Diet and Exercise as Complementary Medicine for the Management of Alzheimer’s Disease: A Narrative Review

1. Introduction

Alzheimer’s Disease (AD), a progressive neurodegenerative disorder, casts a growing shadow on an aging global population in terms of both personal and financial loss [1]. This paper delves into the intricate and multifaceted changes in the brain as AD advances, subsequently exploring the associated cognitive impairments and the promising role of modifiable lifestyle factors, specifically diet and exercise, in mitigating its impact. We first dissect the structural, functional, neurochemical, metabolic, and vascular alterations within the brain that are hallmarks of AD, laying the groundwork for understanding the disease’s profound effects on cognition. Following this, we examine the characteristic cognitive decline observed in AD, focusing on early deficits in memory and executive functions and the progression to language and visuospatial impairments. Finally, we turn our attention to the burgeoning evidence highlighting the potential of dietary interventions and physical exercise as powerful tools in managing AD, exploring their effects on brain health, cognitive function, and underlying AD pathology. By synthesizing current research, this paper aims to provide a comprehensive overview of the interplay between brain changes, cognitive decline, and the modifiable lifestyle factors that hold promise for addressing this devastating disease.

2. Changes in the Brain and Cognition Associated with Ad

2.1. Brain Changes Associated with AD

Brain structure. AD involves brain changes like regional atrophy and enlarged ventricles [2,3]. Key hallmarks are senile plaques (beta-amyloid aggregates) and neurofibrillary tangles (tau protein aggregates), which precede neuronal death [4]. Plaques appear first in the neocortex and spread to other brain regions, including the allocortex, hippocampus, basal ganglia, midbrain, and cerebellum, years before clinical symptoms appear [5]. Tangles emerge later, starting in the transentorhinal region and progressing through the hippocampus and neocortex [6]. Early detection is challenging due to overlapping amyloid and tau pathologies. Advanced imaging, including Magnetic Resonance Imaging (MRI), diffusion tensor imaging, and Positron Emission Tomography (PET) scans using amyloid-specific ligands, aids in identifying micro-structural abnormalities and pathological substances, improving diagnostic capabilities [7,8]. In addition, there is also a correlation between AD neuropathological changes and cognitive impairment, suggesting the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles [9].

Synaptic and neurochemical changes. AD is a progressive and synaptic failure disease. Synaptic pathology and mitochondrial oxidative damage are early events in AD progression [10]. Loss of synapses and synaptic damage are the best correlates of cognitive deficits found in AD patients. As the disease progresses, there are significant changes at the synapse [11]. AD progression is associated with reduced spine density, impaired memory, coordination of activities, and reduced signal transmission. Synapse loss is an early event disease process due to soluble amyloid beta, phosphorylated tau accumulation, and increased production of mitochondrially generated free radicals at synapses [12]. The clinical manifestations of AD result from the impairment in these cerebral pathways, among which the basal forebrain cholinergic innervation of cortical areas is the most vulnerable. Consequently, the cholinergic receptors are dysregulated during AD progression and impairment of the cholinergic system is considered an early event in AD, compromising cognition. Additionaly, the dysregulation of receptors for other endogenous neurotransmitters has also been described in patients and different experimental and animal models [13].

There is evidence of a loss of glutamatergic neurons in AD patients, particularly in the hippocampus’s neocortex and the CA1 region. Additionally, the abnormal accumulation of amyloid-beta and tau proteins may lead to astrocytosis and microgliosis [13]. Although the dopaminergic system is not a key player in AD, the loss of dopaminergic neurons has been identified in the AD brain [14]. A recent meta-analysis linking the dopaminergic system and AD has summarized that the level of dopamine and D1 and D2 receptors are decreased in patients with AD. However, the specific role of this neurotransmitter system remains unclear in AD [15]. Overall, early synaptic failure, mitochondrial oxidative damage, and significant changes in multiple neurotransmitter systems, most notably the cholinergic and glutamatergic pathways, leading to cognitive decline are characteristics associated with AD.

Brain function. Normal cognitive function depends on the brain’s ability to efficiently process and transmit information within and between specialized structural regions and functional networks. AD is characterized by the breakdown of neuronal connectivity within the brain due to structural changes (i.e., brain atrophy and neuronal dysfunction). Early alteration in brain functional connectivity may be associated with AD pathology [16]. Resting-state functional MRI has shown that as tau spreads through functional connections within the brain, lower functional connectivity to tau epicenters is associated with tau spreading through functional connections in both amyloid-beta-negative and amyloid-beta-positive participants [17]. Also, amyloid-beta-PET in tau epicenters mediated the association of tau spreading and functional connectivity to epicenters, suggesting a partial mediating effect of amyloid-beta deposition in tau epicenters on the local impact of tau spreading on functional connectivity. These findings support that tau spreading through connection is locally associated with disrupted functional connectivity between tau epicenter and non-epicenter regions independent of amyloid-beta pathology. Amyloid-beta, other co-pathologies, and the apolipoprotein E epsilon 4 (APOE4) allele can lead to tau-relative functional disconnection vulnerability [18]. Overall, AD disrupts normal cognitive function by breaking down neuronal connectivity, primarily through tau protein spread that weakens functional connections, often independently of amyloid-beta. However, amyloid-beta and other factors can exacerbate this disconnection.

Metabolic changes. Metabolic dysfunction is an established feature of AD supported by brain glucose hypometabolism that can be observed before the development of many AD symptoms [19]. In addition, individuals with insulin resistance (i.e., type 2 diabetes mellitus, hyperlipidemia, obesity, or other metabolic disease) have an increased risk for the development of AD [20]. This association may partly be due to systemic mitochondrial dysfunction [21]. Mitochondria are essential cellular organelles responsible for the energy production necessary for neuronal function and can become impaired in AD, triggering several cellular consequences [22]. Mitochondrial dysfunction is associated with factors such as oxidative stress, disturbances in energy metabolism, failures in the mitochondrial quality control system, and dysregulation of calcium release. These abnormalities are linked to the neurodegenerative processes driving AD development and progression. Mitochondrial abnormalities are among the earliest detectable changes in AD pathology [23]. The mitochondrial cascade hypothesis suggests that mitochondrial dysfunction and Amyloid-beta pathology are interconnected, forming a vicious cycle that accelerates neurodegeneration [24]. However, this theory does not fully encompass sporadic AD, highlighting the importance of incorporating mitochondrial dysfunction into the broader understanding of the disease [25]. Mitochondrial-focused approaches represent transformative strategies to combat AD, including metabolic modulators, mitophagy enhancers, antioxidants, and advanced therapeutic techniques such as mitochondrial transplantation and gene therapy [26,27,28,29,30,31,32,33,34,35].

