The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

Abstract

Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer's disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ε4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults.

Keywords: APOE; Alzheimer's disease; Amygdala; Hippocampus; Polygenic risk score; TREM2.

Fig. 1

Variance explained (R²) by the effect of APOE ɛ4, PRS, and TREM2 rs9394721 on hippocampal volume in the combined all older, and in separate clinical groups. The combined variance explained (R²) by APOE ɛ4, PRS p < 1e04, and TREM2 rs9394721 within a single multiple regression (representing all the variance explained by the AD risk variants investigated) totaled 0.016 in the all-older group. For the separate clinical groups R² = 0.030 in the AD group, 0.032 in the MCI group and 0.003 in the healthy older group. Ns represent the total N of the slightly differing sample sizes for each variant/score (each individual sample size is shown in Tables 3 and 4). *p < 0.05 and **p < 0.001 represent significant p values for the association of the variant/score with hippocampal volume (not corrected for multiple testing). Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein E; MCI, mild cognitive impairment; R², the variance explained by the genotype.