Nutrition: A non‐negligible factor in the pathogenesis and treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a degenerative disease characterized by progressive cognitive dysfunction. The strong link between nutrition and the occurrence and progression of AD pathology has been well documented. Poor nutritional status accelerates AD progress by potentially aggravating amyloid beta (Aβ) and tau deposition, exacerbating oxidative stress response, modulating the microbiota–gut–brain axis, and disrupting blood–brain barrier function. The advanced stage of AD tends to lead to malnutrition due to cognitive impairments, sensory dysfunctions, brain atrophy, and behavioral and psychological symptoms of dementia (BPSD). This, in turn, produces a vicious cycle between malnutrition and AD. This review discusses how nutritional factors and AD deteriorate each other from the early stage of AD to the terminal stages of AD, focusing on the potential of different levels of nutritional factors, ranging from micronutrients to diet patterns. This review provides novel insights into reducing the risk of AD, delaying its progression, and improving prognosis.

Highlights

• Two‐fifths of Alzheimer's disease (AD) cases worldwide have been attributed to potentially modifiable risk factors.

• Up to ≈26% of community‐dwelling patients with AD are malnourished, compared to 7%∼76% of institutionalized patients.

• Undernutrition effects the onset, progression, and prognosis of AD through multiple mechanisms.

• Various levels of nutritional supports were confirmed to be protective factors for AD via specific mechanisms.

1. INTRODUCTION

Alzheimer's disease (AD) is a degenerative disease of the central nervous system (CNS) characterized by progressive cognitive dysfunction and behavioral impairment. As the leading cause of dementia, AD affects more than 50 million people worldwide, as reported by the World Alzheimer's Disease 2021. ¹ In 2019, the World Health Organization declared AD as the seventh leading cause of death worldwide. AD diminishes quality of life and imposes a huge economic burden on families and health care systems. The global cost of AD is expected to reach $2.54 trillion by 2030, rising to $9.12 trillion by 2050. ² Therefore, effective preventive and therapeutic strategies remain urgently needed. Currently, the prevailing hypothesis suggests that the accumulation of amyloid β (Aβ) deposits and the formation of tau protein neurofibrillary tangles in the brain trigger the onset of AD. ³ However, the pathological mechanisms underlying AD remain highly complex and involve multiple factors, such as excessive oxidative stress, immune response dysregulation, and inflammatory insults. ⁴ , ⁵ , ⁶ No therapy for AD exists at the moment. Apart from pharmaceutical treatments targeting the pathology of AD, a consensus among experts to treat high‐risk AD populations by intervening in modifiable risk factors for dementia has been reached. ⁷ , ⁸ , ⁹

The occurrence of approximately two‐fifths of all reported AD cases worldwide may be attributed to potentially modifiable risk factors, which suggests that these cases of dementia can be avoided, ¹⁰ particularly in low‐ and middle‐income countries. ¹¹ This provides a new avenue for the treatment of AD, reducing its incidence by addressing the underlying risk factors for cognitive impairment. ¹² , ¹³ , ¹⁴  According to a Lancet report, modifying 12 risk factors and lifestyles, including dietary interventions, can prevent or delay 40% of the incidence of AD. ¹⁰ In addition, results from well‐designed randomized controlled trials (RCTs) suggest that multidomain lifestyle interventions, including nutritional counseling or dietary guiding, can improve or maintain cognitive functioning in at‐risk older adults in the general population. ¹⁵ , ¹⁶ , ¹⁷ This strong connection between nutrition and cognitive function has attracted research attention; indeed, clinical studies have linked malnutrition and weight loss, adherence to poor dietary patterns, poorer diet quality, and lack of a specific nutrient to a higher risk of AD onset, AD progression, and poorer prognosis. ¹⁸ , ¹⁹ , ²⁰ Furthermore, results from animal studies also suggest that deficiencies in certain nutrients (e.g., vitamins, micronutrients, and lipids) affect AD progression through various mechanisms, such as increasing Aβ deposition, decreasing Aβ clearance, and exacerbating oxidative stress. In contrast, different nutritional patterns can impact AD progression through the gut flora. ²¹ Supplementation with vitamins, folic acid, and other nutrients reduces the risk of AD. ²² In addition, certain dietary patterns, such as the Mediterranean Diet (MeDi), Dietary Approaches to Stop Hypertension (DASH) diet, and the Mediterranean‐DASH Intervention for Neurodegenerative Diseases (MIND) diet, are associated with better cognitive performance. Conversely, poor dietary patterns characterized by a high intake of saturated fats, simple carbohydrates, and sodium are linked to decreased cognitive performance. ²³ The concept of Dietary Inflammatory Index (DII) was developed to characterize the inflammatory potential of diet. ²⁴ Higher DII score was associated with increasing risk of AD incidence. ²⁵ , ²⁶ Therefore, exploring the association between nutrition and AD remains necessary.

The mechanisms by which nutrition influences cognitive function have been investigated previously; however, limited studies have focused on bidirectional relationships. Thus this review aims to fill these gaps by offering a thorough summary and assessment of research on the link between nutritional factors and AD, emphasizing the primary mechanisms through which undernutrition and AD mutually worsen each other. This review also discusses the impact of nutritional factors on the onset, progression, and prognosis of AD and the underlying mechanisms; and clarifies the effects of nutritional composition, food, and dietary patterns on AD, to provide novel insights into strategies for improving the prognosis and regression of patients with AD.