Similar to insulin resistance and mitochondria, there is strong evidence for an inflammatory component of AD [36]. Extrinsic factors, such as brain trauma, diet, systemic and local infections, and the gut microbiota, impact the inflammatory element of AD [37]. Intrinsic factors, including microglial phagocytosis, blood-brain barrier function, cellular metabolism, and cell senescence, also play a central role in neuroinflammation in AD [38]. Cells such as astrocytes, oligodendrocytes, lymphocytes, and peripheral myeloid cells and even vascular cells are activated in AD and contribute to the chronic neuroinflammation that causes a leaky blood-brain barrier [39,40]. A contributing role of the dysregulation of the glymphatic system, or the movement of cerebrospinal fluid into the brain to clear metabolic waste, may also contribute to sustained neuronal inflammation [41]. Thus, like mitochondria, new therapeutic approaches based on targeting the inflammatory component of AD are currently being tested in clinical trials.

Vascular changes. As with many other brain changes associated with AD, vascular changes may potentially precede the onset of the hallmark pathophysiological and cognitive symptoms of the disease [42]. Substantial evidence indicates a strong interplay between vascular changes and amyloid pathology in AD [43]. Studies show reduced cerebral blood flow correlating with amyloid accumulation in early AD and gray matter loss in later stages. Vascular health metrics, including cerebral blood flow changes, indicate disease progression, particularly in preclinical populations [44,45]. Age-related vessel deterioration, microvascular abnormalities, and impaired cerebral blood flow, potentially due to amyloid angiopathy and stagnant capillaries, contribute to AD [46,47]. Structural vascular changes, endothelial dysfunction, blood-brain barrier disruption, and neuroinflammation play pivotal roles in neurodegenerative pathways [47,48,49,50,51]. Zlokovic’s "two-hit" hypothesis proposes that initial vascular dysfunction (hit 1) leads to reduced cerebral blood flow and breakdown of the blood-brain barrier, impairing amyloid clearance. This increases amyloid accumulation (hit 2), further exacerbating vascular dysfunction [52]. These hits affect the neurovascular unit, including vascular smooth muscle cells, pericytes, astrocytes, and endothelial cells, contributing to dementia progression [47,51,52]. Impaired angioneurins expression further disrupts the neurovascular unit, impacting cerebral blood flow and blood-brain barrier integrity and contributing to neurodegeneration. Improved vascular health may reduce AD progression [52,53,54].

2.2. Summary of Pathophysiological Brain Changes Associated with AD

Alzheimer’s Disease involves multifaceted brain changes. Structural changes include regional atrophy, enlarged ventricles, and hallmark plaques/tangles that precede neuronal death. Imaging detects these abnormalities [2]. Functional changes associated with AD disruption in neuronal connectivity, particularly through tau protein spread, lead to functional disconnection. Amyloid-beta and other factors exacerbate this [16,17]. Neurochemical and synaptic changes result in synaptic failure, mitochondrial damage, and neurotransmitter dysfunctions (cholinergic, glutamatergic), which are early events that correlate with cognitive decline [10]. Metabolic changes, including glucose hypometabolism, insulin resistance, and mitochondrial dysfunction, contribute to AD [21]. These factors interact with amyloid and tau pathology [13]. Neuroinflammation, influenced by intrinsic and extrinsic factors, is also crucial [39]. Finally, AD is implicated in cerebrovascular dysfunction, blood-brain barrier disruption, and reduced cerebral perfusion. Vascular changes interact strongly with amyloid pathology, with reduced cerebral blood flow correlating with amyloid accumulation. The "two-hit" hypothesis highlights the interplay between vascular dysfunction and amyloid accumulation [47,52]. In conclusion, AD is a complex neurodegenerative disorder characterized by a confluence of structural, functional, neurochemical, metabolic, and vascular alterations that collectively contribute to progressive cognitive decline.

2.3. Changes in Cognition Associated with AD

Early neuropsychological investigations into AD aimed to define the cognitive profile of patients with mild dementia, revealing a consistent pattern of deficits [55]. A primary finding was a significant impairment in episodic memory, the ability to learn and retain new information [56]. This manifests in everyday challenges like remembering conversations or appointments and laboratory tasks involving learning and recalling stories, word lists, or paired associates [57]. Studies comparing AD patients to healthy older adults demonstrated this striking memory deficit [58]. Furthermore, when compared to other forms of dementia, like frontotemporal dementia or Lewy body dementia, AD patients exhibited a more pronounced difficulty in retaining information over time [59,60].

Beyond memory, early-stage AD patients also showed substantial impairments in executive functions, which encompass abilities like coordinating multiple tasks and shifting between mental sets [61]. These deficits were observed in both individuals with mild and moderate dementia, with evidence suggesting that executive function decline often precedes language and spatial impairments [60,62,63]. Language function is also affected in AD, with semantic memory, the system for processing and storing word meanings, being particularly vulnerable. This is reflected in difficulties with category fluency, naming objects, and making similarity judgments [64,65]. While some studies have reported deficits in word priming, others have not [65]. Visuospatial function, involving spatial reasoning and visual perception, is generally preserved in very early stages, as evidenced by performance on simple copying tasks [66,67]. However, visuospatial impairments become increasingly common as the disease progresses to moderate stages [68]. It’s important to note that while these cognitive changes are typical, AD can present with variations. Some individuals experience a gradual decline in spatial abilities, known as posterior cortical syndrome. In contrast, others primarily exhibit language deficits, which can be challenging to differentiate from primary progressive aphasia, a form of frontotemporal lobar degeneration. These atypical presentations highlight the heterogeneity of AD and underscore the importance of comprehensive neuropsychological assessments [55]. Perception of cognitive decline is heightened in the early stages of AD but diminishes later [69]. Overall, early neuropsychological studies of AD consistently identified core cognitive deficits, notably in episodic memory and executive functions, with language and visuospatial impairments emerging as the disease progresses. However, atypical presentations highlight the disease’s variability.

2.4. Behavior, Mood, and Psychiatric Disturbances Associated with AD

AD is characterized by a spectrum of neuropsychiatric disturbances, including depression, anxiety, apathy, agitation/aggression, psychosis, and cognitive decline [70,71,72,73]. These symptoms manifest as progressive mood changes, such as increased irritability, sadness, and anhedonia. Behavioral alterations, such as agitation, wandering, and repetitive questioning, are also common. Agitation and aggression often stem from confusion, frustration, or misinterpretation of the environment. Depression and apathy can further accelerate cognitive decline and diminish quality of life. Notably, sleep disturbances, a common feature of AD, contribute to both cognitive and behavioral deterioration. The shared neurobiological basis of these symptoms across neurodegenerative diseases, including AD and Parkinson’s Disease, suggests that similar mechanisms, particularly neurotransmitter dysregulation, underlie these mood and behavioral changes [72].

