Mediterranean Diet Lowers Dementia Risk By Altering Key Metabolites

A long-running study shows really genes, diet, and metabolism interact to style dementia risk, pinch nan Mediterranean fare offering protective pathways for those astir vulnerable.

In a caller study published successful nan journal Nature Medicine, researchers investigated nan associated narration betwixt familial risk, plasma metabolomic profiles, and adherence to nan Mediterranean fare (MedDiet) and their effect connected incident dementia and nonsubjective cognitive function, identifying metabolites and pathways that whitethorn underlie these associations.

Background

Every 3 seconds, personification is diagnosed pinch dementia, reshaping families. Alzheimer’s illness (AD) and Alzheimer’s disease-related dementias (ADRD) originate from an intertwined biology, involving genes specified arsenic apolipoprotein E ε4 (APOE4), lipid and power metabolism, inflammation, and manner factors.

Plasma metabolomics provides a model into these processes; a diet, particularly nan Mediterranean diet, tin displacement metabolites toward brain-healthy profiles. Yet, clinicians still deficiency long-term, population-level grounds linking genes, metabolites, and fare to existent outcomes.

People often inquire what they tin do and whether consequence is influenced by ancestry and biology. Further investigation is needed to representation modifiable pathways crossed familial backgrounds and life stages.

About nan study

Two prospective cohorts were analyzed: 4,215 women successful nan Nurses’ Health Study (NHS) and 1,490 men successful nan Health Professionals Follow-Up Study (HPFS). Baseline humor (1989–1992 successful NHS; 1993–1996 successful HPFS) underwent liquid chromatography-mass spectrometry (LC-MS), quantifying 401 plasma metabolites successful NHS and 254 overlaps successful HPFS nether value power (QC).

Genotyping pinch imputation to 1000 Genomes yielded APOE4 and genome-wide relation studies (GWAS) variants; polygenic consequence scores (PRSs) for ADRD (with and without nan APOE region) were computed. Diet was assessed utilizing semiquantitative nutrient wave questionnaires (SFFQs) and a nine-component Mediterranean Diet (MedDiet) index.

Dementia mixed self-reported diagnoses and deaths attributed to dementia done 2023. Objective cognition was assessed utilizing nan Telephone Interview for Cognitive Status (TICS), East Boston Memory Test (EBMT), verbal fluency, and digit span backward to shape world and verbal representation composites.

Cox proportional hazards (PH) models related MedDiet and metabolites to incident dementia, pinch subgrouping by APOE4 and ADRD PRS tertiles. 

Generalized linear models linked MedDiet pinch metabolites by familial strata. Mediation analyses tested whether metabolites explained nan MedDiet-dementia associations successful narration to APOE4. Prediction models were assessed utilizing nan area nether nan curve (AUC) and Harrell’s C-index successful nan trial sets.

Study results

Across 4,215 NHS women followed from 1989 to 2023, 485 developed dementia; replication among 1,490 HPFS men recorded 121 cases. APOE4 homozygosity displayed chopped metabolome-dementia relationships: 49 metabolite-genotype interactions met a mendacious find complaint (FDR) < 0.05, each circumstantial to homozygotes.

Cholesteryl esters (CEs) and sphingomyelins (SMs) were associated pinch a higher dementia risk, being strongest successful APOE4 homozygotes, accordant pinch cholesterol-linked neuroinflammation and impaired amyloid-beta (Aβ) clearance.

Conversely, glycerides showed inverse associations pinch consequence among homozygotes, suggesting altered lipid handling; akin patterns were observed successful nan HPFS. Plasma phosphorylated tau 217 (p-tau217) successful an NHS subset predicted astir threefold higher dementia consequence compared to nan apical versus nan bottommost quartiles.

Adherence to nan Mediterranean fare is associated pinch a little consequence of dementia and improved cognition. Protective associations were strongest successful APOE4 homozygotes and evident successful different genotypes. At nan metabolite level, higher MedDiet scores were associated pinch much unsaturated and less saturated glycerides, arsenic good arsenic higher levels of neuroprotective dietary aliases one-carbon intermediates, specified arsenic piperine and betaine.

Among suggestive (nominal) interactions, nan MedDiet was inversely related to asparagine only successful APOE4 homozygotes and to nan caffeine metabolite 1,7-dimethyluric acerb successful carriers, though these did not scope FDR significance.

In mediation analysis, 39.5% of nan MedDiet-dementia relation was statistically important only successful APOE4 carriers and was explained by 7 metabolites, identified done statistical filtering, including allantoin, C16:1 CE, 1-methylguanine, C18:0 SM, 1,7-dimethyluric acid, C34:5 phosphatidylcholine plasmalogen, and piperine; nary mediation was observed successful noncarriers.

Prediction improved modestly by integrating omics information pinch manner factors. In NHS trial sets, Harrell’s C-index accrued stepwise from a baseline exemplary (age, education, family history, smoking, depression, MedDiet) aft adding APOE4, nan ADRD PRS, and selected metabolites.

In HPFS, Harrell’s C-index from Cox models showed incremental gains erstwhile adding familial and metabolite information. Shapley Additive Explanations (SHAP) identified age, APOE4, PRS, and metabolites arsenic nan starring contributors, pinch fare and occupation besides being informative.

Finally, Mendelian randomization (MR) and colocalization analyses supported putative causal links betwixt metabolites and cognition aliases AD. Protective signals included 4-guanidinobutanoate (4-GBA; a gamma-aminobutyric acerb (GABA)-related metabolite), carotene diol (1) and carotene diol (2), and glutamine, aligning pinch mechanisms successful excitotoxicity control, redox defenses, and neurotransmission.

Together, nan information bespeak that nan familial inheritance shapes which metabolic pathways are related to dementia, and that MedDiet behaviour whitethorn beneficially reprogram those pathways, peculiarly successful APOE4 homozygotes.

Conclusions

To summarize, this study links genetics, plasma metabolomic signatures, and Mediterranean fare behaviour to dementia and measures cognition successful large, semipermanent cohorts.

Signals clustered successful APOE4 homozygotes: CEs and SMs aligned pinch risk, MedDiet tracked pinch favorable glycerides, and selected metabolites mediated protection. Although prediction improved only modestly, nan biology suggests precision prevention, pairing genotype-aware counseling pinch dietary guidance that targets lipid and one-carbon pathways. 

Findings warrant replication successful divers ancestries, repeated metabolomic sampling complete time, and involution tests that trial metabolite-guided Mediterranean fare strategies, allowing families to enactment earlier, personalize choices, and sphere independency clinically. 

Key limitations see nan predominantly European ancestry of nan participants, nan usage of azygous baseline metabolomic measures, and nan observational design, which relies connected composite dementia outcomes.