the synapses per cortical neuron, suggesting that synaptic loss in AD contributes more to cognitive decline than other pathological hallmarks of AD [65, 66].

2.4 Mitochondrial dysfunction

The brain, among other organs, is especially vulnerable to oxidative stress due to its high lipid content, its relatively high oxygen metabolism and its low levels of antioxidant defenses [67]. Mitochondrial oxidative stress is shown to occur early in the progression of AD, before the Aβ deposits are detected [68 –71]. Oxidative stress was reported in the mitochondria of the brain in patients with AD and of AD transgenic mice.

Mitochondrial abnormalities have been found in AD brains, specifically neurons and astrocytes, suggesting that both might be damaged by free radicals [70 , 73]. Superoxide radicals ( $O_{2}^{•}$ ) are thought to be produced in the mitochondrial electron transport chain (ETC) complexes I and III and in components of the TCA cycle, including a-ketoglutarate dehydrogenase [67 , 75]. H₂O₂ and $O_{2}^{•}$ from the mitochondrial matrix and from the inner and outer mitochondrial membranes might be carried to the cytoplasm and may ultimately lead to oxidation of cytoplasmic proteins [67]. Lower levels of three mitochondrial enzymes—alpha ketoglutarate dehydrogenase complex, pyruvate dehydrogenase complex, and cytochrome oxidase—have been reported in AD brain [76].

Synaptic mitochondria are synthesized in the cell body of the neurons and are then transported from the axon or dendrite for cellular energy demands [77, 78], a process known as mitochondrial trafficking [79]. When the mitochondria localized in the cell body are damaged or degraded they might be transported to synaptic terminals by natural mitochondrial trafficking, where they produce lower levels of ATP.

Synaptic terminals require high levels of cellular ATP for multiple synaptic functions, including synaptic transmission for neurotransmitter exocytosis, the potentiation of neurotransmitter release, synaptic growth. Additionally. synaptic terminals require mitochondria for isolating and releasing Ca^2 + for post-tetanic potentiation [80]. Increased levels of efficient mitochondria are necessary in transporting to synaptic terminals. Synaptic mitochondria may be older than cell-body mitochondria and, thus, may be subject to more damage by oxidative stress [81]. The increased damage of synaptic mitochondria is hypothesized to affect neurotransmission and, ultimately, cause cognitive decline in AD patients.

2.5 Diet

It is well established that healthy diet reduces risk of developing dementia and even delaying progression of dementia in elderly individuals [82 –84]. Antioxidant enriched Mediterranean diet (MeDi) has shown beneficial effects against dementia and chronic diseases.

Several studies link nutrition and aging, affecting blood flow, atherosclerosis and arterial plaque formation, inflammation, and mitochondrial dysfunction reactive oxygen species (ROS) buildup in the brain [82 –84]. Researchers have studied the effectiveness of MeDi on neurodegenerative diseases. MeDi is characterized by a high intake of fruits, vegetables, monounsaturated fatty acids, fish legumes, whole grains, and nuts. Moderate alcohol consumption and a low intake of dairy, red meat, saturated fats, and refined grains are encouraged as well [85]. MeDi is thought to have protective effects from the combination of monounsaturated fatty acids and polyphenols from olive oil, polyunsaturated fatty acids from fish, and the antioxidants from fruit, vegetables, and wine [86]. Epidemiological and clinical studies have found that populations subjected to MeDi are at a lower risk of developing neurodegenerative disorders, based on research of the effects of MeDi (Table 1) [120–124 , 131–136].

Table 1
Summary of Mediterranean diet in elderly individuals

Study Number of Subjects Follow up/Duration Main Outcome Measurement Result

Scarmeas et al. [120] 2,258-non-demented 65 years &above 4 years AD incidence Higher adherence to MeDi is associated with lower AD risk

Scarmeas et al. [121] 194 AD, 1,790 non-demented 65 years and above 8.1 years AD incidence Higher adherence to MeDi is associated with lower AD risk

Psaltopoulou et al. [122] 732 non-demented, 60 years and above 8 years MMSE MeDI, MUFA, SFA, and olive oil consumption weakly improve cognitive functions

Scarmeas et al. [123] 1,880 non demented, 65 years and above 4.5 years MCI and AD incidence Higher adherence to MeDi is associated with reduced MCI and AD risk

Scarmeas et al. [124] 2,258 non-demented 65 years &above 5.4 years AD incidence Both higher adherence to MeDI higher physical activity are independently associated with AD risk

Feart et al. 3-city cohort [125] 1,410 non-demented 65 years and above 5 years AD incidence Higher adherence to MeDi is not associated with lower AD risk

Gu et al. [126] 1,219 non-demented 65 years and above 4 years AD incidence Higher adherence to MeDI is associated with lower AD risk

Roberts et al. [127] 329 MCI and 1,640 non-demented, 70–89 years 2.2 years MCI and AD incidence Higher adherence to MeDi is associated with lower MCI and lower AD risk

Tangney et al. [128] 3,790 non-demented, 65 years and above 7.6 years MMSE, SDMT Higher adherence to MeDi is related to slower rates of cognitive decline

Vercambre et al. [129] 2,504 non-demented 65 years and above 5.4 years TICS, delayed recall Higher adherence to MeDi is not associated with cognitive changes

Cherbuin et al. [130] 1,528 non-demented 60–64 years 4 years MCI incidence Higher adherence to MeDi is not associated with lower MCI risk