2.5. Changes in Sleep and Sleep Deprivation Associated with AD

Sleep disorders are very common in neurodegenerative diseases, including AD, and are a key factor in the quality of life of patients and their families. Growing evidence for the role of sleep disorder in the pathophysiology of AD has resulted in the proposal of a bidirectional relationship, with disordered sleep being both a clinical feature of AD and a risk factor [74,75]. Sleep is essential for brain function, including clearing brain metabolites, conserving energy, and consolidating memory. Sleep deprivation can lead to various negative effects, such as poor concentration, emotional instability, increased pain sensitivity, and metabolic and cardiovascular diseases. Factors contributing to sleep deprivation include environmental changes, mental health issues, and lifestyle choices. Disruption of circadian rhythms, such as through shift work, can also negatively impact cognitive performance and overall health.

Sleep and circadian rhythm disturbances are common in AD patients and can appear early in the disease [76]. Sleep-wake cycles and circadian rhythms are critical in controlling Amyloid-beta levels, as sleep disorders can potentially increase them in the brain [77]. Like Amyloid-beta, tau protein levels are also influenced by sleep-wake cycles and significantly increased by sleep deprivation. Thus, tau plays a critical role in neurodegenerative lesions and cognitive decline in AD, with tau pathology possibly preceding amyloid-beta accumulation [78]. Furthermore, the relationship between tau pathology, amyloid-beta, and sleep disorders highlights the need for further research into their interconnected roles in AD progression [79].

2.6. Changes in Appetite Associated with AD

Patients with AD sometimes suffer loss of appetite and decrease their body weight [80,81]. Some patients with vascular dementia have pseudobulbar palsy, resulting in difficulty swallowing, and have a high risk of aspiration pneumonia [82,83]. Similarly, patients with Lewy body dementia have difficulty swallowing and loss of appetite [84], while patients with frontotemporal dementia and semantic dementia increase their appetite, prefer sweet and pungent foods, and want to eat the same foods repeatedly [85,86]. However, most studies focused on specific aspects of eating disturbance, such as swallowing and appetite. Few comprehensive studies have included eating habits and food preferences in patients with AD [87].

2.7. Summary of Changes in Brain and Cognition Associated with AD

AD is a complex neurodegenerative disorder characterized by a confluence of structural, functional, neurochemical, metabolic, and vascular alterations that collectively contribute to progressive cognitive decline [2]. Structurally, AD involves brain atrophy, enlarged ventricles, and the accumulation of amyloid plaques and tau tangles [8]. Functionally, this disrupts neuronal connectivity, primarily through tau protein spread [2,16,17,18]. Neurochemically, synaptic failure and neurotransmitter dysfunctions are prominent, particularly in cholinergic and glutamatergic systems. Metabolically, glucose hypometabolism, insulin resistance, and mitochondrial dysfunction play significant roles, while neuroinflammation, influenced by both intrinsic and extrinsic factors, further exacerbates the disease [24]. Vascular changes, including reduced cerebral blood flow and blood-brain barrier disruption, interact strongly with amyloid pathology, contributing to the progression of AD [40,42,48,52,53]. These pathological changes manifest in cognitive deficits, notably in episodic memory and executive functions, and are accompanied by behavioral, mood, psychiatric, sleep, and appetite disturbances. Early neuropsychological investigations consistently identify core cognitive deficits, while neuropsychiatric symptoms such as depression, agitation, and sleep disorders further diminish the quality of life [2,73]. Metabolic dysfunctions such as mitochondrial dysfunction and neuroinflammation are also key components of AD [24]. Changes in appetite and weight are also observed. Overall, AD involves a complex interplay of multifaceted brain changes that lead to progressive cognitive decline [2].

3. Modifiable Risk Factors in Ad

The 2024 Lancet Commission report highlights 14 modifiable risk factors for the prevention and delay of AD, 7 of which are associated with lifestyle [88]. High low-density lipoprotein (LDL) cholesterol, hypertension, obesity, type 2 diabetes, depression, sedentary lifestyle, and excessive alcohol consumption are all strongly associated with increased AD risk and can be mitigated through diet and exercise. Each of these factors contributes to the neuropathological changes found in AD, including vascular disease, amyloid accumulation, neuroinflammation, energy dysregulation, and neurotransmitter dysfunction. For example, elevated LDL cholesterol has been linked to increased amyloid plaque formation [89], while hypertension compromises cerebral blood flow and contributes to white matter damage [90]. Obesity in midlife is associated with chronic inflammation and insulin resistance, both of which can accelerate neuronal dysfunction [91].

Type 2 diabetes increases AD risk through mechanisms such as impaired glucose metabolism and increased oxidative stress [92]. Depression is both a potential early sign of and a contributing factor to AD, potentially due to genetics, AD-related biomarkers elevated in depression, and elevated inflammation that causes vascular damage and weakens the blood-brain barrier [93]. A sedentary lifestyle compounds many of these effects by negatively influencing glycemic control [94] and increasing risk factors such as cardiovascular disease, cognitive decline, and depression [95]. Finally, excessive alcohol consumption is connected to systemic inflammation, reduced brain volumes, and disruptions to neurotransmission [96].

Together, these modifiable risk factors underscore the critical role that diet and regular exercise, which are the focus of this narrative review, play in supporting overall brain health [97,98]. Interventions centered on diet and physical activity not only reduce the prevalence of these conditions but also offer a robust, multi-modal strategy for lowering AD risk, improving AD symptoms, and slowing cognitive decline. Additional information related to these two adjunction and complementary therapies is detailed within.

4. Effects of Diet on Cognition and Brain Health in Patients with Ad

Whereas there are a plethora of diets, foods, and natural products that have been investigated for impact on brain health in cognitively intact individuals and the prevention of AD [98], a limited number of these dietary interventions have been implemented in trials for individuals with AD. Recent reviews and meta-analyses have focused on a small subset of individual and multi-ingredient vitamins, minerals, fatty acids, and other natural products explored within the context of placebo-controlled, randomized controlled trials (RCT) that have had positive, albeit mixed effects [99,100]. Conversely, only a few holistic dietary approaches have either changed the dietary pattern in part or completely in trials for individuals with AD [101,102,103,104].