2. IN PATIENTS WITH AD

2.1. Prevalence of malnutrition in patients with AD

Malnutrition, defined as overnutrition or undernutrition, is prevalent among older adults. Approximately 10% of homebound older adults, 30% of older adults in nursing homes, and 70% of older adults in hospitals experience malnutrition. ²⁷ Malnutrition is more common and has a greater impact on patients with AD. ²⁸ Evidence from observational studies has indicated that the prevalence of malnutrition ranges from 0% to 26% in community‐dwelling patients, ²⁹ , ³⁰ , ³¹ with a higher rate of 7% to 76% in institutionalized patients. ³² , ³³ Longitudinal studies have shown that the prevalence of malnutrition increases as AD progresses, with a lower risk in patients with mild cognitive impairment (MCI)—the reversible intermediate stage between cognitive changes associated with normal aging and more severe cognitive decline associated with dementia—than AD, but a higher risk than in adults with healthy cognition. ²⁹ , ³² , ³⁴ However, no definitive conclusions have been reached regarding the specific prevalence of malnutrition in patients with AD, possibly because the prevalence varies according to geographic region, study population, definitions, and methodology. Strong evidence has indicated a close connection between undernutrition and AD. Therefore, more data from well‐designed RCTs are urgently required to determine the correlation between the severity of nutritional deficiencies and the stage of AD.

2.2. Mechanisms and manifestations of undernutrition in each stage of AD

Undernutrition can occur at any stage of AD, and is caused by an imbalance between nutrient or energy intake and requirements, specifically due to decreased energy intake and increased energy expenditure (Figure 1). ³⁵ , ³⁶ For each stage of AD, different factors, such as weight loss, sarcopenia, and frailty, play important roles. ³⁷ Therefore, it is essential to identify nutritional deficiencies in patients with AD and take early intervention to prevent and slow the onset and progression of the disease.

FIGURE 1.

The vicious circle among Alzheimer's disease (AD) development and undernutrition. Created with BioRender.

In the early stages of AD, impairments in different cognitive domains that reduce food intake lead to malnutrition in patients with MCI; for example, memory loss may lead to forgetfulness regarding meals, impaired executive functioning can diminish the capacity to utilize utensils and engage in cooking activities, aphasia can hinder the ability to articulate food‐related needs and express hunger, and impaired decision‐making may impede timely food choices and decrease overall food intake, ultimately resulting in weight loss, ³⁸ , ³⁹ symbolizing poor nutritional status. In addition, the high prevalence of sensory dysfunctions, particularly in the gustatory and olfactory senses, in patients with early‐stage of AD ⁴⁰ , ⁴¹ , ⁴² , ⁴³ contributes to poorer nutritional status by limiting appetite or changing food preferences. ⁴³ , ⁴⁴ , ⁴⁵ The first and the most common symptom of undernutrition in patients with AD is considered to be weight loss, ⁴⁶ which can occur several years before AD diagnosis, and is likely to worsen as the disease progresses. ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ Moreover, lower baseline body mass index (BMI) and non‐obese BMI loss are significantly associated with an increased risk of MCI and AD, ¹⁸ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷ amplified by apolipoprotein E (APOE) ɛ4. ⁵⁸ Therefore, nutritional support to high‐risk populations and patients with early‐stage AD may reduce the incidence and delay the development of AD.

Meanwhile, for mid‐ to late‐stage disease, AD‐related brain atrophy may affect brain regions involved in appetite control and energy balance, including the medial temporal cortex, hypothalamus, and anterior cingulate cortex. ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² , ⁶³ Decreased metabolism in these brain regions causes anorexia nervosa, which leads to nutritional deficits and reduced myosin synthesis, and tends to present more significant weight loss and sarcopenia. ⁶⁴ Evidence from cross‐sectional and prospective studies suggests that apart from its impact on morbidity, weight loss contributes to the promotion of AD‐derived MCI progressing to AD. ⁶⁵ , ⁶⁶ , ⁶⁷ Greater weight loss leads to faster cognitive decline. ⁶⁸ , ⁶⁹ Sarcopenia has the same impact on AD progression. ⁷⁰ , ⁷¹ , ⁷² , ⁷³ , ⁷⁴ Furthermore, undernutrition adversely affects the prognosis of AD, ⁷⁵ and is the strongest predictor of death in patients with AD. ²⁰ , ⁷⁶ As the disease worsens, nutritional support shifts the emphasis from preventing AD to delaying AD progression and improving the prognosis.

In the terminal stages of AD, the development of severe behavioral and psychological symptoms of dementia (BPSD) further exacerbates undernutrition. Evidence indicates that patients with AD facing the risk of undernutrition or nutritional deficiencies generally exhibit higher Neuropsychiatric Inventory (NPI) scores than those with normal nutritional status. ⁷⁷ Disinhibition and aggressive behaviors, such as agitation and wandering, can elevate total energy expenditure. ⁷⁸ , ⁷⁹ , ⁸⁰ Conversely, apathy and appetite loss may reduce energy intake. ³⁴ Furthermore, oropharyngeal dysphagia, which is common in late‐stage AD, affects 80% of elderly patients with AD, ⁸¹ and is associated with malnutrition and weakness. ⁸² , ⁸³ In addition, medications, particularly cholinesterase inhibitors, are widely used in the treatment of AD and can also contribute to weight loss through adverse gastrointestinal effects. ⁸⁴ , ⁸⁵ , ⁸⁶ , ⁸⁷ , ⁸⁸ , ⁸⁹ The multidimensional concept of frailty, ⁹⁰ , ⁹¹ which reflects changes in body composition, compromised energetics, and homoeostatic decompensation, was applied to terminal‐stage AD patients with undernutrition. ⁹² , ⁹³ , ⁹⁴ Reversing frailty reduces the incidence of AD ⁹⁵ ; therefore, advanced‐stage patients with AD have great potential to improve quality of life and reduce mortality.

