Multidomain Prevention of Alzheimer’s Disease: Integrating Lifestyle, Metabolic, and Emerging Strategies (2026)

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. With limited disease-modifying therapies, preventive strategies targeting modifiable risk factors are increasingly critical. Evidence from observational studies and randomized controlled trials suggests that multidomain interventions—including lifestyle modification (diet, physical activity, cognitive engagement), vascular risk management, sleep optimization, and social engagement—may delay cognitive decline and reduce AD risk. Biological mechanisms include improved cerebral perfusion, enhanced neurotrophic signaling, reduced oxidative stress, and glymphatic clearance of neurotoxic proteins. While definitive prevention is not yet established, integrating multidomain interventions from midlife onward may reduce disease burden at both individual and population levels.

Keywords: Alzheimer’s disease, dementia, prevention, multidomain intervention, lifestyle factors, diet, exercise, cognitive reserve.

1. Introduction

Alzheimer’s disease (AD) is characterized by progressive memory loss, executive dysfunction, and behavioral changes (Livingston et al., 2020). Alzheimer’s disease is the most common form of dementia which amounts to 50% to 70% of all cases. Vascular dementia, usually from either multiple strokes or severe atherosclerosis makes up to 25% of cases.

Other causes are Lewy body dementia (LBD), syphilis, chronic mercury, lead, cadmium, and aluminum exposure, Parkinson’s disease, Creutzfeldt-Jacob disease, hypothyroidism, vitamin B1 deficiency, vitamins B12 and folate deficiencies, MTHFR mutation and others.

With global aging populations, prevalence is projected to increase substantially, resulting in significant health, social, and economic burden. An estimated 1 million Americans are expected to develop dementia annually by 2060—roughly double today’s numbers—researchers said in a Jan. 13, 2025 report, adding that the risk of developing the neurological condition may be higher than previously thought. Published in the journal Nature Medicine (2025), the researchers’ study found a higher lifetime risk than previously thought: After age 55, people have up to a four in 10 chance of eventually developing dementia if they live long enough.

While genetic risk factors, including APOE ε4 allele status, contribute to susceptibility, modifiable lifestyle and vascular risk factors offer an opportunity for intervention (National Institute on Aging, 2020). This review synthesizes evidence on multidomain preventive strategies, biological mechanisms, and future research directions.

2. Biological and Epidemiological Basis for Prevention

Epidemiological studies suggest that up to 40% of dementia cases may be attributable to modifiable risk factors (Livingston et al., 2020). Cardiovascular risk factors—including hypertension, diabetes, dyslipidemia, and obesity—are strongly associated with AD risk (Norton et al., 2014). Vascular dysfunction contributes to microinfarcts, white matter lesions, and impaired Aβ clearance, providing a mechanistic link between systemic health and neurodegeneration (Blondell, Hammersley-Mather, & Veerman, 2014). Cognitive reserve, influenced by early-life and lifelong intellectual engagement, is also protective; low educational attainment and limited cognitive stimulation correlate with higher dementia risk (Richard et al., 2023).

A related report by the 2024 update of the Lancet Commission on dementia provides new hopeful evidence about dementia risk reduction by up to 45%. The report summarised the new research since the 2020 report of the Lancet Commission on dementia, prioritising systematic reviews and meta-analyses and triangulating findings from different studies showing how cognitive and physical reserve develop across the life course and how reducing vascular damage (eg, by reducing smoking and treating high blood pressure) is likely to have contributed to a reduction in age-related dementia incidence. Evidence is increasing and is now stronger than before that tackling the many risk factors for dementia that they modelled previously (ie, less education, hearing loss, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol consumption [ie, >21 UK units, equivalent to >12 US units], traumatic brain injury [TBI], air pollution, and social isolation) reduces the risk of developing dementia. In this report, they add the new compelling evidence that untreated vision loss and high LDL cholesterol are risk factors for dementia.

A March 2024 meta-analysis, published in the American Journal of Clinical Nutrition, indicates that daily MVM (MultiVitamin Mineral) significantly benefits both global cognition and episodic memory. These findings within the COSMOS (COcoa Supplement and Multivitamin Outcomes Study) trial support the benefits of a daily MVM in preventing cognitive decline among older adults.

A May 2024 study (Nature) suggests that specific nutrients abundant in the Mediterranean diet could be nature’s own anti-aging elixir for the brain, offering a potential new way, aside from medication, to combat age-related cognitive decline. Published in npj Aging in May 2024, the study combined advanced neuroscience and nutritional science techniques to pinpoint nutrient biomarkers associated with healthy brain aging. It focused on 100 cognitively healthy people aged 65 to 75 and examined the effects of fatty acids, vitamins, antioxidants, and carotenoids on brain health. The researchers identified a specific combination of nutrients linked to slower brain aging and improved cognitive performance. These included:

• Fatty acids: vaccenic acid, gondoic acid, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), eicosadienoic acid, and lignoceric acid, found in foods like fatty fish and nuts
• Carotenoids: lutein, lutein, and zeaxanthin, found in fruits, vegetables, and egg yolks
• Vitamin E: found in peanuts, avocado, and fish
• Choline: found in eggs, meat, fish, and dairy.