Chan et al. [131] n = 877 * Community Screening Instrument for Dementia Higher adherence to MeDi was associated with lower risk of cognitive impairment

Samieri et al. [132] 16,058 non-demented 70 years and above 6 years TICS, delayed recall Long-term MeDI is associated with improved global cognitive function and verbal memory

Ye et al. [133] n = 1,269 12 months MMSE Higher adherence to MeDi was associated with lower risk of cognitive impairment

Corley et al. [134] n = 882 * NART &WTAR Higher adherence to MeDi was associated with higher cognitive performance

Koyama et al. [135] n = 2,326 8 years MMSE Higher adherence to MeDi was associated with higher cognitive performance (in black adults only)

Olsson et al. [136] n = 564 12 years Cognitive dysfunction outcomes Higher adherence to MeDi was associated with reduced cognitive dysfunction

Study	Number of Subjects	Follow up/Duration	Main Outcome Measurement	Result
Scarmeas et al. [120]	2,258-non-demented 65 years &above	4 years	AD incidence	Higher adherence to MeDi is associated with lower AD risk
Scarmeas et al. [121]	194 AD, 1,790 non-demented 65 years and above	8.1 years	AD incidence	Higher adherence to MeDi is associated with lower AD risk
Psaltopoulou et al. [122]	732 non-demented, 60 years and above	8 years	MMSE	MeDI, MUFA, SFA, and olive oil consumption weakly improve cognitive functions
Scarmeas et al. [123]	1,880 non demented, 65 years and above	4.5 years	MCI and AD incidence	Higher adherence to MeDi is associated with reduced MCI and AD risk
Scarmeas et al. [124]	2,258 non-demented 65 years &above	5.4 years	AD incidence	Both higher adherence to MeDI higher physical activity are independently associated with AD risk
Feart et al. 3-city cohort [125]	1,410 non-demented 65 years and above	5 years	AD incidence	Higher adherence to MeDi is not associated with lower AD risk
Gu et al. [126]	1,219 non-demented 65 years and above	4 years	AD incidence	Higher adherence to MeDI is associated with lower AD risk
Roberts et al. [127]	329 MCI and 1,640 non-demented, 70–89 years	2.2 years	MCI and AD incidence	Higher adherence to MeDi is associated with lower MCI and lower AD risk
Tangney et al. [128]	3,790 non-demented, 65 years and above	7.6 years	MMSE, SDMT	Higher adherence to MeDi is related to slower rates of cognitive decline
Vercambre et al. [129]	2,504 non-demented 65 years and above	5.4 years	TICS, delayed recall	Higher adherence to MeDi is not associated with cognitive changes
Cherbuin et al. [130]	1,528 non-demented 60–64 years	4 years	MCI incidence	Higher adherence to MeDi is not associated with lower MCI risk
Chan et al. [131]	n = 877	*	Community Screening Instrument for Dementia	Higher adherence to MeDi was associated with lower risk of cognitive impairment
Samieri et al. [132]	16,058 non-demented 70 years and above	6 years	TICS, delayed recall	Long-term MeDI is associated with improved global cognitive function and verbal memory
Ye et al. [133]	n = 1,269	12 months	MMSE	Higher adherence to MeDi was associated with lower risk of cognitive impairment
Corley et al. [134]	n = 882	*	NART &WTAR	Higher adherence to MeDi was associated with higher cognitive performance
Koyama et al. [135]	n = 2,326	8 years	MMSE	Higher adherence to MeDi was associated with higher cognitive performance (in black adults only)
Olsson et al. [136]	n = 564	12 years	Cognitive dysfunction outcomes	Higher adherence to MeDi was associated with reduced cognitive dysfunction

*utilized questionnaire based on past dietary choices, duration not specified. AD, Alzheimer’s disease; MCI, mild cognitive impairment; MeDi, Mediterranean diet; MMSE, Mini-Mental State Examination; MUFA, monounsaturated fatty acids; NART, National Adult Reading Test; SDMT, Symbol Digit Modalities Test; SFA, saturated fatty acids; TICS, Telephone Interview for Cognitive Status; WTAR, Wechsler Test of Adult Reading.

Antioxidant intake and diet supplementation has been linked to improved cognitive functioning and lower levels of Aβ. Antioxidants, such as vitamin C, vitamin E, Beta carotene, ginkgo biloba, melatonin, curcumin, CoQ10, lipoic acid, N-acetyl-1-cysteine, catalase mimetic, ferulic acid, Zeolite supplementation, and others, have been studied to investigate their effects on AD progression [137–142 , 144–167].

Studies using mouse models of AD have shown improved cognitive behavior and reduced Aβ pathology, when the mice were fed with antioxidant supplemented diet (Table 2) [137–142 , 144–167]. These mouse model studies have shown reduced levels of Aβ, phosphorylated tau, reduced mitochondrial abnormalities, reduced inflammatory responses and improved cognitive behavior. Overall, antioxidant supplemented diet has shown strong positive effects against AD pathologies.