2.3. Mechanisms underlying undernutrition exacerbate AD

Undernutrition exacerbates AD through various mechanisms, of which genetic predisposition is one of the most significant. The adverse effect of weight loss on AD is amplified by APOE ɛ4, ⁵⁸ probably mediated by lipid metabolism. ⁹⁶ , ⁹⁷ Another mechanism through which undernutrition exacerbates AD is the aggravation of AD biomarkers. Previous studies have suggested that poor nutritional status, including weight loss, lowers the levels of Aβ42/40 and increases those of total tau (t‐tau), phosphorylated tau (p‐tau, and neurofilament light (NFL) in cerebrospinal fluid (CSF). ²⁸ , ⁹⁸ A similar association between lower body weight and plasma AD biomarkers has been reported. ⁹⁹ Patients with poor nutritional status tend to have unhealthy gut microbes, ¹⁰⁰ and gut dysbiosis–mediated dysfunction in the microbiota–gut–brain axis signaling is linked to AD development. ¹⁰¹ Moreover, a common feature of undernutrition is the deficiency of specific nutrients that maintain cerebral metabolism. For example, lack of vitamin B and other antioxidants exacerbates the oxidative stress response and contributes to neuroinflammation. ¹⁰² Based on blood–brain barrier (BBB) imaging technology, previous studies have confirmed that a lack of omega‐3 polyunsaturated fatty acids (PUFAs) would disrupt BBB integrity and glymphatic function, ⁹⁶ , ¹⁰³ , ¹⁰⁴ which decreases effective brain‐waste clearance, especially the clearance rate of Aβ and iron, ¹⁰⁵ , ¹⁰⁶ ultimately leading to AD.

3. POTENTIAL IMPACT OF NUTRITIONAL SUPPORT ON THE PREVENTION AND TREATMENT OF AD

3.1. Impact of nutritional composition on AD

3.1.1. Vitamins

Elevated plasma homocysteine levels are recognized as an independent risk factor for AD. ¹⁰⁷ B vitamins (folate, vitamin B6, and vitamin B12) are involved in homocysteine metabolism and can reduce its plasma concentrations, implying that supplementation with B vitamins can potentially improve cognition. Results from animal studies have found that cognitive deficits are present in mouse models of AD fed a vitamin B–deficient diet ¹⁰⁸ by elevating Aβ deposits in the hippocampus and cortex (Table 1). ¹⁰⁹ Vitamin B12 markers may be independent predictors of CSF biomarkers of AD and cognitive function. ¹¹⁰ Furthermore, a double‐blind RCT found that supplementation with 0.8 g of folic acid per day for 3 years significantly improved cognitive function in individuals 50–70 years of age. ¹¹¹ Another RCT found positive therapeutic effects of folic acid and vitamin B12 supplementation on the cognitive performance of patients with AD. ¹¹² However, other interventional studies have not found improved cognition following vitamin B supplementation. ¹¹³ In a meta‐analysis of 95 studies involving 46,175 subjects, vitamin B supplementation was associated with slowing cognitive decline; however, subgroup analyses revealed that the correlation between vitamin B supplementation and changes in Mini‐Mental State Examination (MMSE) scores was not significant in individuals with pre‐existing dementia at baseline. Notably, the effects were particularly significant in individuals who received the intervention for more than 12 months and those without dementia. ¹¹⁴ This evidence suggests that vitamin B supplementation does not improve cognitive function in patients with established dementia but positively affects individuals who receive early intervention in the preclinical phase and those who receive long‐term intervention. However, consensus on the accurate definition of optimal timing and dosage for intervention remains lacking.

TABLE 1.

Summary of the major dietary sources of nutrition and their mechanisms of improving cognition.

Nutrient	Major dietary sources	Mechanisms of improving cognition
Vitamin A (Carotenes)	Yellow or orange vegetables (sweet potatoes, carrots, and pumpkins), dark leafy vegetables (spinach, broccoli, and endives), and yellow or orange fruits (apricots, peaches, mangoes, and melons) 115	Reducing inflammatory molecules 116 Enhancing Aβ clearance 117
Vitamin B9 (folate)	Dark‐green leafy vegetables, legumes, oranges and grapefruit, peanuts and almonds, offal (liver and kidney), and baker's yeast 118	Modulating brain lipid metabolism 119 Reducing the deposition of Aβ and tau phosphorylation 120 , 121
Vitamin B12 (cobalamin)	Animal products (dairy products, eggs, meats, fish, and liver), foods that contain yeast or have been exposed to microbial fermentation (e.g., beer), and fortified foods (e.g., ready‐to‐eat cereals) 122	Inducing oxidative stress 123 Delaying Aβ‐induced paralysis 124
Vitamin C (ascorbic acid)	Fruits (berries, citrus fruits, kiwis, lychees, and papayas), vegetables (Brussels sprouts, cauliflowers, cabbages, sweet peppers, and tomatoes), and herbs and spices (parsley, sorrel, and chives) 125	Inhibiting oxidative and inflammatory pathways 126 Suppressing Aβ fibrillogenesis 127
Vitamin D (25 hydroxyvitamin D)	Fish (especially fatty fish) and fish liver, full‐fat dairy products (or fortified low‐fat ones), egg yolk, meat and meat products, and offal (particularly liver) 128	Modulating age‐related increase in pro‐inflammatory state and Aβ burden 129 , 130 Influenced by gene regulation 131
ω3‐PUFAs	Fish (for eicosapentaenoic acid and docosahexaenoic acid) and some vegetable oils and nuts (e.g., linseeds, rapeseed oil, and walnuts for α‐linolenic acid) 132	Reducing the cerebral Aβ deposition, improving brain energy metabolism, and lessening oxidative stress levels 133

Abbreviations: Aβ, amyloid β peptide; ω3‐PUFAs, Omega‐3 unsaturated fatty acids.