Vitamins & Minerals. Appropriate vitamin and mineral intake is vital for the optimal functioning of the body and the brain. A deficiency in B complex vitamins, for example, can cause elevated levels of homocysteine. Homocysteine has been established as a strong, independent risk factor for Alzheimer’s and related dementias [105]. This is due in large part to its role in cardiovascular disease and AD pathology [106]. Accordingly, there has been extensive research examining the effect of B vitamin supplementation in patients with AD. A 2022 systematic review and meta-analysis examined the impact of B vitamin supplementation on the rate of cognitive decline in 6,155 participants across 14 RCTs. The analysis revealed that not only was supplementation associated with a benefit to cognition versus placebo, but in studies where the placebo group showed cognitive decline, vitamin B supplementation slowed cognitive decline for the intervention group [107]. Vitamin D deficiency is also considered a risk factor for dementia. Along with correcting the deficiency, vitamin D supplementation is also suspected to provide neuroprotection via its antioxidant and anti-inflammatory properties. While cohort studies have found a reduced incidence of AD in individuals taking Vitamin D supplements [108], intervention studies in patients with AD are mixed, with the majority of studies finding no benefit of supplementation on cognition [109,110,111]. Those studies that have found a benefit often have multiple limitations that make interpretation of results difficult [112].

Aside from the elevated systemic inflammation associated with age [113], there are many metabolic and cardiovascular risk factors associated with AD that contribute to the inflammatory status of an individual. Therefore, an emphasis has been placed on investigating natural products known to have anti-inflammatory or antioxidant properties. There are several vitamins and minerals with anti-inflamatory and/or antioxidant and have been investigated in RCTs for their ability to reduce AD symptoms and/or slow disease progression. The most promising of these natural products include thiamine, vitamin E, vitamin C, and selenium. A 2022 systematic review concluded that although there was insufficient evidence for the use of vitamin E and C in improving cognition in individuals with AD, thiamine, both alone and with folic acid had a positive impact on cognition [109]. The literature also supports that supplementation with selenium improves cognition in patients with AD [114].

Omega 3-Fatty Acids. There is a vast literature on the benefits of omega-3 fatty acids in the support of healthy brain aging, due to their role in cell membrane structure, anti-inflammatory activity, and in supporting a healthy vascular system [115]. In observational studies, omega-3 fatty acids are associated with improved cognition [116], but this has not been replicated widely in interventions with patients diagnosed with Alzheimer’s disease. In a 2020 systematic review and meta-analysis, 38 moderate-quality RCTs provided evidence that omega-3 fatty acid supplementation (with intervention duration at an average of 20.5 months) had little to no effect on new neurocognitive outcomes or cognitive impairment [117]. A 2022 RCT with a sample size of 163 AD patients and an intervention duration of 24 months found that while omega-3 supplementation did not reduce cognitive, functional, or depressive symptom outcomes, there was improvement in the intervention group on sub-items of the ADAS-cog associated with language ability and visuospatial skills [118].

Other Natural Products. There are several other plant-derived compounds that have been evaluated for their ability to improve AD symptoms or slow cognitive decline, but few have been implemented in human clinical trials, let alone trials involving AD patients. Curcumin, a polyphenol extracted from tumeric, and the phytobioactive compounds in ginseng, are both considered anti-inflammatory and antioxidant and have been investigated for their neuroprotective benefits in AD populations [119,120]. The benefits, however, have not been verified, as these studies are limited due to methodological issues, and conclusive evidence has yet to be provided.

Multi-ingredient Intervention. Researchers have also considered how multiple vitamins, minerals, and natural products might work synergistically to improve symptoms and disease progression in AD. Although not conducted in AD patients, there is evidence that daily multivitamin-mineral supplementation is effective in improving both general cognition and episodic memory in older adults over a 2-year period [121]. Souvenaid, a supplemental drink designed to improve brain function and cognition, has been investigated for its effectiveness in patients with AD, but a meta-analysis of four studies concluded that there was no evidence to support its ability to slow the progression of AD and mixed evidence of its impact on cognition [122].

Dietary Interventions. Considering a more ecological approach, researchers have explored how whole diets or dietary patterns might impact symptoms and disease progression in AD. The ketogenic diet has been studied extensively for its ability to shift the body into ketosis, where the use of ketones as a primary energy source has been found to improve brain energy metabolism and cognition [103] Ketones have also been found to positively affected brain insulin resistance, mitochondrial function, and neurotransmission [123]. In two recent reviews examining a total of 18 RCTs, a ketogenic diet adherence was associated with improved general cognition, mental state, and episodic memory in patients with MCI and AD [104]. Ketones can also be provided by supplementing medium-chain triglycerides (MCT oil). A recent review found that while some studies have reported improvements in brain energy metabolism, more studies are needed to assess their effects on cognition [124].

Time-restricted eating, such as intermittent fasting, has been investigated for its positive impact on several AD risk factors like cerebrovascular disease and inflammation [125]. This is largely due to its ability to improve insulin sensitivity, which in turn also reduces the risk of type 2 diabetes and obesity. Intermittent fasting also helps the body produce ketones, which is important for minimizing the effect of amyloid beta and improving cognition. Intermittent fasting also improves mitochondrial health and reduce inflammation and oxidative stress, both of which are important for suppring cardiovascular health [125]. Although not in AD, a small, yet promising 3-year study of 99 patients with mild cognitive impairment, intermittent fasting improved cognitive function, insulin sensitivity, and inflammation [126].

While not as widely studied in AD patients, the Healthy Diet Index and Mediterranean Diet were examined in the multi-modal lifestyle intervention MIND-AD_mini. The study included an intervention group that received diet education and a supplemental drink and found a reduced likelihood of declining CDR-SOB scores (Clinical Dementia Rating- Sum of Boxes), but not global CDR scores [101].

Summary of the Effects of Diet on AD

Research exploring the impact of dietary interventions on AD reveals a disparity between the plethora of investigated options for cognitively healthy individuals and the limited number tested in those with established AD. Reviews and meta-analyses focusing on specific vitamins, minerals, fatty acids, and other natural products in placebo-controlled trials have yielded mixed results [107,109,112,117,118]. Similarly, only a few holistic dietary approaches have been examined. Regarding specific nutrients, B vitamin supplementation appears promising for slowing cognitive decline in AD patients [107], while the role of vitamin D remains inconclusive despite observational links [112]. Thiamine and selenium have shown some cognitive benefits, whereas vitamins E and C lack sufficient evidence [109,114]. Omega-3 fatty acids, beneficial for general brain health, have demonstrated little overall cognitive improvement in AD, though some language and visuospatial benefits were noted in one study [117]. Other natural products like curcumin [119] and ginseng [120] require more rigorous investigation. Multi-ingredient interventions show some promise in older adults without AD, but specific formulations for AD, like Souvenaid, lack strong evidence [122]. Shifting focus to broader dietary patterns, the ketogenic diet has shown potential for improving cognition and memory in individuals with MCI and AD [104]. Time-restricted eating has also demonstrated cognitive benefits in MCI [125]. While the Healthy Diet Index and Mediterranean Diet were explored in a multimodal study, significant cognitive benefits in AD were not consistently observed [101]. Overall, while certain dietary components and patterns offer potential, more robust research is needed to establish effective dietary interventions for individuals living with AD.