Table 2

Summary of antioxidant enriched diet supplements in mouse models of Alzheimer’s disease

Transgenic Line	Antioxidant	Treatment Period	Major Findings	Reference
Tg2576	Melatonin	Not available	Melatonin partially inhibited the expected time-dependent elevation of Aβ	Matsubara et al. [137]
Tg2576	Ginkgo Biloba	6 months	Blocked age-dependent spatial cognition; no change in Aβ levels	Stackman et al. [138]
Tg2576	Vitamin E	4 weeks	Reduced learning deficits; reduced lipid peroxidation levels	Conte et al. [139]
APP 695 Tg	Melatonin	4 months	Melatonin partially inhibited learning and memory deficits; decreased choline acetyltransferase activity	Feng et al. [140]
Tau	Vitamin E	Not available	Delayed development of tau pathology, which correlated with improvement in the health and attenuation of moto weakness	Nakashima et al. [141]
Tg2576	Vitamin E	8 months-mid groups; 6 months-older groups	Reduced Aβ and lipid peroxidation; reduced lipid peroxidation	Sung et al. [142]
Tg2576	Melatonin	4 months	No change in Aβ level	Quinn et al. [143]
PS1 I.235P	CoQ10	60 days	Attenuated Aβ pathology; reduced MDA levels; upregulated SOD activity	Yang et al. [144]
APP	R-lipoic acid	10 months	Reduced oxidative modifications; no change in Aβ levels	Siedlak et al. [145]
ApoE4	R-lipoic acid Acetyl-1-carnitine	Not available	Improved spatial and temporal memory	Shenk et al. [146]
APP/PS1	Vitamin C	Not available	Improved cognitive behavior; no change in amyloid pathology	Harrison et al. [147]
NSE/APP	Lipoic acid exercise	16 weeks	No change in Aβ; ameliorated spatial learning and memory deficits	Cho et al. [148]
APP/PS1	Melatonin	1 Month	Increased mitochondrial function	Dragicevic et al. [149]
APP	Vitamin C	6 months	Reduced Aβ oligomers; reduced tau phosphorylation; reduced oxidative stress	Murakami et al. [150]
Tg19959	CoQ10	5 months	Improved cognitive behavior; reduced Aβ pathology	Dumont et al. [151]
3XAD. Tg	MitoQ	5 months	Prevented cognitive decline, oxidative stress, Aβ accumulation, synaptic loss, and caspase activation	McManus et al. [152]
3XAD.Tg	Melatonin + exercise	6 months	Protected against cognitive impairment, oxidative stress and mtDNA changes	Garcia-Mesa et al. [153]
3XAD.Tg	Catalase mimetic	5 months	Protected against oxidative stress, DNA, and protein oxidation; reduced Aβ and tau phosphorylation	Clausen et al. [154]
APP/PS1	Melatonin	Long-term	Reduced hippocampal protein oxidation; improved cognitive behavior	Baño Otalora et al. [155]
APP/PS1	Ferulic acid	6 months	Enhanced novel object recognition; reduced amyloid deposition, and inflammation	Yan et al. [156]
APP/PS1	Pyrrolyl alpha nitronyl nitroxide	1 month	Improved spatial learning and memory; reduced astrocyte activation, Aβ pathology and tau phosphorylation	Shi et al. [157]
APP/PS1	Zeolite supplementation	5 months	Increased endogenous SOD; reduced Aβ levels and plaque load	Montinaro et al. [158]
APP/PS1	Curcumin/ Melatonin hybrid	12 weeks	Decrease accumulation of Aβ, reduced inflammatory responses, oxidative stress, and improved synaptic dysfunction	Gerenu et al. [159]
AβPP(swe)/PSEN1dE9	Melatonin	12 months	Decreased Aβ levels, increased cytochrome c oxidase activity	O’Neal-Moffitt et al. [160]
APP/PS1	Ferulic Acid	3 months	Decreased levels of Aβ, improved cognitive behavior	Jung et al. [161]
APP/PS1	Ginkgo biloba	3 months	Decreased learning impairment, decreases levels of Aβ, reduced inflammatory activation	Zheng-Yi Li et al. [162]
PSAPP	Ferulic acid and octyl gallate	3 months	Decreased Aβ deposition, oxidative stress and inflammation	Mori et al. [163]
APP/PSEN1	Vitamin C	4 months	Reduced mitochondrial dysfunction and lower levels of oxidative stress	Dixit et al. [164]
Xpg	Vitamin E	12 weeks	Reduces signs of oxidative stress, number of p53-positive cells, indicative of a lower number of cells dying due to DNA damage over time	La Fata et al. [165]
APP/PS1	Vitamin E + Fish Oil	7 months	Improve behavioral performance, reduced levels of Aβ, decreased levels of oxidative stress	Dong et al. [166]
P301S Tau	a-Lipoic acid	10 weeks	Tau-induced iron overload, lipid peroxidation, and inflammation were significantly blocked	Zhang et al. [167]

Aβ, amyloid-β; MDA, malondialdehyde; SOD, superoxide dismutase.

Further, studies of elderly individuals that were administered with antioxidants enriched diets as supplements. As shown in Table 3 [169–171 , 180–183], all studies did show beneficial effects, meaning individuals supplemented with antioxidants showed improved cognitive functioning and reduced risk for AD.

