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Long touted for its cardiovascular and overall health benefits, a Mediterranean-style diet is associated with improved cognition and a reduced risk for Alzheimer’s disease (AD), particularly in those having the highest genetic risk, new research showed.

In a large prospective study, individuals carrying two copies of the apolipoprotein E4 (APOE4) gene variant had metabolic profiles that increased their risk of developing dementia. Those who adhered closely to the Mediterranean diet scored better on cognitive tests and had a substantially lower risk for dementia. For APOE4 homozygotes, the risk was reduced by about one third compared with only a 5% reduction in those with one or no copies.

“By looking at genetic risk, we found that people with two copies of APOE4, those most vulnerable to Alzheimer’s disease, appeared to gain the greatest benefit from the Mediterranean diet,” first author Yuxi Liu, PhD, Massachusetts General Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, Boston, told Medscape Medical News. “Our results suggest that precision nutrition — adapting dietary recommendations to a person’s genetic background — could be a promising approach to dementia prevention.”

The study was published online on August 25 in Nature Medicine.

How the Med Diet Offsets Dementia Risk

AD and related dementias are highly heritable, with up to 80% of risk estimated to be genetic. Carrying one copy of APOE4 increases dementia risk three- to fourfold, whereas the presence of two copies raises the risk eight- to twelvefold compared with absence of the variant.

To examine whether diet could modify this vulnerability, investigators analyzed long-term dietary and metabolic data from two well-established cohorts. Previous studies of Mediterranean and MIND diets have shown mixed results, and the team hypothesized that genetic risk could help explain these inconsistencies.

The analysis included 4215 women in the Nurses’ Health Study, followed up from 1989 to 2023 (mean baseline age, 57 years), and a replication cohort of 1490 men in the Health Professionals Follow-Up Study, followed up from 1993 to 2023 (mean baseline age, 63 years). Participants completed food-frequency questionnaires, provided blood samples for genetic and metabolomic profiling, and were tracked for dementia incidence and cognitive decline.

Compared with noncarriers, APOE4 heterozygotes had approximately double the risk for dementia (hazard ratio [HR], 2.02; 95% CI, 1.68-2.44; P < .001), whereas homozygotes had more than a fivefold risk (HR, 5.12; 95% CI, 3.25-8.06; P < .001).

Greater adherence to the Mediterranean diet significantly reduced overall dementia risk (P = 9.7 × 10^-6). The strongest protection was seen in APOE4 homozygotes (HR, 0.72; 95% CI, 0.58-0.89; P = .002), and results were consistent across both cohorts.

APOE4 homozygotes also displayed distinctive metabolite profiles linked to dementia risk, including elevations in cholesteryl esters and sphingomyelins and lower levels of protective glycerides. Nearly 40% of the diet’s benefit in this group appeared to be mediated through favorable shifts in these plasma metabolites.

“We can actually see how the Mediterranean diet changes the blood chemistry of people with APOE4,” Liu said. “That provides a biological explanation for why the diet may be especially protective in this high-risk group.”

Strengths, Limitations

Commenting for Medscape Medical News, Puja Agarwal, PhD, assistant professor at Rush Medical College and the Rush Alzheimer’s Disease Center, Chicago, said the study is notable for its large sample size, replication across two cohorts, and detailed metabolic analysis.

“For individuals with the APOE4 allele, adopting a Mediterranean or similarly healthy dietary pattern should be encouraged, not only for potential brain benefits but also for overall health,” Agarwal said.

However, Agarwal noted that the observational design limits causal inference and that the study population predominantly consisted of White and highly educated individuals, which may reduce generalizability.

While the findings highlight the promise of precision nutrition, the authors agreed that more work is needed before genetics and metabolomics can be incorporated into routine dementia risk models or clinical practice.

Even so, the study offers valuable insights into the interplay between diet and biology, suggesting new approaches for mitigating dementia risk in genetically susceptible individuals.

“The next step is to better understand the biology of the metabolites we identified,” Liu said.

“In future studies, we hope to explore whether targeting these pathways through diet or other interventions can move us closer to truly personalized strategies for dementia prevention,” she added.

The study was supported by grants from the National Institutes of Health. Liu and colleagues reported having no relevant financial relationships.