5. Effects of Exercise on Brain Health and Cognition in Patients with Ad

Physical activity is any bodily movement produced by skeletal muscles that requires energy expenditure. Exercise, on the other hand, is a subset of physical activity that is planned, structured, and repetitive, intending to improve or maintain physical fitness [127]. Regular endurance and resistance exercise training decreases age-related morbidity and mortality, improves risk factors for chronic disease, and helps maintain independent functioning [128,129,130]. Physical activity, including exercise, has been recognized as a means of preventing and managing AD.

5.1. Effects of Exercise on AD

Prevention. Growing evidence shows that physical activity and exercise play a significant role in preventing AD [131]. Animal studies indicate that exercise fosters brain health by stimulating neurogenesis [132], enhancing neuronal survival [133], boosting synaptic plasticity [134], and promoting vascularization [135,136]. In healthy older adults, exercise correlates with reduced cerebral amyloid deposition and modulates vascular dementia risk factors [137,138,139]. Specifically, it decreases inflammatory markers and elevates neuroprotective proteins such as BDNF while also improving glucose metabolism [140,141,142]. Endurance exercise, widely studied for its cognitive benefits, exhibits positive associations with cognitive function and a reduction in age-related brain volume decline in observational and some randomized trials [143,144,145]. Resistance training, although less researched, has demonstrated improvements in executive function, memory, and global cognition and offers unique benefits to muscle and bone health [146,147,148,149,150,151]. Combined aerobic and resistance training appears to be optimal for insulin resistance [152,153,154,155,156] and physical function [152,153,155], although there is a lack of direct comparison studies on cognition [157]. Emerging research highlights the potential cognitive benefits of alternative exercises such as yoga [158,159], Tai Chi [160,161], and high-intensity interval training (HIIT) [162,163,164,165,166,167], demonstrating improvements in memory, executive function, and brain structure. However, limitations exist, including the absence of a systematic review, the lack of studies testing current public health exercise recommendations, and the unclear role of alternative exercises in conjunction with traditional forms. Further research is needed to fully understand the independent and combined impacts of various exercise modalities on cognitive function and brain health in older adults.

In addition to prevention studies, low levels of physical activity is a risk factor associated with AD at a later age [168]. Findings from population-based cohort studies of older adults who exercise suggest that they are more likely to maintain their cognitive function as they age [169]. The English Longitudinal Study of Ageing (ELSA) suggests that inactive, low, and moderate-to-high active groups had a cumulative incidence of AD of 4.8% (95% CI: 4.4 to 5.4), 0.9% (95% CI:0.8 to 1.1), and 0.2% (95% CI: 0.1 to 0.5), respectively. In adjusted analyses, participants in the low and moderate-to-high active groups had, respectively, 60% and 78% lower risk of developing AD than the inactive group. Survival analyses revealed significant between-group differences in the cumulative incidence of dementia over 15 years based on the physical activity categories. This study suggests that even low levels of physical activity have beneficial effects in preventing AD [169]. A recent meta-analysis revealed a decreased risk of AD (0.86, 95% CI 0.80 to 0.93, n = 128, 261) is associated with physical activity participation. Neither baseline age, follow-up length, nor study quality significantly moderated the associations. Dose-response meta-analyses revealed significant linear, spline, and quadratic trends within estimates for all-cause dementia incidence but only a significant spline trend for AD. This suggests that physical activity is associated with a lower incidence of AD, even in longer follow-ups, supporting physical activity as a modifiable protective lifestyle factor, even after accounting for the effects of reverse causation [170].

Disease management. A recent meta-analysis of eight cohort and case-control studies examined whether physical exercise could improve, or at least maintain, the physical and functional capacity, cognitive performance, neuropsychiatric symptoms, and quality of life of patients with AD [171]. Six of the eight studies assessed physical function, and five of those reported positive effects of exercise on physical function tasks post-intervention [172,173,174,175,176]. One intervention even noted that, one year post-intervention, all groups showed deterioration. However, this was greater for the control group (p = .003) than for the physical exercise group [172]. This suggests a protective effect could, therefore, be attributed to physical exercise. Five of the eight studies assessed cognitive function, and all five reported a positive impact of exercise on cognitive function following the intervention [173,175,176,177,178]. Similarly, two of eight studies examined neuropsychiatric symptoms, and both reported positive effects of exercise post-intervention [176,177]. In addition, two of the eight studies examined the quality of life and reported a positive impact of exercise in one, while the other study reported no difference [173,177]. Similarly, a meta-analysis of 16 trials revealed that physical activity (PA) significantly improved global cognition in AD (SMD = 0.41, p < 0.01) [179]. Aerobic exercise (SMD = 0.60) was more effective than mixed exercises (SMD = 0.24). Shorter exercise sessions (<45 minutes, SMD=0.66) yielded greater cognitive benefits than longer ones (SMD = 0.27). Moderate to severe AD stages showed larger improvements (SMD = 0.75) compared to mild to moderate stages (SMD = 0.20). The time of the exercise session had a significant impact on cognition (β = -0.0105, p = 0.03). Nine studies within the meta-analysis indicated that PA also significantly improved Activities of Daily Living (ADL) in AD patients (SMD = 0.56, p < 0.001). Other factors, such as exercise duration and frequency, did not show significant differences in cognitive outcomes. Together, these studies suggest that participation in physical activity is beneficial for cognitive function, physical outcomes, and overall disease management in individuals with AD.