Table 3

Summary of antioxidant diet supplements in elderly individuals

Study population	Antioxidant and Population Size	Treatment Period	Major Findings	Reference
Rural Elderly, Southwestern Pennsylvania	Antioxidant supplementation, n = 1,059	2 years	Cognitive decline not reduced by antioxidant supplementation	Mendelsohn et al. [168]
Mexican-American Population (Non-Hispanic White and Non-Hispanic black)	Serum antioxidant measurement; n = 4,809	not applicable	Low vitamin D levels correlated with poor cognitive functions	Perkins et al. [169]
Japanese American Male Population	Vitamin E, Vitamin C; n = 3,385	2 years	Improve cognitive functions with diet supplemented with vitamin E and or C supplementation	Masaki et al. [170]
Netherland population	Antioxidant supplement; n = 5,395	6 years	Dietary high intake of vitamin E and C associated with lower risk of AD	Engelhart et al. [171]
Washington Heights-Inwood Colombia population	Vitamin E; n = 4,023	4 years	No positive effects of vitamin D in diet	Luchsinger et al. [172]
Elderly Women, Nurse Health Study	Vitamin E, Vitamin C; n = 14,968	5 years	Improved cognitive functions	Grodstein et al. [173]
Cache County population	Vitamin E, vitamin C; n = 4,740	4 years	Reduced prevalence and incidence of AD associated with combined vitamin E and C supplements	Zandi et al. [174]
Honolulu-Asia Aging Population	Vitamin E; n = 2,459	30 years	No effect shown by vitamin E and vitamin C in diet	Laurin et al. [175]
Duke establishment population	Vitamin E, Vitamin C; n = 616	10	No positive effects from dietary intake of vitamin E and vitamin C	Fillenbaum et al. [176]
Chicago Health aging study population	Vitamin E; n = 1,041	7 years	Vitamin E intake via food associated with reduced risk for AD	Morris et al. [177]
Canadian population	Combined Vitamin C and vitamin E; n = 894	5 years	Combined vitamin C and E improve cognitive functions	Maxwell et al. [178]
Group Health Cooperative study population	Vitamin E, Vitamin C, Vitamin E and C combined; n = 2,969	5.5 Years	No positive effect from vitamin E, vitamin C, and combined vitamin E and C	Gray et al. [179]
Netherland Population	Vitamin E, Vitamin C, beta carotene, and flavonoids; n = 5,395	9.6 years	Vitamin E intake was associated with a reduced risk of dementia	Devore et al. [180]
Kungsholmen Project on Elderly Individuals	Vitamin E forms, n = 232	6 years	High plasma levels of vitamin E are associated with a reduced risk of AD in advanced age	Mangialasche et al. [181]
CAIDE Study on Elderly Individuals	Vitamin E forms, n = 140	8 years	Increased levels of Vitamin E forms were associated with decreased cognitive impairment	Mangialasche et al. [182]
Canadian Study of Health and Aging	Vitamin E and C; n = 5,269	5 years	Vitamin E and C supplements is associated with a reduced risk of cognitive decline	Basambombo et al. [183]

However, randomized antioxidant clinical trials using patients with AD showed no beneficial effects in AD progression, thus suggesting that antioxidant enriched diet is not good for AD patients. These findings also indicate that prevention of AD by antioxidant intake is more efficient than curing AD (Table 4) [184 –190].

Table 4

Summary of diet supplements in patients with Alzheimer’s disease

Study Population	Antioxidant and Population Size	Treatment Period	Major Findings	Reference
Alzheimer’s Disease Cooperation Study Population	Vitamin E 2000 IU/day; n = 341	2 years	Disease progression slowed by vitamin E	Sano et al. [184]
Age-related Eye Disease Study Population	Vitamin C 500 mg, Vitamin E 400 IU, Beta Carotene 15 mg/ daily; n = 2,166	6.9 years	No significant positive effects in treated individuals	Yaffe et al. [185]
Alzheimer’s Disease Cooperative Study Population	Vitamin E 2000 IU, Donepezil mg/day; n = 769	3 years	MCI patients unaffected by vitamin E; donepezil associated with lower rate of AD progression in first 12 months	Petersen et al. [186]
Women’s Health Study Population	Vitamin E 600 IU, Supplementation on Alternate Days; n = 38,876	6 years	No effect on cognitive function	Kang et al. [187]
Alzheimer’s Disease Cooperative Study Population	800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of CoQ 3 times/d; n = 78	4 months	Antioxidants did not influence CSF biomarkers relating to amyloid or tau pathology.	Galasko et al. [188]
Memory Clinic of the Department of Psychiatry of the University Medical Center Hamburg-Eppendorf	400 I.U. Vitamin E and 1,000 mg vitamin C per day; n = 23	12 months	Supplementation with vitamins E and C did not have a significant effect on the course of AD	Arlt et al. [189]
Veteran Affairs Study Population	2000 IU/d of vitamin E (α-tocopherol), 20 mg/d of memantine, the combination; n = 613	5 years	Slower functional decline in groups receiving alpha tocopherol compared with placebo	Dysken et al. [190]

AD, Alzheimer’s disease; CSF, cerebrospinal fluid; MCI, mild cognitive impairment.

Taken together, the evidence from these studies suggest that antioxidant intake and MeDi have a preventative effect on age-related cognitive decline and dementia risk.

In clinical settings, there are factors that limit the effectiveness of antioxidant supplementation in diets of AD patients. Natural antioxidants do not reach the ROS producing organelles, mitochondria in the brain after crossing blood-brain barrier and scavenge free radicals and keep neurons free from toxins. In some cases, the design of clinical trials could limit the effectiveness of antioxidant supplementation therapy, such as conducting in advanced stage of AD patients, not optimizing the dose of antioxidants, or combination of antioxidants [94].

Recently researchers have developed a new diet, the Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND diet), to reduce cognitive decline and dementia in elderly persons [87]. The MIND diet is a hybrid between the MeDi and the DASH diet. The MIND diet, similar to the MeDi, emphasizes plant-based foods and limitations on red meats and saturated fats, but the MIND diet focuses on specific berries and leafy-green vegetables. Morris et al. (2014) showed that, compared to the MeDi or DASH diet, the MIND diet shows the greatest association with a slower rate of cognitive decline.

