Prediction of Episodic Memory With Multiomics Scores

Episodic memory (EM) refers to the ability to encode and recall events-a vital cognitive function for healthy cognitive aging and an endophenotype for dementia.

Using genome- and metabolome-wide least absolute shrinkage and selection operator (LASSO) analysis, we developed polygenic (LASSO-PRS) and metabolic risk scores (MRS) in ∼68.5-year-old individuals (n = 897). We also applied the Bayesian regression method PRS-CS to an external genome-wide meta-analysis (GWAMA, N = 29,785, age > 18 years) to derive another PRS (GWAMA-PRS). We assessed incremental variances (R ²) in EM explained by the PRSs and MRS separately and in combination beyond the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score in 104 independent ∼68.5-year-old individuals. Finally, we validated the PRSs in 2 independent pediatric cohorts (N = 309, age = ∼11.9 years; N = 443, age = ∼8.6 years).

In the independent sample of ∼68.5-year-old individuals, compared with CAIDE score alone, accounting additionally for either MRS, LASSO-PRS, or GWAMA-PRS increased R ² by 1.6, 5.6, and 4.5 percentage points (pp), respectively, while accounting additionally for MRS + LASSO-PRS or MRS + GWAMA-PRS increased R ² by 7.8 and 6.4 pp, respectively. Both LASSO-PRS (all false discovery rate [FDR]-adjusted p values = .01-.03) and GWAMA-PRS (all FDR-adjusted p values = .03) were significantly associated with EM in all models, while the CAIDE score and MRS were not (all FDR-adjusted p values > .05). PRSs were not associated with EM in the pediatric cohorts (all FDR-adjusted p values > .05).

Genomics added predictive value to EM beyond epidemiological risk factors in adults, but the same was not observed with metabolomics. Adult-derived PRSs did not predict EM in children.