Prioritizing multidomain lifestyle interventions

Given that most medical conditions arise from multiple interacting factors, it is not surprising that multidomain interventions — rather than single-domain approaches — show the greatest promise for supporting both cardiovascular and brain health. Although the evidence indicates that multidomain interventions can provide meaningful benefit, results across studies have been mixed. This raises an important clinical question: Which patient populations are most likely to benefit?

This article summarizes the latest research examining which subgroups respond most robustly to multidomain lifestyle interventions.

Which Populations Benefit Most From Multidomain Lifestyle Interventions?

Multidomain lifestyle interventions—typically combining diet, physical activity, cognitive training, and vascular risk factor management—show the greatest cognitive benefit in older adults at elevated risk for dementia, rather than in unselected general populations. The most responsive groups include those with higher cardiovascular risk, APOE4 carriers, individuals with lower baseline cognitive function, and those with underlying Alzheimer’s pathology (amyloid-positive).

Risk-Stratified Older Adults Show the Largest Gains

The landmark FINGER trial specifically recruited participants aged 60–77 with elevated dementia risk (CAIDE ≥6), demonstrating significant cognitive benefit from a multidomain intervention.¹˒² This targeted-risk approach stands in contrast to broader trials (MAPT, preDIVA), which showed overall null results, but positive effects within higher-risk subgroups:

• Individuals with multiple vascular risk factors

• Those with higher predicted dementia risk scores

• Amyloid-positive individuals on PET imaging³˒⁴

  
  

Collectively, these findings support a risk-stratified precision-prevention model.

APOE4 Carriers Benefit Disproportionately

Genetic susceptibility does not diminish the effectiveness of lifestyle interventions. In fact:

• APOE4 carriers in FINGER demonstrated greater cognitive improvement (MD 0.14) compared with non-carriers (MD 0.04).⁵

• A meta-analysis of two trials confirmed enhanced benefit among APOE4 carriers.⁶

Newer analyses incorporating composite Alzheimer’s genetic risk scores indicate that women with the highest genetic risk show the largest intervention response, while lower-risk individuals show minimal benefit.⁶

Men exhibited more modest gene–intervention interactions.

Baseline Cognitive Status and Sociodemographic Factors

A Cochrane review found that individuals with lower baseline MMSE scores experienced greater benefit.⁵ However, FINGER’s prespecified subgroup analyses found no significant effect modification by baseline cognition.⁷

Notably, age, sex, education level, income, and cardiovascular comorbidity did not modify intervention response in FINGER, suggesting broad applicability once elevated risk is established.⁷

Cardiovascular Risk Profiles

Individuals with higher cardiovascular genetic risk (CAD-GRS above median) showed cognitive benefits similar to those with elevated Alzheimer’s genetic risk.⁶ MAPT subgroup analyses also identified participants with more vascular risk factors as benefitting most.⁴

These findings reinforce the central role of vascular and metabolic pathways in dementia prevention.

Amyloid-Positive Individuals

In the MAPT amyloid-PET substudy:

• Amyloid-positive participants showed cognitive benefit from multidomain lifestyle interventions.³

This underscores that interventions may improve cognitive outcomes even when underlying Alzheimer’s pathology is present, likely by reducing neurovascular burden and enhancing cognitive reserve.

Clinical Implications

The evidence supports prioritizing multidomain interventions for:

• Older adults with elevated dementia risk (CAIDE ≥6 or similar stratification)

• APOE4 carriers and women with high AD genetic risk

• Individuals with multiple vascular risk factors

• Those with subtle or mild cognitive impairment, not frank dementia

• Amyloid-positive individuals in preclinical or early symptomatic stages

Notably, the intervention benefits a large elderly at-risk population regardless of most baseline characteristics, suggesting broad applicability once elevated risk is established.⁷ The key is identifying individuals at increased risk rather than applying interventions to unselected general populations.

References:

1. Kivipelto, M., Mangialasche, F., & Ngandu, T. (2018). Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nature Reviews Neurology, 14(11), 653–666.

2. Ngandu, T., Lehtisalo, J., Solomon, A., et al. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER). The Lancet, 385(9984), 2255–2263.

3. Scheltens, P., De Strooper, B., Kivipelto, M., et al. (2021). Alzheimer's disease. The Lancet, 397(10284), 1577–1590.

4. Scarmeas, N., Anastasiou, C. A., & Yannakoulia, M. (2018). Nutrition and prevention of cognitive impairment. The Lancet Neurology, 17(11), 1006–1015.

5. Hafdi, M., Hoevenaar-Blom, M. P., & Richard, E. (2021). Multi-domain interventions for the prevention of dementia and cognitive decline. Cochrane Database of Systematic Reviews, 11, CD013572.

6. Saadmaan, G., Dalmasso, M. C., Maria, M., et al. (2025). Alzheimer and cardiovascular genetic scores and cognition: The FINGER randomized controlled trial. Brain.

7. Rosenberg, A., Ngandu, T., Rusanen, M., et al. (2018). Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial. Alzheimer’s & Dementia, 14(3), 263–270.

Disclaimer:

Always consult your healthcare provider before making changes to medications, supplements, lifestyle habits, or treatment plans. Do not delay seeking professional care because of something you read here.

Discussions about mental and physical health are educational and not individualized medical guidance. Tools and worksheets are for general well-being and are not designed to diagnose or treat health conditions. 

The information on this site — including articles, videos, links, and downloadable materials — is for general educational purposes only and is not a substitute for medical or psychiatric advice, diagnosis, or treatment. Use of this site does not create a clinician–patient relationship.

Content in the Clinician Hub is for professional development only and is not intended as clinical directives or patient-specific recommendations.

Your use of this site is voluntary and at your own risk. Mind in Balance, New Path Psychiatric, LLC, and Linda Keddington disclaim liability for any outcomes related to actions taken based on this content.