Aside from its antioxidant effects, diet may induce epigenetic and neurogenic changes in AD. For example, choline, betaine, methionine and folate taken in through diet can alter methylation patterns of DNA and histones which in turn results in changes in gene expression [88]. Folate and B12 in the form of methylcobalamin are responsible of replenishing cellular SAM [89]. SAM, available largely by diet, regulates gene expression by donating a methyl group in DNA methylation. Absence of folate and vitamin B12 contributes to the accumulation of HCY (folate/methionine/homocysteine metabolic process in which DNA methylation occurs) and SAH (intermediate of SAM which is converted to HCY) and the reduction of SAM. SAM is necessary for the appropriate methylation of genes implicated in the processing of AβPP, therefore, Aβ formation and accumulation occurs when these genes are silenced [90]. Altered HCY and SAM metabolic mechanisms are suggest to be linked with the onset of AD [90].

2.6 Physical activity

Several studies have shown that physical activity decreases cognitive impairment and reduces the risk for dementia [88 , 191–226]. Studies have also shown that in some cases, mild forms of physical activity can improve cognitive functioning. Further, randomized control studies show that relatively inactive seniors who participate in a regular exercise regimen are shown to have improve cognitive functioning.

To determine the effects of physical exercise, several groups conducted physical activities such as treadmill, wheel running, walking, and running in mouse models of AD. As shown in Table 5 [88 , 191–213], animals exposed to exercise did show beneficial effects, including reduced ROS and mitochondrial dysfunction, reduced levels of Aβ₄₀ and Aβ₄₂ and phosphorylated tau, reduced inflammatory responses and increased synaptic proteins, and improved cognitive behavior [88 , 191–213].

Table 5
Summary of physical exercise in mouse models of Alzheimer’s disease

Line of Mice Physical Exercise Duration and Memory Task Results References

TgCRND8 Mice Run Morris water maze for 5 months Run group showed increased rate of learning Adlard et al. [91]

APP 23 Mice Wheel Running 11 months and Morris Water Maze &Rotorod Reduced FL-APP and Aβ levels and improved cognitive behavior Wolf et al. [191]

APP SWE Mice Run Radial arm water maze for 3 weeks Exercise improved spatial learning Parachikova et al. [192]

APP SWE Mice Run Run 60 min/day-4 months, object recognition memory Run group showed increased object recognition Yuede et al. [193]

Human Tau23 Mice Treadmill 60 min/D-5 days/week-3 months Increased antioxidant enzymes Leem et al. [193]

Thy-Tau22 Mice Run 9 months- Y maze Run prevented memory loss and cholinergic neuron loss Belarbi et al. [194]

APP/PS1/Tau Mice Run Morris water maze for 7 months Run group showed increased synaptic functions Garcia-Mesa et al. [195]

Human PS2 Mice Treadmill 3 months, Morris water maze 60 min/day- 5 days/week Exercise improved cognitive behavior (reduced escape distance and latency to find the platform) Um et al. [196]

APP/PS1 Mice Treadmill 5–11 months, 30 min/d-5 days/week Inhibited neuropathology in hippocampus Liu et al. [197]

APP/PS1 Treadmill 20 weeks Attenuated ROS generation, mtDNA oxidative damage and restored function of impaired mitochondrial antioxidant enzymes in Tg mice Bo et al. [198]

P301S tau Treadmill 12 weeks Exercise improved general locomotor and exploratory activity and reduced hyperphosphorylated tau Ohia-Nwoko et al. [199]

3xTgAD Running wheel 6 months Restored synaptic and neuroprotective proteins downregulated in 3xTg mice Revilla et al. [200]

male APPswe/PS1dE9 Treadmill 5 months Improved spatial memory by regulating BDNF expression and microglia activation Xiong et al. [201]

2xTg Run 7 months; Morris water maze Improved cognitive behavior and lower levels of soluble and insoluble Aβ₄₀ and Aβ₄₂ Rao et al. [202]

3xTg Treadmill 12 weeks reversed the impaired cognitive declines and significantly improved the Aβ and tau pathology Cho et al. [203]

APP/PS1 Treadmill 10 weeks long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration Lin et al. [204]

TgCRND8 Wheel Running 5 months reduces Aβ plaque burden, facilitates Aβ clearance, and induces autophagy Herring et al. [205]

TgCRND8 Run 2 months; Y-maze prevented further cognitive deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology Maliszewska-Cyna et al. [206]

Tg4-42 Wheel running 3.5 months enhanced physical activity counteracts neuron loss and behavioral deficits Hüttenrauch et al. [207]

APPswe/PS1ΔE9 Wheel Running 10 weeks decreased Aβ burden, improved spatial memory performance, reduced neuronal loss, increased hippocampal neurogenesis and reduced spatial memory loss Tapia-Rojas et al. [208]

hTau Wheel running 2 months Reduced tau phosphorylation Gratuze et al. [209]

2xTg Running Wheel 3 weeks reduces Aβ production by enhancing α-secretase processing of AβPP Nigam et al. [210]

NSE/APPsw Tg Treadmill; Morris Water Maze 12 weeks decreased Aβ production and alleviates cognitive deficits Koo et al. [211]

3xTg Wheel Running 8 weeks normalized hypothalamic inflammation and neurodegeneration as well as glucose metabolism Do et al. [212]

