High meat intake may have a neuroprotective effect against cognitive decline and dementia, particularly in older adults who carry the apolipoprotein E (APOE) epsilon 4 allele — a genetic variant associated with increased Alzheimer’s disease (AD) risk.

In a population-based cohort study of more than 2000 adults, individuals at genetic risk for AD in the highest quintile of meat intake had significantly better cognitive outcomes and a lower incidence of dementia than those with lower intake, corresponding to a 55% reduction in dementia risk.

In contrast, APOE4 noncarriers — those without the allele linked to increased AD risk — showed no significant association between meat intake and cognitive outcomes. However, across all APOE genotypes, a higher proportion of processed meat relative to total meat intake was associated with an increased risk for dementia.

“There is a lack of dietary research into brain health, and our findings suggest that conventional dietary advice may be unfavorable to a genetically defined subgroup of the population. For those who are aware that they belong to this genetic risk group, the findings offer hope; the risk may be modifiable through lifestyle changes,” lead investigator Jakob Norgren, PhD, researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet in Huddinge, Sweden, said in a release.

The study was published online on March 19 in JAMA Network Open.

A Different Response to Diet?

The APOE epsilon 4 allele — the strongest common genetic risk factor for AD — is associated with an increased risk for cognitive decline and dementia.

An ancient allele, the APOE epsilon 4 is thought to have arisen in populations with more meat-based diets, at a time when humans relied heavily on animal-derived foods for survival. Building on this evolutionary context, the investigators hypothesized that APOE4 carriers may respond differently to modern dietary patterns, with higher meat intake potentially conferring cognitive benefit.

For the study, the investigators analyzed 2157 community-dwelling adults (mean age, 71.2 years; women, 62%) from the Swedish National Study on Aging and Care-Kungsholmen. Participants were dementia-free at baseline and followed for up to 15 years. The cohort was largely of Northern European ancestry, although detailed race and ethnicity data were not reported.

Diet was assessed using self-reported food frequency questionnaires standardized to 2000 kcal/d intake, with participants categorized into quintiles. The highest intake group consumed a median of approximately 869 g/wk of meat compared with 247 g/wk in the lowest intake group.

Cognitive function was evaluated longitudinally using repeated standardized over the study period. Analyses were adjusted for age, sex, education, and lifestyle factors.

The primary outcome was total meat intake in g relative to total caloric intake. The secondary outcome was the ratio of processed to total meat intake, with processed meat defined as meat that had been preserved or altered through salting, curing, fermentation, smoking, or other processes.

Meat Intake and Cognition

A total of 1680 participants had longitudinal cognitive data, including 569 with APOE epsilon 3/epsilon 4 or epsilon 4/epsilon 4 genotypes. During follow-up, 296 participants developed dementia, and 690 died without dementia.

Among participants with APOE epsilon 3/epsilon 4 or epsilon 4/epsilon 4 genotypes, higher meat intake was associated with significantly better cognitive outcomes. Compared with the lowest intake group, those in the highest intake group showed improved cognitive trajectories (beta = 0.32; 95% CI, 0.07-0.56; P = .01).

In the same genetic subgroup, higher meat intake was associated with a lower risk for dementia. At lower intake levels, APOE epsilon 3/epsilon 4 and epsilon 4/epsilon 4 carriers had more than twice the risk for dementia compared with individuals who were not carriers.

There was also a significant interaction between meat intake and APOE genotype for cognitive outcomes (P for interaction = .004), which signaled that the effect of diet differed depending on genetic risk.

“The expected excess risk among participants with APOE epsilon 3/epsilon 4 and epsilon 4/epsilon 4 genotypes was absent in the highest quintile of meat consumption across global cognition, episodic memory (a hallmark feature of Alzheimer pathology), and dementia outcomes,” the investigators wrote.

“Given that these genotypes account for approximately 70% of Alzheimer dementia cases in Northern Europe and North America, the absolute number of potentially preventable cases is substantial,” they added.

Toward Precision Nutrition?

The type of meat consumed also influenced outcomes. A higher intake of processed meat was associated with worse cognitive outcomes and increased dementia risk, regardless of genotype, with a sub-distribution hazard ratio of 1.14 (95% CI, 1.01-1.29; P = .04).

When specific meat types were examined, higher intake of unprocessed red meat was associated with lower dementia risk across the cohort, whereas no such association was observed for processed meat.

There was no substantial difference between unprocessed red meat and poultry. After excluding participants with possible baseline cognitive impairment, the protective association for unprocessed meat became stronger and extended to total meat intake.

In post hoc analyses, higher intake of unprocessed meat was also associated with reduced all-cause mortality, but only among individuals with APOE ε3/ε4 or ε4/ε4 genotypes. This reduces the likelihood of survival bias because higher meat intake in this group was associated with both lower dementia risk and longer survival.

The investigators pointed out that the study has several limitations, including its observational design, reliance on self-reported dietary data, and limited generalizability due to a predominantly Northern European population. They also noted the potential for residual confounding and the inability to infer causation.

They emphasized the need for clinical trials to determine whether dietary recommendations tailored to APOE genotype can improve cognitive outcomes.

“Results reinforce the urgency of investing in precision nutrition research with a focus on APOE, which could ultimately inform future policy development,” the investigators concluded.

The researchers said the findings suggest that the cognitive effects of diet may differ by APOE genotype, raising the possibility that dietary recommendations for dementia prevention could be refined based on genetic risk.

The Swedish National Study on Aging and Care-Kungsholmen (SNAC-K) data collection is financially supported by the Swedish Ministry of Health and Social Affairs, participating county councils and municipalities, and Swedish Research Council (current grant: 2021-00178). Norgren was funded by the Swedish Alzheimer Foundation and Swedish Dementia Foundation for the project Optimizing Dietary Recommendations for Alzheimer Prevention: Investigating a Possible Mismatch Between Official Dietary Guidelines and APOE4- Specific Dietary Adaptation.