Glial-specific polygenic risk and mediterranean diet impact cognitive performance and dementia-related outcomes in...

Alzheimer's disease (AD) polygenic risk scores (PRS) reflect cumulative genome-wide genetic risk but lack cell-type specificity and functional context.

We examined the relationships between cell-type-specific ADPRS, domain-specific cognitive performance, and AD or amnestic mild cognitive impairment (aMCI) prevalence among elders. Secondary analyses evaluated additive and multiplicative interactions between ADPRS and adherence to Mediterranean diet (MedDiet), a known AD modifiable risk factor. Cross-sectional analyses were performed in a community cohort of 1,172 older individuals (57% females; mean age 74 years) from the Hellenic Longitudinal Investigation of Aging and Diet. Genome-wide ADPRS was calculated, along with ADPRS specific for six brain cell types: excitatory neurons (Ex), inhibitory neurons (In), astrocytes (Ast), microglia (Mic), oligodendrocytes (Oli), and oligodendrocyte precursor cells (Opc).

Genome-wide (OR = 1.38, 95%CI: 1.13-1.67) and Mic-ADPRS (OR = 1.37, 95%CI: 1.14-1.66) were associated with AD/aMCI diagnosis. Further, exploratory analyses revealed an additive interaction between Mic-ADPRS and MedDiet adherence; individuals with high Mic-ADPRS/low MedDiet adherence had a 1.68-fold higher AD/aMCI risk than those with low Mic-ADPRS/high MedDiet adherence. A nominal association was also observed between Ast-ADPRS and poor memory in the entire cohort (β=-0.052, p = 0.022) as well as in the cognitively normal sub-group of individuals (β=-0.046, p = 0.048).

These findings support a cell-type-informed framework of AD genetic risk, implying microglial-related polygenic contributions to disease onset, and a broader astrocyte-related polygenic influence on memory functioning in older age, regardless of AD/aMCI diagnosis. In addition, Mic-ADPRS and MedDiet adherence may jointly increase AD/aMCI liability, yet further investigation in diverse ancestral populations and biomarker-based longitudinal studies is warranted to clarify the potential implications for AD prevention.