APP/PS1 Treadmill 5 months Attenuated Aβ burden and astrocyte activation Zhang et al. [213]

Line of Mice	Physical Exercise	Duration and Memory Task	Results	References
TgCRND8 Mice	Run	Morris water maze for 5 months	Run group showed increased rate of learning	Adlard et al. [91]
APP 23 Mice	Wheel Running	11 months and Morris Water Maze &Rotorod	Reduced FL-APP and Aβ levels and improved cognitive behavior	Wolf et al. [191]
APP SWE Mice	Run	Radial arm water maze for 3 weeks	Exercise improved spatial learning	Parachikova et al. [192]
APP SWE Mice	Run	Run 60 min/day-4 months, object recognition memory	Run group showed increased object recognition	Yuede et al. [193]
Human Tau23 Mice	Treadmill	60 min/D-5 days/week-3 months	Increased antioxidant enzymes	Leem et al. [193]
Thy-Tau22 Mice	Run	9 months- Y maze	Run prevented memory loss and cholinergic neuron loss	Belarbi et al. [194]
APP/PS1/Tau Mice	Run	Morris water maze for 7 months	Run group showed increased synaptic functions	Garcia-Mesa et al. [195]
Human PS2 Mice	Treadmill	3 months, Morris water maze 60 min/day- 5 days/week	Exercise improved cognitive behavior (reduced escape distance and latency to find the platform)	Um et al. [196]
APP/PS1 Mice	Treadmill	5–11 months, 30 min/d-5 days/week	Inhibited neuropathology in hippocampus	Liu et al. [197]
APP/PS1	Treadmill	20 weeks	Attenuated ROS generation, mtDNA oxidative damage and restored function of impaired mitochondrial antioxidant enzymes in Tg mice	Bo et al. [198]
P301S tau	Treadmill	12 weeks	Exercise improved general locomotor and exploratory activity and reduced hyperphosphorylated tau	Ohia-Nwoko et al. [199]
3xTgAD	Running wheel	6 months	Restored synaptic and neuroprotective proteins downregulated in 3xTg mice	Revilla et al. [200]
male APPswe/PS1dE9	Treadmill	5 months	Improved spatial memory by regulating BDNF expression and microglia activation	Xiong et al. [201]
2xTg	Run	7 months; Morris water maze	Improved cognitive behavior and lower levels of soluble and insoluble Aβ₄₀ and Aβ₄₂	Rao et al. [202]
3xTg	Treadmill	12 weeks	reversed the impaired cognitive declines and significantly improved the Aβ and tau pathology	Cho et al. [203]
APP/PS1	Treadmill	10 weeks	long-term exercise protects neurons in the amygdala and hippocampus against AD-related degeneration	Lin et al. [204]
TgCRND8	Wheel Running	5 months	reduces Aβ plaque burden, facilitates Aβ clearance, and induces autophagy	Herring et al. [205]
TgCRND8	Run	2 months; Y-maze	prevented further cognitive deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology	Maliszewska-Cyna et al. [206]
Tg4-42	Wheel running	3.5 months	enhanced physical activity counteracts neuron loss and behavioral deficits	Hüttenrauch et al. [207]
APPswe/PS1ΔE9	Wheel Running	10 weeks	decreased Aβ burden, improved spatial memory performance, reduced neuronal loss, increased hippocampal neurogenesis and reduced spatial memory loss	Tapia-Rojas et al. [208]
hTau	Wheel running	2 months	Reduced tau phosphorylation	Gratuze et al. [209]
2xTg	Running Wheel	3 weeks	reduces Aβ production by enhancing α-secretase processing of AβPP	Nigam et al. [210]
NSE/APPsw Tg	Treadmill; Morris Water Maze	12 weeks	decreased Aβ production and alleviates cognitive deficits	Koo et al. [211]
3xTg	Wheel Running	8 weeks	normalized hypothalamic inflammation and neurodegeneration as well as glucose metabolism	Do et al. [212]
APP/PS1	Treadmill	5 months	Attenuated Aβ burden and astrocyte activation	Zhang et al. [213]

AD, Alzheimer’s disease; Aβ, amyloid-β; BDNF, brain-derived neurotrophic factor; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; Tg, transgenic.

In studies of subjects with MCI and patients with AD, researchers designed studies that increased the daily activity level of the test populations. As shown in Table 6, MCI subjects exposed physical activity showed improved cognitive status, global cognitive functioning, and improved memory [227–233]. Overall, these findings clearly indicate that physical activity is beneficial to subjects with MCI.