5.2. Mechanism of Action for the Effect of Exercise on AD Pathology

Brain structure. Studies investigating the relationship between physical activity and brain volume in individuals with AD have yielded mixed results, suggesting a complex interplay between factors. Using tensor-based morphometry imaging, Boyle et al. found that physical activity has a protective effect on brain volume in relation to AD in individuals enrolled in the Cardiovascular Health Study [180]. Higher physical activity levels were correlated with increased overall brain and parietal lobe volume and reduced ventricular dilation, factors often compromised in AD. Conversely, a higher Body Mass Index (BMI) was associated with reduced brain volume, particularly in the frontal, temporal, parietal, and occipital lobes, including the orbitofrontal cortex and anterior cingulate gyrus. Overlapping brain regions, including the orbitofrontal cortex, posterior cingulate gyrus, and posterior hippocampus, are affected by both physical activity and BMI. AD and Mild Cognitive Impairment (MCI) are associated with decreased brain volume, particularly in the frontal lobe and ventricular dilation. While physical activity did not show a direct interaction with AD/MCI diagnosis, BMI did, demonstrating that higher BMI and AD/MCI are associated with reduced brain volume, predominantly in the frontal lobe [180].. Cross-sectional research also shows a significant positive correlation between cardiorespiratory fitness and parietal and medial temporal volume in AD patients. In contrast, non-demented patients did not exhibit a significant relationship between brain volume and cardiorespiratory fitness globally. In early-stage AD, cardiorespiratory fitness was also associated with regional brain volumes in the medial temporal and parietal cortices, suggesting that maintaining cardiorespiratory fitness may modify AD-related brain atrophy [181]. Very few RCTs have been conducted to evaluate the impact of exercise on brain structure in patients with AD. A recent meta-analysis [182] found three studies evaluating the influence of a physical activity intervention on regional brain volume. Morris and colleagues [183] found that individuals with probable AD enrolled in a 26-week RCT comparing the effects of 150 minutes of aerobic exercise per week versus non-aerobic stretching showed that a change in cardiorespiratory fitness was positively correlated with changes in memory performance and bilateral hippocampal volume. Vidoni et al. [184] on the other hand, it was found that 52 weeks of aerobic exercise also significantly improved cardiorespiratory fitness (11% vs. 1% in the control group); however, there were no differences in change measures of amyloid, brain volume, or cognitive performance compared to control. Similarly, Frederiksen et al. did not find evidence to support the effect of a 16-week aerobic exercise intervention on brain volume changes in patients with AD. Overall, the effect of physical activity on brain volume and structural changes in individuals with AD remains inconclusive.

Brain function. Few studies have investigated the impact of physical activity on brain function in patients with AD. Several studies have investigated the relationship between physical activity level and brain function in individuals at risk for AD, specifically in those carrying the APOE4 allele. The findings suggest that higher cardiorespiratory fitness or reported physical activity is associated with greater brain activity when compared to those with lower cardiorespiratory fitness or physical activity levels [185,186]. In addition, brain imaging (functional MRI) has been used to understand and predict cognitive decline, particularly in relation to AD risk and physical activity. Early cognitive decline can lead to increased brain activity, as measured by the BOLD signal, during episodic memory tasks, making it challenging to interpret fMRI results accurately [187]. Paradoxically, higher brain activation during these tasks can predict future cognitive decline. Semantic memory, which encompasses general knowledge, is less affected by normal aging but is more susceptible to early AD. Lower brain activation during semantic tasks may indicate a higher risk of cognitive decline. Semantic memory areas overlap with brain regions affected by AD, making it a potentially more reliable marker than episodic memory. Studies show that higher PA is linked to greater brain activation during the famous name task, particularly in individuals with APOE4 [188]. This suggests that PA may provide neuroprotection and delay cognitive decline, especially in those at genetic risk. In addition, Woodard et al. [188] demonstrated that even among individuals with the genetic marker for increased Alzheimer’s risk, high levels of physical activity resulted in brain scans that resembled those of individuals with low genetic risk. Therefore, while the mechanisms are complex and require further study, evidence suggests that physical activity may modulate brain function in individuals at risk for AD, potentially offering a protective effect, particularly in those with genetic predispositions, such as the APOE4 allele.

Amyloid-β and Tau. Exercise may help regulate the production and clearance of amyloid beta and tau, which are previously discussed hallmarks of AD. A recent systematic review and meta-analysis examining the anti-amyloid effect of regular exercise in animal models suggests that regular aerobic exercise is associated with a decrease in amyloid beta [189]. This reduction of amyloid beta was associated with a decrease in the amyloidogenic pathway and an increase in the non-amyloidogenic pathway. Hence, regular physical exercise has been shown to exhibit an anti-amyloid effect in experimental models of AD, leading to positive alterations in amyloid precursor protein processing through various signaling pathways [189,190]. Similarly, in animal models of tauopathy, exercise has been shown to reduce brain tau phosphorylation [191,192]. However, models are limited.

Research exploring the impact of exercise on Amyloid Beta in humans is still limited. A meta-analysis of eight studies found no overall effect favoring exercise interventions was observed for both negative (SMD95% = 0,286 [-0,131; 0,704]; p = 0,179) or positive AD status (SMD95%=0,110 [-0,155; 0,375]; p = 0,416) [193]. The absence of an overall effect favoring exercise interventions was also found for Amyloid beta peptides (SMD95% = 0,226 [-0,028; 0,480]; p = 0,081) and soluble amyloid precursor protein components (SMD95% = -0,038 50 [-0,472; 0,396]; p = 0,863) levels. This suggests that exercise interventions do not improve Amyloid beta-related pathology in both healthy individuals and individuals with dementia (SMD95% = 0,157 [-0,059; 0,373]; p = 0,155), indicating that the beneficial effects of exercise for AD reported in previous studies are related to other mechanistic effects rather than direct amyloid effects. Similarly, the findings for the effect of exercise on Tau in human patients have also yielded no significant effects, per a meta-analysis including four studies [194,195].

Neurotrophic Factors. Physical activity stimulates the release of brain-derived neurotrophic factor (BDNF), promoting neuronal growth and survival in mouse models [196,197] and some non-demented older adults [198,199]. However, a meta-analysis by Huang and colleagues included eight studies (7 RCTs and 1 non-RCT) that measured BDNF from blood samples. The results revealed no significant effect on exercise’s ability to change BDNF levels in individuals with AD [194].

Inflammation. Exercise can reduce inflammation in the brain, which is linked to AD progression [200]. A meta-analysis by Huang and colleagues included nine studies (7 RCTs and 2 non-RCTs) evaluated the effects of exercise on inflammatory factors, with eight including Tumor necrosis factor (TNF-α) and six including Interleukin-6 (IL-6) [194]. For TNF-α, the meta-analysis indicated an insignificant effect, however, subgroup analyses revealed aerobic exercise had a significant decreasing impact on the level of TNF-α (SMD = −1.21; 95%CI: −2.29, −0.14). The result of the meta-analysis for IL-6 showed that exercise interventions could significantly decrease the level of IL-6, with a pooled SMD of −0.45 (95% CI: −0.72, −0.18) and low heterogeneity (I2 = 17.0%). No significant differences were found for other inflammatory factors including Interleukin-10 or C-reative protein.

