# Sex differences in APOE- and PICALM-related cognitive profiles in healthy middle-aged adults

## TL;DR

This study found that genetic risk factors for Alzheimer's disease affect cognitive performance differently in men and women, suggesting early signs of risk.

## Contribution

The study reveals sex-specific gene-cognition interactions in healthy middle-aged adults, highlighting early risk indicators.

## Key findings

- APOE ε3ε4 in women with lower cognitive performance is linked to worse recognition accuracy and more perseverations.
- PICALM GG interacts with education to influence fluid intelligence in women.
- In men, APOE ε3ε4 and APOE×PICALM interactions are associated with reduced fluid intelligence and episodic memory.

## Abstract

The APOE

ε4
and PICALM GG genotypes are strong genetic risk factors for Alzheimer’s disease. This study aimed to identify cognitive subgroups using unsupervised machine learning and to investigate the influence of APOE and PICALM genotypes on cognitive performance.

Cognitive, genetic and demographic data from 192 healthy middle-aged adults (50–63 years) from the PEARL-Neuro Database were analyzed using agglomerative hierarchical clustering. Neuropsychological tests included the California Verbal Learning Test, Raven’s Progressive Matrices, and the Edinburgh Handedness Inventory. Subsequent analyses used linear regression models to assess the effects of APOE, PICALM, and their interaction on cognitive outcomes.

Two cognitive subgroups (better vs. worse performance) were identified for both females (n = 60/43) and males (n = 38/51). In women with lower cognitive performance, the presence of the APOE

ε3ε4
allele was significantly associated with a higher number of perseverations (CVLT9:
pFDR=0.02
,
R2=0.18
) and lower recognition accuracy (CVLT12:
pFDR=0.04
,
R2=0.12
). A significant PICALM GG

×
education interaction was observed for fluid intelligence (
pFDR=0.03
,
R2=0.34
). In men with lower cognitive performance, the APOE

ε3ε4
genotype was associated with lower fluid intelligence scores (RPM:
pFDR=0.04
,
R2=0.09
). Furthermore, significant APOE

×

PICALM interactions were found for verbal learning (CVLT1:
pFDR=0.03
,
R2=0.16
) as well as delayed cued recall (CVLT6:
pFDR=0.03
,
R2=0.12
; CVLT8:
pFDR=0.03
,
R2=0.13
).

This study revealed significant sex differences in gene–cognition interactions. In females with lower cognitive performance, the genotype APOE

ε3ε4
was associated with poorer recognition, while the combined effects of APOE

×

PICALM in males were associated with weaker episodic memory. Although performance remained within normative ranges, these subtle differences may indicate early risk and warrant longitudinal monitoring.