Table 6

Summary of physical exercise in subjects with mild cognitive impairment

Study	Participants	Intervention	Outcome
Lautenschlager et al. [214]; n = 170	Women 43%, Mean Age 68	Physical activity group N = 85, walking, strength training 3×50 min/week 24 weeks; control group received educational materials	Intervention improved cognitive delayed recalls
Lam et al. [215]; n = 389	Women 44%, Mean Age 70, MMSE 28	Divided study population into 4 groups. G1 2×60 min walking/week + vit B; G2 placebo activity + vit B; G3 2×60 min walking/week +placebo supplement and G4 2×60 min walking/week +placebo activity and supplement	Improved attention, delayed recall; No MMSE improvement
Nagamatsu et al. [216]; n = 86	Women 100%. Mean Age 75, MMSE 27. Community Dwelling	RT, n = 28, 2×60 min/week, 26 weeks; AT (walking), n = 30, 2×60 min/week, 26 weeks; BAT, n = 28, 2×60 min/week, 26 weeks	RT improved in the Stroop test; AT improved verbal memory; AT and RT improved reaction times in spatial memory
Varela et al. [217]; n = 48	Women 56% Mean Age 78.3; MMSE 20	A group N = 17 aerobic exercise (cycling) 3×30/week, 12 weeks; B group n = 16 aerobic exercise (cycling), 3×30 min/week, 12 weeks; C group n = 15 recreational activity 3×30 min/week. 12 weeks	Changes between groups were not significant
Suzuki et al. [218]; n = 100	Women 45%, Mean Age 75.4, MMSE 27- Community Dwelling	Exercise Group n = 50, 25 amnestic MCI and 25 other MCI (aerobic, strength training, balance and dual tasking); Control Group n = 50, 25 amnestic MCI and 25 other MCI	MMSE improved in the exercise group in amnestic MCI; WMS-LM1 improved in all exercise cases
Singh et al. [219]; n = 100	Women 68%, Mean Age 70.1, community-dwelling	Exercise group n = 73, All with MCI (Computer-based multimodal and multi-domain cognitive exercises and progressive resistance training); Control group n = 27,	Improvement in global cognitive functioning, ADL, and mood.
Train the Brain Consortium (2017) [220]; n = 113	All MCI positive	Exercise group n = 55 (cognitive training with aerobic exercise); Control Group n = 58	improved cognitive status and indicators of brain health in MCI subjects

ADL, Activities of Daily Living; AT, aerobic training; BAT, balance and tone training; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; RT, resistance training; WMS, Wechsler Memory Scale.

In the studies of patients with AD, with minimal exercise did show some positive effects, but not significant (Table 7) [221 –226]. These observations indicate physical activity may be helpful.

Table 7

Summary of physical exercise in patients with Alzheimer’s disease

Study	Participants	Intervention	Outcome
Chrisstofoletti et al. [221]; n = 54	Women 69%, Mean Age 74.3, Mean MMSE 13–19	Group 1, n = 17; physiotherapy, 5×2h/week, 24 weeks. Group 2, n = 17, physiotherapy 3×60 min/week, 24 weeks Control group n = 20	Group 1 improved in verbal fluency and clock drawing test compared to control group; Group 2 did not show improvement
Eggermont et al. [222]; n = 97	Women 81%, Mean Age 85.4, Mean MMSE 17.7, nursing home residents	Exercise group n = 51, waling 5×30 min/week, 6 weeks, Control group n = 46	Memory domain-no difference and executive functions-no difference
Kemoun et al. [223]; n = 38	Women 74%, Mean Age 81.8; Mean MMSE 12	Intervention group, n = 20, walking, ergoncycling, dancing 3×60 min/week, 15 weeks Control n = 18, no physical activity	ERFC score increased in the intervention group
Yaguez et al. [224]; n = 27	Women 59%, Mean Age 73.1; MMSE 22.1–26.3	Exercise group n = 15 brain Gym training 1×2h/week, 6 weeks Control group-psychological support	Exercise group improved visual memory, sustained attention
Vreugdenhil et al. [225]; n = 40	Women 60% Mean Age 74.1, MMSE 10–28, community dwelling	Exercise group n = 20-home-based exercise and walking Control group n = 20	MMSE is increased by 2.6 points
Holthoff et al. [226]; n = 30	Mean Age; 72.4; MMSE 20.6	Intervention group n = 15 (passive, motor-assisted or active resistive leg training and changes in direction on a movement trainer in order to combine physical and cognitive stimuli); Control group n = 15	Improved cognitive functioning (executive functioning and language ability)

ERFC, Rapid Evaluation of Cognitive Functions test; MMSE, Mini-Mental State Examination.

Animal models serve as a translational approach in relating physical activity to neurocognitive plasticity in humans. In Adlard et al. [91], researchers measured the number of Aβ plaques in 250 mice with AD immediately before and after they were subjected to regular exercise on an exercise wheel, at least 5 min per hour. The mice showed a decrease in Aβ plaques in the frontal cortex and hippocampus after a 3-week exercise regimen [91]. Cotman and Berchtold [92] demonstrated that enhanced learning on water maze tasks has been associated with an increased production of brain-derived neurotrophic factor (BDNF). BDNF is responsible for neuroprotection to promote cell survival, neurite outgrowth, and synaptic plasticity [92]. Cotman and Berchtold demonstrated that endogenous administration of BNDF increases cell proliferation, blocking the BDNF reduces cell proliferation.

Another molecule affected by exercise is the insulin-like growth factor-1 (IGF-1). When IGF-1 release is blocked, BDNF and exercise-induced cell proliferation are inhibited. IGF-1 also regulates the secretion of vascular endothelial growth factor (VEGF), a growth factor involved in blood vessel growth. Inhibiting IGF-1 has been found to suppress the growth of new capillaries [93].

2.7 Other risk factors

2.7.1 Type 2 diabetes mellitus and obesity

Multiple studies have shown a lower cognitive performance and increased risk of dementia in those persons with type 2 diabetes mellitus [94]. While there is a strong positive correlation between diabetes and dementia, it is not strongly supported by experimental data. A recent study showed that people with MCI are at increased risk of developing dementia [95]. Furthermore, individuals with MCI and diabetes are at a higher risk of developing dementia than individuals with MCI and no diabetes [110].