Metabolism. Participation is physical activity and exercise is assocaiated with improved metabolic indicators and insulin sensitivity [201] and Mitochondrial function in older adults [202]. Twelve studies (10 RCTs and 2 non-RCTs) measured the effects of exercise interventions on metabolic indicators, such as insulin, cholesterol, and cortisol [194]. Eight of them included cholesterol markers, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride. The meta-analysis for LDL revealed a significant effect induced by exercise, with a pooled SMD of −0.26 (95% CI: −0.50, −0.01; I2 = 0.0%). In contrast, no significant effects were found on HDL, triglycerides, and total cholesterol. In addition, one study evaluated the effects of exercise interventions on cortisol secretion [203]. Considering the diurnal rhythm of cortisol, Ho et al. [203] collected the salivary samples at five-time points and found that the exercise groups showed a more dynamic diurnal pattern of cortisol secretion compared with the control groups. Current research also shows that exercise promotes mitochondria communication with other organelles in AD neurons, however, the therapeutic potential of exercise is not conclusive [204,205].

Vascular changes. Pre-clinical and clinical studies suggest that exercise may enhance cerebral blood flow and vascular function, thereby promoting vascular repair in the aging and AD- affected brain [206]. Additionally, gender and APOE status may moderate the cerebrovascular response to exercise in healthy older adults [207] as well as amyloid burden [208]. Unfortunately, limited studies exploring the impact of exercise on cerebrovascular function in patients with AD are available. One small study in 39 patients with AD show that individuals who completed moderate to high-intensity aerobic activity and strength training, increased flow-medicated dilation (+ 3.725%, p < 0.001), passive leg movement (+ 99.056 ml/min, p = 0.004), the area under the curve (+ 37.359AU, p = 0.037) and vascular endothelial growth factor (+ 8.825 pg/ml, p = 0.004) after 6 months. In the control group, no difference between pre-and post-treatment was found for any variable. Additionally, an increase in blood flow and shear rate was observed during exercise (p < 0.05 for both), but not during the control treatment [209].

Improved Cognitive Function. Exercise in healthy older adults has been shown to affect cognitive function positively in observational and some randomized trials [143,144,145,146,147,148,149,150,151]. Regular physical activity can enhance memory, attention, and executive function in individuals with early-stage AD [210]. A recent review by Demurtas et al. [210] found that in patients with AD, physical activity/exercise effectively improved global cognition (SMD = 1.10; 95% CI 0.65–1.64). Thus, this review suggests that physical activity/exercise positively affects several cognitive aspects of AD, but additional RCTs are still needed to confirm this relationship [210]. In addition, Liang et al. [211], in a systematic review of 21 studies also reports improvements in the mini-mental state exam (MMSE) and Alzheimer’s Disease Assessment Sclae- Cognition (ADAS-cog) with participation in exercise (MMSE: SMD = 0.46, 95% CI = 0.29 ∼ 0.63, p < 0.01; ADAS-cog: SMD = −0.23, 95% CI = −0.4 ∼−0.06, p < 0.01). Regular exercise appears to positively impact various cognitive functions, including memory, attention, and executive function, in healthy older adults and individuals with AD, as indicated by improved scores on cognitive assessments. However, further research is needed to solidify these findings.

Behavioral symptom management. Physical activity is a favorable non-pharmacological means for attenuating the neuropsychiatric symptoms of elderly people with AD [210]. Liang et al. [211] showed that participation in exercise is associated with improvements in neuropsychological symptoms (Neuropsychiatric Inventory Questionnaire, NPI: SMD = −0.3, 95% CI = −0.52 ∼−0.08, p < 0.01). Similarly, a review of 13 studies by McCartney et al. [212] suggests that exercise is effective in reducing agitation and studies with higher adherence to exercise demonstrated more positive effects on agitation and behaviours that challenge. Additionally, in healthy older adults, exercise has a positive impact on the prevention of the development of circadian rhythm disturbances and stimulates the resynchronization of circadian rhythms. This overall helps to promote restful sleep [79,213,214]. Previous RCTs in older adults show that older adults can successfully improve their sleep quality through exercise [215]. Moderate physical activity has also been found to improve sleep in individuals with AD [216]. Physical activity offers a beneficial non-drug approach for reducing neuropsychiatric symptoms like agitation and improving sleep quality by regulating circadian rhythms in elderly individuals, including those with AD.

5.3. Influence of Exercise Type on AD

Aerobic Exercise, including activities like walking, jogging, swimming, and cycling, have shown promising results in mitigating the effects of AD. A recent meta-analysis of RCTs by Zhang et al. [217] included 15 RCTs. The authors found a significant effect of aerobic exercise on increasing MMSE score in AD patients [weighted mean difference (WMD), 1.50 (95% CI, 0.55 to 2.45), p = 0.002]. Subgroup analyses showed that interventions conducted 30 min per session [WMD, 2.52 (95% CI, 0.84 to 4.20), p = 0.003], less than 150 min per week [WMD, 2.10 (95% CI, 0.84 to 3.37), p = 0.001], and up to three times per week [WMD, 1.68 (95% CI, 0.46 to 2.89), p = 0.007] increased MMSE score significantly. In addition, a worse baseline cognitive status was associated with greater improvement in MMSE scores. Unfortunately, aerobic exercise in humans has not been shown to reduce amyloid accumulation in cognitively normal older adults at risk for AD [44] or individuals with AD [193]. Inter-individual differences in aerobic fitness and cognitive responses to aerobic exercise in older adults with mild-to-moderate dementia due to AD [218]. However, additional research is needed to determine the impact of aerobic exercise on AD prevention and the reduction of pathology and associated symptoms.

Strength training, also known as resistance exercise, is characterized by contractions of specific muscles against external resistance. It has emerged as an essential strategy to improve muscle mass and strength, bone density, overall body composition, as well as functional capacity and balance, thereby attenuating or even reversing sarcopenia and reducing difficulties in task performance [219,220]. It may improve cognitive function and overall physical health, which is essential for maintaining independence in individuals with AD. Overall, fewer RCTs utilizing resistance training have been completed compared to those utilizing aerobic exercise. Vital et al. [221] found in a sample of 34 older adults with AD that there was no significant difference associated with cognition in patients with AD when comparing resistance training and social gathering group activities. However, this is a single study. Additionally, although reviews [222] suggest that resistance training may prevent or ameliorate AD, this relationship has not been fully characterized; therefore, additional research is warranted.

Mind-body exercises, such as Yoga and tai chi, can enhance balance, coordination, and cognitive function in older adults [223]. Unfortunately, no research is currently available on the association between AD symptoms and mind-body exercise. In individuals with MCI, yogic practices can have positive effects on sleep, stress levels, BDNF, serotonin levels, and brain volume. As both in vitro and/or in vivo studies have shown that sleep, stress levels, and serotonin directly act on amyloid-beta, it is tempting to speculate that yoga and meditation might slow disease progression in AD patients [224]. However, given the lack of RCTs to test this hypothesis, additional research is needed.