Among the clinical studies on the effects of different vitamin interventions in AD, the largest body of evidence supports the positive effects of vitamin D. ¹¹³ In vitro and in vivo experiments have confirmed that vitamin D prevents neuronal death by enhancing calcium homeostasis and activating macrophages to clear Aβ plaques and reduce oxidative stress (Table 1). ¹³⁴ A previous study on APPswe/PSEN1dE9 (APP/PS1) transgenic mice demonstrated that vitamin D deficiency exacerbates AD‐like pathology by promoting inflammatory stress, increasing Aβ production, and enhancing tau phosphorylation by reducing antioxidant capacity in the brain. ¹²⁹ However, these damages tend to occur with advanced age or later stage in AD, and only high levels of supplemental vitamin D provided prior to the onset of major symptoms can effectively ameliorate AD working memory and endogenous neurogenesis. ¹³⁵ The timing of early intervention is also important. Indeed, a longitudinal follow‐up study with an average of 5.8 years found that subjects with the highest intake of food‐sourced vitamin D had a significantly lower risk of dementia than those with the lowest intake, ¹³⁶ consistent with findings from interventional studies. ¹³⁷ , ¹³⁸ Similarly, meta‐analyses and Mendelian randomization (MR) studies have shown that higher serum 25(OH)D levels, the primary form of vitamin D stored in the body, are associated with a lower risk of AD and vice versa. ¹³⁹ , ¹⁴⁰ , ¹⁴¹ However, other studies have reported no significant association between vitamin D levels and cognitive function in patients with AD. ¹⁴² , ¹⁴³ These conflicting results may be attributed to the study design, including the small sample size and relatively short observation period. In addition, genetic factors may play a role, as vitamin D requires binding to the vitamin D receptor (VDR) for its biological function, and polymorphisms in the VDR gene affect vitamin D function. A meta‐analysis revealed that the VDR ApaI (rs7975232) and BsmI (rs1544410) gene polymorphisms are significant predictors of MCI, while TaqI (rs731236) gene polymorphisms may predict AD. ¹³¹ The effects of the therapeutic interventions involving vitamin D supplementation vary owing to genetic differences among individuals. Furthermore, vitamin D reduces psychiatric symptoms in patients with AD. ¹⁴⁴ , ¹⁴⁵ The molecular mechanism involved was later revealed through pharmacogenomic analysis, and high‐impact genes were identified, including the calcium homeostasis‐associated genes Notch Receptor 4 (NOTCH4), Catechol‐O‐Methyltransferase (COMT), Calcium Voltage‐Gated Channel Subunit Alpha1 C (CACNA1C) and Dopamine Receptor D3 (DRD3). ¹⁴⁶ This finding emphasizes the critical role of vitamin D–mediated calcium‐related signaling pathways in the development of psychiatric symptoms in patients with AD and provides new directions for drug development. ¹⁴⁷

Retinoic acid, the most potent form of vitamin A, induces hippocampal neurogenesis and neuronal differentiation, ¹⁴⁸ rescues vitamin A deficiency–induced spatial memory impairment, ¹⁴⁹ and reverses age‐related memory deficits. ¹⁵⁰ Besides the mechanistic evidence supporting a vitamin A–mediated role in cognition, clinical research also supports the role of β‐carotene in favorably influencing cognition as a vitamin A precursor (Table 1). ¹⁵¹ Vitamin C, or ascorbic acid, is a potent antioxidant that plays an essential neuroprotective role, which not only relies on the inhibition of oxidative and inflammatory pathways, ¹²⁶ but also on the chelation of iron, copper, and zinc, and on the suppression of Aβ fibrillogenesis (Table 1). ¹²⁷

Therefore, considering the undeniable roles of vitamins in antioxidation, anti‐inflammation, and regulation of the gut microbiota, vitamins are a potential multi‐target therapeutic approach for the prevention and treatment of AD. Evidence‐based medical recommendations have affirmed the vital role of vitamin supplementation in preventing AD and improving cognitive impairment. ¹⁵² , ¹⁵³ Further research is warranted to explore the optimal dose and timing of these micronutrient supplements to facilitate clinical application.

