Biomarkers

Area of Science:

• Neuroimaging Genetics
• Alzheimer's Disease Research
• Brain Aging

Background:

• Hippocampal volume is a critical in vivo imaging biomarker for Alzheimer's disease (AD) risk and progression.
• Previous studies indicate accelerated hippocampal atrophy in females with increasing AD pathology.
• Genome-wide association studies (GWAS) for hippocampal volume have largely excluded sex-specific genetic analyses.

Purpose of the Study:

• To investigate the sex-specific genetic architecture of hippocampal volume across multiple aging and AD cohorts.
• To identify genetic loci associated with hippocampal volume, considering sex-specific effects and interactions.

Main Methods:

• Analysis of 5,523 non-Hispanic White participants from eight aging and AD cohorts.
• Segmentation of hippocampal volume and estimated total intracranial volume (eTIV) from T1-weighted MRIs.
• Genome-wide association studies (GWAS) performed at baseline and longitudinally, with sex-stratified and sex-interaction models, followed by meta-analysis.

Main Results:

• Identified three genome-wide significant genetic loci associated with hippocampal volume.
• A novel locus on chromosome 14 near AKAP6 showed significant sex-specific effects on hippocampal volume change over time, primarily in females.
• A previously reported AD risk variant near SHARPIN on chromosome 8 demonstrated significant effects on hippocampal volume in males but not females.

Conclusions:

• Extended findings of a known AD risk variant (near SHARPIN) to hippocampal volume.
• Provided evidence for novel sex-specific genetic effects influencing hippocampal volume.
• Results underscore the importance of considering genetic predictors and sex differences in neuroimaging biomarkers for AD.