6. Exercise and AD Summary

Regular physical activity, particularly structured exercise, is increasingly recognized for its potential in preventing and managing AD. In prevention, exercise in animal models promotes brain health through neurogenesis, neuronal survival, synaptic plasticity, and vascularization [131,222,225]. Studies in healthy older adults link exercise to reduced amyloid deposition, modulation of vascular risk factors, decreased inflammation, and increased neuroprotective proteins like BDNF, alongside improved glucose metabolism [44,185,189,190,201,208]. While endurance training shows cognitive benefits and reduced brain volume decline, resistance training improves executive function, memory, and global cognition [44,173,176,183,217]. Combined aerobic and resistance training appears optimal for metabolic and physical function, and emerging research suggests benefits from yoga, Tai Chi, and HIIT, though more systematic research is needed. Population-based studies indicate that even low physical activity levels are associated with a lower risk of developing AD [169,226].

In managing existing AD, exercise has shown promise in improving physical and functional capacity, cognitive performance, and neuropsychiatric symptoms, although effects on quality of life are less consistent. Meta-analyses suggest that physical activity significantly improves global cognition and activities of daily living in AD patients, with aerobic exercise and shorter sessions potentially being more effective [179,182,211,217,227]. Mechanistically, while the impact of exercise on brain structure in AD is still under investigation with mixed results, some studies suggest a protective effect on brain volume and a correlation between cardiorespiratory fitness and brain volume in specific regions [179,217]. Exercise may also modulate brain function, particularly in individuals at genetic risk for AD [185]. While animal studies show exercise can regulate amyloid-beta and tau, human studies have not yet demonstrated a significant direct impact on these AD hallmarks [10,44,189]. However, exercise can influence neurotrophic factors (though not consistently BDNF in AD patients), reduce inflammation (especially TNF-α with aerobic exercise and IL-6), improve metabolic indicators like LDL cholesterol, enhance vascular function, and ultimately lead to improved cognitive function and behavioral symptom management in individuals with AD [174,199,206]. Different types of exercise, such as aerobic, strength training, and mind-body practices, show varying degrees of benefit, warranting further specific investigation [217,221,222,224].

6.1. Exercise Recommendations for Individuals with AD

Strong evidence exists of a protective effect of regular exercise against AD risk. However, the dose-response association is unclear [227]. Based on current meta-analysis and systematic reviews, aerobic exercise, especially when conducted for 30 minutes per session, less than 150 minutes per week, and up to three times per week, improves cognitive function in AD patients. Additionally, a worse basal cognitive status contributed to more significant improvements in cognitive function [217,227]. Unfortunately, the evidence for other forms of exercise, including resistance training and mind-body exercises, is currently unavailable.

6.2. Diet and Exercise, the Effect of Combined Intervention on AD

Limitations of Available Research

Dietary research on AD is hampered by several inherent limitations. The complexity of nutritional interventions, involving numerous interacting components, contrasts with the simplicity of single-compound drug trials, making it challenging to pinpoint specific beneficial elements. The typically slow progression of AD necessitates lengthy and costly studies to observe meaningful effects, often plagued by difficulties in maintaining participant adherence and high dropout rates. The heterogeneity of AD, with its diverse presentations influenced by individual factors, further complicates the identification of universally effective dietary strategies. Blinding participants and researchers to dietary changes is often impractical, introducing potential bias. Accurately assessing long-term dietary intake remains a methodological challenge, relying on potentially inaccurate recall-based methods. Many current studies suffer from small sample sizes, limiting their statistical power. The timing of intervention relative to the disease stage is critical but often variable across studies. Participant-related factors, such as advanced age, co-existing health conditions, cognitive impairment affecting eating habits, and varying socioeconomic circumstances influencing access to specific foods and support, add further layers of complexity. Finally, the sensitivity of cognitive tests to detect subtle dietary-induced changes and the limited immediate responsiveness of AD biomarkers pose challenges in measuring outcomes. Overcoming these limitations through more rigorous study designs, larger and more diverse cohorts, extended intervention durations, improved assessment methods, and relevant outcome measures is essential to advance our understanding of the role of diet in addressing AD.

Similar to the research on diet, the research on the effects of exercise on brain health and cognition in the context of AD also faces several limitations. While animal studies offer promising insights into the mechanisms by which exercise might prevent AD, including promoting brain health at a cellular level and potentially regulating amyloid and tau, these findings haven’t consistently translated to human studies, particularly concerning direct impacts on AD’s biological hallmarks. The effects of exercise on brain structure in individuals with AD also remain unclear, with studies yielding mixed results. Furthermore, the influence of exercise on neurotrophic factors like BDNF in AD patients is not consistently observed. Research on alternative exercise types beyond aerobic and resistance training, such as yoga, Tai Chi, and HIIT, is still emerging and requires more systematic investigation. A lack of direct comparative studies between different exercise modalities and the need for more robust RCTs further limit the current understanding. Establishing optimal exercise parameters and consistently demonstrating improvements in quality of life for AD patients also present ongoing challenges. The complexity of interpreting brain function changes in early AD and the limited research on cerebrovascular function in this population add to the existing limitations. Finally, the potential role of mind-body exercises in managing AD symptoms warrants dedicated future research [171].

7. Conclusion

In conclusion, this paper has illuminated the intricate cascade of structural, functional, neurochemical, metabolic, and vascular alterations that characterize the AD brain, culminating in a progressive decline in cognitive abilities, particularly episodic memory and executive functions, and often accompanied by behavioral, mood, sleep, and appetite disturbances. Furthermore, it has explored the significant role of modifiable lifestyle factors, specifically diet and exercise, in potentially mitigating the impact of this devastating disease. While research into specific dietary components and holistic dietary patterns offers some promising leads, particularly regarding B vitamins and the ketogenic diet, the evidence for consistent benefits in established AD remains limited and requires further rigorous investigation. Similarly, physical activity, especially aerobic exercise, demonstrates potential in improving cognitive function, managing neuropsychiatric symptoms, and possibly influencing underlying AD pathology. However, the precise mechanisms and optimal exercise parameters are still being elucidated. Despite the encouraging findings, both dietary and exercise research in the context of AD face considerable limitations, including the complexity of interventions, challenges in study design and adherence, the heterogeneity of the disease, and difficulties in accurately measuring long-term effects on both cognition and brain biology. Recognizing and addressing these limitations in future research endeavors is crucial to fully harness the therapeutic potential of these modifiable lifestyle factors in the ongoing fight against AD.