3.1.2. Lipids

Omega‐3 unsaturated fatty acids (ω3‐PUFAs) comprise eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Supplementation with ω3‐PUFAs prevents and treats early‐stage AD through various mechanisms, including antioxidants and inhibition of neuroinflammatory and Aβ‐producing processes (Table 1). ¹⁵⁴ , ¹⁵⁵ Specifically, ω3‐PUFAs significantly increased the expression level of low‐density lipoprotein receptor related protein 1 (LRP1) expression in the endothelial capillaries of APP/PS1 mice, thereby facilitating Aβ efflux into the bloodstream and lowering Aβ accumulation in the brain. In addition, these supplements inhibited nuclear factor kappa B (NF‐κB) activation, decreased the production of pro‐inflammatory cytokines (interleukin 1β [IL‐1β] and tumor necrosis factor α [TNF‐α]), and suppressed glial cell activation. ¹⁵⁶ Supplementation with EPA and DHA has also yielded consistent results. ¹⁵⁷ , ¹⁵⁸ A series of prospective studies yielded the same conclusion that higher levels of ω3‐PUFAs intake and higher levels of blood DHA and EPA are associated with lower AD risk and mortality. ¹⁵⁹ , ¹⁶⁰ , ¹⁶¹ , ¹⁶² , ¹⁶³ A network meta‐analysis comparing the potential benefits of ω3‐PUFAs and current U.S. Food and Drug Administration (FDA)–approved AD medications on overall cognitive functioning in individuals with AD showed that high‐dose (1500–2000 mg/day) EPA‐based ω3‐PUFAs improved cognitive level, quality of life, and behavioral deficits in patients with AD with better efficacy and safety than AD medications. ¹⁶⁴ However, the data remain inconsistent, possibly due to DHA characteristics and individual heterogeneity, among other factors. ¹⁶⁵ Some scholars have suggested that the negative results are attributed to DHA being highly susceptible to oxidation and that the exertion of its clinical benefits may depend on the availability of circulating antioxidants. In another study on DHA with or without lutein, an antioxidant, healthy elderly individuals in the DHA with lutein group had a greater reduction in the cognitive outcome index than those who received DHA alone or placebo. ¹⁶⁶ Another influencing factor is the function of substance exchange at the BBB, where DHA access to the brain is affected by multiple transport proteins on the BBB (fatty acid–binding protein 5 [FABP5], fatty acid transport proteins [FATP‐1 and FATP‐4], and Mfsd2a). ¹⁶⁷ , ¹⁶⁸ , ¹⁶⁹ BBB transport of DHA is reduced in APP/PS5 mice due to decreased FABP1 expression at the BBB. ¹⁶⁷ In this regard, an animal study proposed intranasal administration to bypass the BBB, which allows the molecule to directly target the CNS via the olfactory and trigeminal nerves. ¹⁷⁰ The authors demonstrated that the intervention of nanocarrier DHA administered via the intranasal route reduced tau phosphorylation and restored cognitive function in both acute and chronic mouse models of AD, whereas oral administration was ineffective. This will aid in delivering DHA to the brain to prevent or treat AD. ¹⁷¹ The effect of DHA intervention is also strongly correlated with the presence or absence of the APOE ɛ4 allele, which is associated with lower levels of DHA transport to the CSF, both in animals and humans. ¹⁷² , ¹⁷³ This population, therefore, has a higher need for DHA, and DHA supplementation is more effective in improving cognition and delaying hippocampal atrophy in this population than in non–APOE ɛ4 carriers (including APOE ɛ2 or APOE ɛ3 carriers). ¹⁷⁴ , ¹⁷⁵ , ¹⁷⁶ , ¹⁷⁷ The differential results in these studies may be attributed to differences in the cognitive parameters assessed, disease severity, study period, population selected, and ω3‐PUFA dosage. However, it can be confirmed that supplementation with ω3‐PUFAs in cognitively normal populations, preclinical stages, and early stages of AD is effective.

3.1.3. Polyphenols

Polyphenols, natural antioxidants primarily found in fruits and vegetables, can be categorized into flavonoid and non‐flavonoid molecules. ¹⁷⁸ As the major nutritional components emphasized in both the MeDi and the MIND diet, polyphenols are safe and demonstrate significant neuroprotective effects in various neurodegenerative diseases, particularly AD. ¹⁷⁹ , ¹⁸⁰ , ¹⁸¹ Findings from cohort studies and clinical trials indicate that flavonoids, which are abundant in cocoa, blueberries, and orange juice, are linked to enhanced hippocampal‐dependent memory and reduced risk of developing AD. ¹⁸² , ¹⁸³ Similarly, other common polyphenols found in grapes and berries may slow progressive cognitive decline in AD by reducing neuroinflammation and exerting antioxidant effects. ¹⁸⁴ , ¹⁸⁵ Curcumin, quinic acid, anthocyanins, and other polyphenols support neurological stability by regulating the composition and metabolism of the intestinal flora and gut microbiota, and the signaling transmission along the gut–brain axis. ¹⁸⁶ , ¹⁸⁷ , ¹⁸⁸ Therefore, polyphenols have considerable potential as novel, safe, and multitarget therapeutic agents for preventing and combating AD. However, owing to differences between individuals in the absorption, distribution, metabolism, and excretion of bioactive compounds; the bioavailability of different polyphenols; and the heterogeneity in their biological response, the effect of polyphenols varies. ¹⁷⁸

3.1.4. Other nutritional compositions

Proteins and amino acids contribute to maintaining neuronal integrity, reducing inflammation, and supporting muscle retention, all essential for cognitive health. ¹⁸⁹ A recent prospective cohort study demonstrated protective associations between improved protein intake and a reduced risk of cognitive impairment. ¹⁹⁰ However, there are no specific recommendations for protein intake in older adults, ¹⁹¹ necessitating further research to develop guidelines regarding protein intake to maintain optimal cognitive function in older adults.