A study suggests that in diabetes patients, elevated HbA1c levels are associated with brain hypometabolism rather than amyloid accumulation [96] Further, the study suggests that metabolic dysfunction in diabetics can cause neural injury that may precede symptoms of cognitive impairment associated with AD pathology. Therefore, researchers are unable to establish a direct link between diabetes and the gross pathology of AD. However, there is much evidence that relates diabetes to the risk of AD through vascular pathways as well as other biological mechanisms such as inflammation, defective insulin signaling, and mitochondrial dysfunction.

Several studies have investigated risk factors that are involved in AD development and progression. Findings from these studies point to a link between obesity and a risk for developing AD, specifically obesity during mid-life. This risk changes with age, and even being overweight or even obese later in life can reduce the risk for AD. A study found that individuals who were overweight in midlife had a lower risk for developing dementia compared to individuals who were underweight [97]. However, various studies present conflicting relationship between obesity and risk of AD.

The mechanism linking obesity and AD is thought to involve leptin. In a study of AD risk factors, researchers found that obesity-related leptin modulates Aβ in patients with AD. Brain lipids involved in Aβ-related pathogenic pathways have been well-studied. Leptin, implicated in lipid homeostasis, was found to reduce β-secretase activity and may alter the lipid composition of membrane lipid rafts. The study suggests that leptin is able to regulate bidirectional Aβ kinesis, reducing levels extracellularly [98].

Studies support that leptin may facilitate learning and memory performance. Since leptin receptors are present in hippocampus and its receptors share similarities to those of interleukin-6 family of cytokines that modulate long-term potentiation in the hippocampus, it is believed to influence memory performance [99]. Intravenous injection of leptin administered to rats showed improved performance on behavioral performance and memory tasks. Further, impaired leptin functions are linked to increased risk for AD [100 –102]. While there is support that obesity has a protective role in AD, some evidence supports an inverse relationship between obesity and AD, while other studies show no association. This suggests that there is no conclusive link between obesity and AD.

2.7.2 Midlife vascular risk factors

Like obesity as a risk factor for AD, there is an inconsistent trend in studies associating hypertension and AD progression. There is some evidence that suggest that later-life hypertension has a protective effect against cognitive decline [103, 104].

Several studies also point to no association between mid-life hyperlipidemia and dementia, including no evidence that high cholesterol levels increase the chance of vascular dementia [105, 106]. There is some evidence that suggests that drugs used to control cholesterol, statin, may reduce the risk of dementia [107 –109]. However, this evidence is weak, citing inconsistent results.

2.7.3 Traumatic brain injury

There is strong evidence that associates severe traumatic brain injury (TBI) with increased risk for AD and other forms of dementia [110 –114]. This risk is further increased in individuals that participate in physical sports with repeated head injuries such as football and boxing [115 –117]. The specific aspect of TBI (intensity, repetitiveness) that links to AD is unknown, yet there is substantial evidence that relates TBI to neurodegenerative diseases.

2.7.4 Depression

A history of depression is suggested to increase the risk for dementia in several studies, however, some studies suggest that depression symptoms are independent of symptoms associated with dementia and cognitive decline. An alternate explanation is that depression can be an early marker for cognitive decline rather than a risk factor for AD [118].

Depression and AD are often found to be comorbid in affected individuals, appearing in about 50% of patients with AD. Further, AD is more prevalent among women, comprising about two thirds of the affected population and also show increased incidence of depression. A study finds that the incidence of depression and AD is correlated with the number of women undergoing ovarian failure, those who are unable to produce ovarian steroid production, and women in the postmenopausal stage. Estradiol is found to be essential in serotonin neuron function and health. Serotonin neurons deteriorate and becomes dysfunctional in the absence of estradiol. Researchers suggest that this event precede or occur alongside AD in female patients [14].

In another study, the effects of selective serotonin reuptake inhibitors (SSRIs) were studied in the treatment of AD. SSRIs are drug treatments used to treat depression and anxiety and have been previously shown to reduce Aβ levels circulating in the cerebrospinal fluid, suggesting it to be an effective treatment for psychiatric disorders in AD patients. Researchers found that neurosteroids and SSRIs reduce AD pathology in AD neurons and increases cell survival in serotonin neurons [119].

3 CONCLUSIONS AND FUTURE DIRECTIONS

AD is a major healthcare concern in the society. AD is a mental illness characterized by memory loss and multiple cognitive impairments without cure. Currently, we do not have a drug/agent that can delay and/or prevent progression of disease in elderly individuals and patients with AD. Tremendous progress has been made in understanding molecular and cellular bases of both early-onset familial and late-onset sporadic AD; a large number of animal (both vertebrate and non-vertebrate) and cell models were made. In terms of treatment, every drug/agent is failed to restore and/or prevent AD in elderly individuals. Current research using rodent models revealed that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive functions. Furthermore, the use of antioxidants in the diets of elderly individuals and AD patients were investigated. The use of antioxidants in elderly individuals showed beneficial effects, but limited successes in randomized clinical trials in AD patients. This article critically assessed the current status of healthy diets and regular exercise on dementia in elderly individuals. The current data on healthy diets and regular exercise suggest that healthy diets, regular exercise, and better lifestyle are likely to delay the progression of dementia and reduce the risk of AD in elderly individuals.

Footnotes

ACKNOWLEDGMENTS

Work presented in this article is supported by NIH grants R01AG042178, R01AG047812, R01NS105473, and R41AG060836, the Garrison Family Foundation, CH Foundation and Alzheimer’s Association SAGA grant (to PHR).

Authors’ disclosures available online ().

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