Associations between rare microglia‐linked Alzheimer's disease risk variants and subcortical brain volumes in young individuals

Abstract

Introduction Recent exome sequencing studies have identified three novel risk variants associated with Alzheimer's disease (AD). However, the mechanisms by which these variants confer risk are largely unknown. Methods In the present study, the impact of these rare coding variants (in ABI3, PLCG2 , and TREM2 ) on all subcortical volumes is determined in a large sample of young healthy individuals (N = 756–765; aged 22–35 years). Results After multiple testing correction ( P CORRECTED < .05), rare variants were associated with basal ganglia volumes ( TREM2 and PLCG2 effects within the putamen and pallidum, respectively). Nominal associations between TREM2 and reduced hippocampal and thalamic volumes were also observed. Discussion Our observations suggest that rare variants in microglia-mediated immunity pathway may contribute to the subcortical alterations observed in AD cases. These observations provide further evidence that genetic risk for AD may influence the volume of subcortical volumes and increase AD risk in early life processes.

Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer’s polygenic risk reveals autobiographical deficits and cingulate cortex correlates

“…iPSc collection and generation) [ 3 ]; (2) genetics-first characterisation can occur across the entire lifespan, establishing precise timelines for trajectories of genetic risk, enhancing prediction, intervention opportunities, adding a layer of precision to the commonly used characteristics [ 49 ], and (3) empower clinical trials for individuals at increased genetic risk, with implications for timeliness, power, and cost [ 50 ]. Recall-by-genotype of less common, missense single-nucleotide variants (for example, functional, amino-acid change conferring SNPs within genes such as ABI3 , PLCG2 , TREM2 ) could also further provide mechanistic insight into the aetiology of preclinical AD, with known functional roles in modifying immune system physiology [ 51 , 52 ], which have further been linked to features of brain health [ 53 – 55 ]. In conclusion, we document the first recall-by-genotype study for AD-PRS and observe neurocognitive features with distinct profiles between participants with very low and high AD-PRS.…”