Glucose is the primary energy source for maintaining brain metabolism, and insulin plays a key role in the development of AD; therefore, any alterations in glucose metabolism and insulin signaling in the brain can induce early neuronal loss and the impairment of synaptic plasticity years before the clinical manifestation of AD. ¹⁹² , ¹⁹³ , ¹⁹⁴ , ¹⁹⁵ , ¹⁹⁶ , ¹⁹⁷ , ¹⁹⁸ Characterized by reduced responsiveness of brain cells to insulin, brain insulin resistance (BIR) exacerbates Aβ deposition, tau hyperphosphorylation, and neurofibrillary tangle accumulation by regulating the activation of mitogen‐activated protein kinase (MAPK) and phosphatidylinositol‐3‐kinase/protein kinase B (PI3K/AKT) signaling pathways, and the activity of insulin‐degrading enzyme and protein phosphatase 2A, leading to neuronal death and cognitive decline. ¹⁹⁹ Considering the strong link between key AD features and BIR, a new perspective suggests that Alzheimer's disease is a type 3 diabetes. ²⁰⁰ In cognitively healthy individuals, fasting glucose levels in the upper threshold of the normal range are linked to increased AD risk, ²⁰¹ and greater impairment in the hippocampus and amygdala. ²⁰² Furthermore, refined carbohydrates, which can rapidly increase blood glucose levels, are associated with the risk of AD in APOE ε4 allele carriers, ²⁰³ by potentially modulating the plasma Aβ of the APOE ε4 status. ²⁰⁴ These findings indicate an association between high glycemic load and poor cognitive performance and a higher risk of AD.

3.2. IMPACT OF DIETARY FACTORS IN AD

3.2.1. Coffee

Higher coffee consumption has been associated with a reduced risk of AD, with potential mechanisms involving the amelioration of neuronal loss and promotion of cellular and molecular markers of neurogenesis, as demonstrated in animal studies. ²⁰⁵ A meta‐analysis of nine prospective cohort studies suggested that a diminished risk of developing AD was observed with daily consumption of one to two cups of coffee. ²⁰⁶ However, a longitudinal study reported no significant protective effects. ²⁰⁷ These inconsistent results may be due to the amount and type of coffee as well as to cytochrome 450 (CYP)1A2 polymorphisms, which determine caffeine metabolism speed and play a role in the direction of the association between coffee‐drinking habits and AD later in life. ²⁰⁷ , ²⁰⁸ , ²⁰⁹

3.2.2. Dairy

There is no conclusive evidence regarding the relationship between milk intake and cognitive function (or phenotype). The prevailing hypothesis is that a greater milk intake is associated with a lower risk of AD. One 17‐year cohort study suggested that milk and dairy intake could prevent AD, ²¹⁰ and the same result was observed in other MR studies, ²¹¹ , ²¹² proving that this association is causal. Other studies have shown the negative effects of milk and dairy on cognitive function. ²¹³ , ²¹⁴ , ²¹⁵ Of interest, the type of milk has a potential influence on AD: fermented milk or dairy product consumers show a lower risk of AD by suppressing microglial activation and increasing intestinal microbial diversity. ²¹⁶ , ²¹⁷ , ²¹⁸

3.3. Impact of dietary patterns in AD

Diet is a modifiable environmental factor. A growing number of studies have focused on the effects of diet on AD, reporting that dietary patterns can modulate neurodegenerative diseases through microglia‐mediated peripheral inflammatory pathways, including the gut flora. ²¹⁹ Changing dietary patterns hold promise for improving cognitive decline and reducing AD risk. Dietary studies have focused primarily on individual food components and nutrients. However, dietary patterns, as a whole, are valuable in the study of AD because they reflect daily eating behaviors and patterns, and the various components or “neurotrophins” included in a good dietary pattern can potentially provide synergistic and protective effects. Evidence from human neuroimaging studies suggests that, unlike single nutrients, dietary patterns begin to play a role in early‐middle age not only by influencing AD biomarkers and structural changes in the brain but also by influencing brain bioenergetics. ⁹⁷ It has also been suggested that these effects stem from the direct effects of specific dietary components of these patterns on the brain and the indirect harm through the reduction of AD and related dementia risk factors such as diabetes, obesity, and cardiovascular disease. ²²⁰ Although the exact mechanisms involved remain unclear, numerous studies have revealed that various good dietary patterns, including the MeDi, DASH diet, and MIND diet, have protective effects against AD. ²²¹ , ²²² , ²²³ , ²²⁴ Below, we summarize the current research focusing on this issue (Table 2 and Figure 2).

TABLE 2.

Summary of the dietary components and micro/macronutrient emphasis included in the MeDi and the DASH and MIND diets; and evidence for their effects on cognitive outcomes in the past 5 years.

Dietary pattern	Dietary components 221 , 222		Micro/macronutrient emphasis 97	Evidence of dietary patterns’ effects on cognitive outcomes
MeDi 225	High amounts	Olive oil, fish, breads and other forms of cereals, fruits, vegetables, legumes, nuts, beans, seeds	Folate, vitamin E, carotenoids, flavonoids, other antioxidants, dietary fiber, omega‐3 fatty acids	Observational studies:●●●●●●●●●●●●■■ Intervention studies: ●●■
	Moderate amounts	Dairy products, poultry, alcohol
	Restricted amounts	Red meat, processed meat, sweets	Saturated fatty acids
DASH 225 , 226	High amounts	Grains, fruits, vegetables, legumes, nuts, seeds, low‐fat dairy products	Potassium, magnesium, fiber, calcium, monounsaturated fats, and protein	Observational studies: ● Intervention studies:
	Moderate amounts	Poultry, fish
	Restricted amounts	Red meat, sweets, saturated fat, total fat, cholesterol, sodium	Saturated fats, cholesterol, and sodium
MIND 227 , 228	High amounts	Olive oil, fish, whole grains, berries, green leafy vegetables, other vegetables, nuts, beans, poultry	Vitamin E, folate, flavonoids, carotenoids, dietary fiber, monounsaturated fats,	Observational studies: ●●●●●● Intervention studies: ■
	Moderate amounts	Alcohol/wine
	Restricted amounts	Red meat and products, pastries and sweets, cheese, butter/margarine, fast fried foods	Saturated and trans fatty acids

Note: Each circle represents a study.