A 2022 review paper, retrieved a total of 4310 articles and 43 articles to be incorporated in the review. Findings revealed a trend of significant association between low levels of B vitamins (folate and vitamin B12), vitamin D, vitamin A, vitamin E, omega 3 fatty acid, and albumin, and high homocysteine levels in blood with an increased risk of mild cognitive impairment among older adults.

Related: 

• Top Modifiable Risk Factors That Can Help Prevent Dementia, According to a 2024 Lancet Study
• Egg Consumption Could Help Prevent Alzheimer's, According to a 2024 Study

3. Modifiable Lifestyle Factors

3.1 Physical Activity and Exercise

Regular physical activity is among the most robust lifestyle correlates of reduced dementia risk. Observational studies show that higher levels of midlife and late‑life physical activity are associated with 30–45% lower risk of dementia, including AD (New York Post). Biological mechanisms include enhanced cerebral perfusion, increased neurotrophic factors (e.g., BDNF), improved metabolic health, and reduced neuroinflammation. Sedentary behaviour, even among those meeting exercise guidelines, has been linked to adverse outcomes, suggesting the importance of reducing overall inactivity. (Verywell Health)

Structured exercise interventions may also improve cognition and quality of life in individuals with mild cognitive impairment (MCI) and early AD, though effects on disease progression are still being determined. (SpringerLink)

3.2 Diet and Nutritional Patterns

Dietary patterns such as the Mediterranean, DASH, and MIND diets—rich in fruits, vegetables, whole grains, lean proteins, and healthy fats—are associated with slower cognitive decline and reduced AD risk.

These diets may exert neuroprotective effects through anti‑inflammatory, antioxidant, and vascular mechanisms. (Alzheimer’s Association) 

3.3 Sleep Quality and Circadian Regulation

Sleep disturbances are increasingly recognised as potential contributors to AD pathogenesis, possibly due to impaired glymphatic clearance of Aβ and tau during sleep. Interventions to improve sleep hygiene and treat sleep disorders may support brain health, although clinical evidence on AD risk reduction is still emerging. (PubMed)

3.4 Cognitive and Social Engagement

Engagement in cognitively stimulating activities (learning languages, musical instruments, complex hobbies) and social interaction correlates with better cognitive outcomes. These activities are thought to enhance neural connectivity and cognitive reserve, thereby delaying clinical manifestations of AD pathology. (PubMed)

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4. Randomized Controlled Trials and Multidomain Interventions

4.1 FINGER and Related Trials

FINGER trial from Lancet (2015) is a landmark RCT proving multidomain strategies can improve cognitive outcomes in older adults at risk of AD. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is among the most pivotal RCTs supporting multidomain prevention. FINGER demonstrated that a structured combination of diet, exercise, cognitive training, and vascular risk monitoring improved or maintained cognitive functioning in at‑risk older adults compared with controls. (Lancet 2015)

Subsequent multidomain interventions, including updated protocols like FINGER 2.0, incorporate individually‑tailored programs and social engagement components, reinforcing the multidimensional nature of effective prevention strategies. (SpringerLink)

U.S. POINTER is a large multicentre RCT published in JAMA (2025) with structured lifestyle interventions showing statistically greater cognitive benefit over two years. (JAMA 2025)

4.2 Other RCT Evidence and Limitations

Not all multidomain trials have shown significant reduction in dementia incidence. For example, the PreDIVA trial, focusing on intensive cardiovascular risk management in older adults, did not significantly reduce all‑cause dementia or death, highlighting heterogeneity in intervention effects and populations studied. (SpringerLink)

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5. Mechanistic Pathways

Modifiable lifestyle factors influence AD risk through interconnected pathways:

• Vascular health: Ensures adequate cerebral perfusion and waste clearance.

• Metabolic regulation: Reduces insulin resistance and chronic inflammation.

• Neurotrophic signaling: Promotes synaptic plasticity and neurogenesis.

• Oxidative stress: Antioxidant‑rich diets and physical activity buffer oxidative damage.

These mechanisms underscore why a combination of factors may be more efficacious than single interventions. (PubMed)

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6. Discussion

Current evidence indicates that multidomain lifestyle interventions hold the most promise for AD prevention, particularly when initiated in midlife or earlier. While observational studies provide strong associative data, RCTs like FINGER offer the best experimental support to date, though larger and longer trials are needed to establish causality and optimal intervention designs.

Challenges:

• Heterogeneity of interventions, populations, and outcomes.

• Difficulty quantifying adherence and lifestyle exposures.

• Ethical and logistical constraints limit long‑term RCTs. (Scientific American)

Future Directions:

• Precision prevention tailored to genetic risk (e.g., APOE ε4 carriers).

• Integration of digital biomarkers for real‑time monitoring.

• Longer follow‑up and larger sample trials comparing multidomain strategies.

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7. Conclusion

Preventing Alzheimer’s disease remains a complex challenge, but a robust body of evidence supports multidomain interventions targeting lifestyle and vascular risk factors. While individual preventive measures may not guarantee protection, their combined implementation — especially from midlife onward — offers the best current strategy to delay cognitive decline and lower AD risk.

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