# Prediction of Episodic Memory With Multiomics Scores

## TL;DR

Genomic markers improve prediction of memory performance in older adults beyond traditional and metabolomic risk factors, suggesting potential for early dementia risk assessment.

## Contribution

Demonstrates that polygenic risk scores enhance episodic memory prediction in adults, but not in children, and metabolomic scores do not add predictive value.

## Key findings

- Polygenic risk scores (LASSO-PRS and GWAMA-PRS) significantly increased episodic memory prediction beyond the CAIDE score in older adults.
- Metabolic risk scores did not show significant associations with episodic memory in the studied population.
- Polygenic risk scores were not predictive of episodic memory in pediatric cohorts.

## Abstract

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 (R2) 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 R2 by 1.6, 5.6, and 4.5 percentage points (pp), respectively, while accounting additionally for MRS + LASSO-PRS or MRS + GWAMA-PRS increased R2 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.

Episodic memory—the ability to encode and recall events over a short time interval—is important for healthy aging and is often affected early in dementia. In our study, genomic markers enhanced prediction of memory performance beyond traditional risk factors, such as age and lifestyle, and metabolomic markers in individuals without dementia. This suggests that genomic markers could support risk stratification of dementia before its onset, allowing for timely support and preventive strategies.

Episodic memory—the ability to encode and recall events over a short time interval—is important for healthy aging and is often affected early in dementia. In our study, genomic markers enhanced prediction of memory performance beyond traditional risk factors, such as age and lifestyle, and metabolomic markers in individuals without dementia. This suggests that genomic markers could support risk stratification of dementia before its onset, allowing for timely support and preventive strategies.