Abbreviations: DASH, dietary approaches to stop hypertension; MeDi, Mediterranean diet; MIND, Mediterranean‐DASH intervention for neuro‐degenerative delay.

●:A protective effect from observational or intervention studies.

■:A neutral (no significant) effect from observational or intervention studies.

FIGURE 2.

Features and different emphases of MeDi, DASH and MIND. Created with BioRender. DASH, dietary approaches to stop hypertension; MeDi, Mediterranean diet; MIND, Mediterranean‐DASH intervention for neuro‐degenerative delay.

3.3.1. MeDi

MeDi emphasizes an abundance of plant foods (fruits, vegetables, whole grains, nuts, and legumes), olive oil as the main source of fat, a moderate to high intake of fish, and a relatively low intake of red meat, as well as a regular, but moderate intake of alcohol, with anti‐inflammatory and antioxidant properties and an impact on telomere length. ²²⁹ MeDi is one of the most widely recognized diets for disease prevention and healthy aging, and has positive effects on cognition. ²³⁰ A cross‐sectional study found that higher MeDi adherence was associated with greater mesial temporal gray matter volume, better memory, and less Aβ and p‐tau181 pathology, ²³¹ confirming MeDi as a protective factor against memory loss and middle temporal atrophy, consistent with previous findings showing that MeDi reduces the accumulation of AD pathologies. ²³² The results of a meta‐analysis that included 19 cross‐sectional studies and 14 longitudinal follow‐up studies indicated that high adherence to the MeDi dietary pattern reduced the risk of overall cognitive decline in older adults, ²³³ consistent with the results of a previous RCT. ²³ Of interest, the beneficial effects of MeDi in combating the risk of AD are not solely attributed to the quality of the food itself but also to the quantity of food consumed. ²³⁴ Better results were observed in trials with restricted caloric intake, likely due to reduced insulin resistance. ²³⁵ , ²³⁶

3.3.2. DASH

The DASH diet emphasizes a high intake of plant foods but places more emphasis on low sodium and higher dairy intake than MeDi, and limits sweetened beverages, red meat, and alcohol intake. This type of dietary pattern is intended to prevent hypertension and cardiovascular disease. ²³⁷ , ²³⁸ , ²³⁹ In addition to the protective effects of the overall food components of the nutritional model on cognition, the DASH diet may affect cognition by preventing hypertension from affecting cerebral perfusion. ²⁴⁰ , ²⁴¹ , ²⁴² In observational studies, long‐term DASH diets were associated with better cognitive status, slower cognitive performance in older adults, and slower cognitive decline in older adults. ²⁴³ , ²⁴⁴ However, it was less protective against cognitive impairment than the MeDi and MIND diet. ²²⁷ The evidence remains inconsistent because the duration of the intervention was too short to observe the full effect. ²⁴⁵ In addition, older adults with severe cardiovascular disease were excluded from the study as they have more severe autoregulation of the brain, ²⁴⁶ resulting in selection bias and failure to observe any effect. Future RCTs should expand the study population to characterize the potential benefits of a DASH diet. 

3.3.3. MIND

The MIND diet is a combination of MeDi and the DASH diet and incorporates foods associated with a reduced risk of AD, slowed cognitive decline, and fewer neuropathic changes in AD, based on evidence from epidemiological and animal studies, to enhance neuroprotective effects. Compared with MeDi and the DASH diet, the MIND diet emphasizes berries and dark leafy greens, which are rich in vitamin E, folate, flavonoids, carotenoids, dietary fiber, and monounsaturated fats. In addition, saturated fat and sugar‐heavy foods, such as red meat, processed meats, butter, margarine, full‐fat cheese, pastries, candy, and fried foods, are consumed. In a 12‐year prospective observational study, the MIND diet, but not the MeDi diet, reduced the incidence of AD, ²⁴⁷ and similar results were found in a meta‐analysis. ²⁴⁸ Apart from better cognitive function, adherence to the MIND diet was also significantly associated with larger gray matter volumes in certain brain regions, especially hippocampus and amygdala. ²⁴⁹ More direct evidence that the MIND diet is associated with lower AD pathology was found in an analysis of a follow‐up study comparing the MIND diet with Aβ load and p‐tau in postmortem brain tissue in older adults, which showed that the MIND diet was associated with less postmortem AD pathology, primarily Aβ load in the brain, and a dietary composition analysis found that a higher intake of green leafy vegetables was associated with less AD pathology. ²⁵⁰ Interventional studies have yielded inconsistent results, in a recent large 3‐year RCT, 604 cognitively not impaired participants with a family history of dementia, a BMI >25, and a poor diet (MIND score <8) at baseline were randomized to a mildly calorie‐restricted MIND. However, no significant differences were observed between the two groups, either in the cognitive scores or in magnetic resonance imaging (MRI) measurements, including white matter hyperintensities (WMHs), hippocampal volume, gray matter, and total white matter volume. ²⁵¹ Because enrollment in this trial required subjects to have a family history of dementia, poor eating patterns, and to be overweight, which are potential risk factors for AD and cognitive decline, it is possible that the results cannot be extrapolated to all backgrounds. Cross‐national differences in food availability, eating behaviors, and other lifestyle factors diminish the generalizability of dietary effects on cognitive impairment and dementia risk. Further research is warranted to develop and refine specific MIND diets for different populations.

3.3.4. Other dietary patterns

The Mediterranean‐ketogenic diet (MMKD) has a protective effect against metabolic dysregulation and seizures, increases Aβ42, and decreases tau in the CSF of MCI patients by modulating the gut microbiome signature and organic acids metabolite, as well as by increasing cerebral perfusion and cerebral ketone body uptake. ²⁵² , ²⁵³ MMKD also improves modifiable risk factors for AD, such as increased high‐density lipoprotein cholesterol (HDL‐C) and reduced BMI, and reverses serum metabolic disturbances linked to AD, such as a microbiome‐mediated increase in valine levels and a reduction in systemic inflammation. ²⁵⁴ Intermittent fasting restricts several nutrient components, including glucose, resulting in a salutary effect on AD, ²⁵⁵ through 2‐deoxyglucose, a glucose analog–mediated transcription of the pro‐plasticity factor brain‐derived neurotrophic factor (BDNF) in the brain, as well as sirtuin 3 (SIRT3)‐mediated hippocampal synaptic adaptations. ²⁵⁶ , ²⁵⁷ The role of plant‐based dietary patterns in the development of dementia remains unclear. A 10‐year national community‐based cohort study in China found that older adults with increased adherence to an overall plant‐based diet and healthy plant‐based diet over 3 years had a lower risk of cognitive impairment than those with increased adherence to an unhealthy plant‐based diet. ²⁵⁸ Meanwhile, another study found no strong evidence of an overall association between plant‐based eating and the risk of dementia. ²⁵⁹ These contradictory findings may be attributed to genetic variability and differences in lifestyle factors.

4. AND FUTURE DIRECTIONS

This review concluded that nutritional factors and cognitive function interact and that undernutrition leads to a high incidence, rapid progression, and poor prognosis of AD through various mechanisms. Our findings provide new directions for the prevention of AD, as well as novel insights to improve patient prognosis. This review also focused on the specific manifestations of malnutrition in patients with AD and its underlying mechanisms to aid in formulating precise interventions to prevent malnutrition and improve AD prognosis. This review suggests that AD is closely related to nutritional status. Previous studies have demonstrated the potential of nutritional support in combating AD. However, inconsistent results persist, which may be attributed to factors such as study design (e.g., whether calorie intake is restricted in dietary pattern studies), population heterogeneity (e.g., differences between individuals in the absorption, distribution, metabolism, and excretion of bioactive compounds), bioavailability of nutrients, or the duration of the intervention (e.g., the beneficial effect of B vitamins was especially significant in populations that received intervention for more than 12 months). Future studies should investigate the factors responsible for the inconsistent results and ensure consistency in population selection, intervention design, and outcome measures to enhance external validity. Due to the limited number of clinical studies, no specific clinical guidelines (e.g., optimal timing, dosage, or nutritional components) for nutritional interventions in AD currently exist. This review highlights the critical need for nutritional support for patients with AD at all stages, as earlier interventions lead to better outcomes. Considering the complex biological mixture of various nutritional components in dietary patterns, a dietary approach is more effective in preventing or combating cognitive decline than supplementing single nutritional components. ²⁶⁰

Future research should focus on areas of nutrition that have been minimally studied so far, including water intake, hydration status, and the DII. ²⁵ , ²⁶¹ , ²⁶² Clinical trials are also warranted, since the current practice is observational and susceptible to reverse causation and over‐adjustment, making it difficult to derive a definitive causal relationship. Expanding the scope and scale of the research design, such as nutritional interventions, and more well‐designed RCTs are warranted to avoid bias. The specific mechanisms also warrant further in vivo and in vitro studies. Further improvements in assessing dietary methods are needed, along with daily dietary assessments, which are critical to real‐world research. The current common dietary assessment method is the Food Frequency Questionnaire, which is prone to recall biases associated with memory deficits. ²⁶³

Therefore, the validity and reproducibility of the data obtained on this basis warrant improvement, and immediate questionnaires for different study populations are needed to obtain accurate data, such as software that allows for the uploading of images, videos, or audio recordings of meals. ²⁶⁴ , ²⁶⁵ , ²⁶⁶ , ²⁶⁷ Omics techniques can provide precise data by measuring differences in DNA or RNA, proteins, and metabolome levels, which will aid in identifying novel nutritional biomarkers; therefore, they should be used in nutritional analyses. ²⁶⁸ , ²⁶⁹ , ²⁷⁰ Crucially, for clinical application, it is essential to identify affordable, easily detectable, sensitive, and specific nutrition‐related biomarkers for AD. In addition, there is a need to create more robust models to predict the morbidity, progression, and mortality associated with AD based on nutritional factors status. Due to the reduced function of the BBB in patients with AD, ²⁷¹ , ²⁷² , ²⁷³ the ability to extract nutrients from circulation is also reduced, which diminishes the ability of dietary intake of nutrients to reverse AD pathology. Future efforts should be focused on tackling the issue of poor nutrient absorption in patients with AD. Furthermore, precision medicine should be introduced into the study of nutrition and AD to develop a more effective individualized nutritional intervention program. ²⁷⁴ , ²⁷⁵ , ²⁷⁶ Artificial intelligence and machine learning will be vital in supplying essential preliminary evidence for preventive nutritional care in patients with AD. ²⁷⁷

CONFLICT OF INTEREST STATEMENT

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be interpreted as potential conflicts of interest. Author disclosures are available in the Supporting Information.

Supporting information

Supporting Information

Wen B, Han X, Gong J, et al. Nutrition: A non‐negligible factor in the pathogenesis and treatment of Alzheimer's disease. Alzheimer's Dement. 2025;21:e14547. 10.1002/alz.14547