Alzheimer's Imaging Consortium.

Area of Science:

• Neurogenetics
• Alzheimer's Disease Research
• Biomarker Discovery

Background:

• Individual variability in brain amyloid burden suggests underlying biological factors.
• Investigating genetic determinants of amyloid pathology is crucial for understanding Alzheimer's disease (AD).

Purpose of the Study:

• To examine the association between polygenic risk scores (PRS) and amyloid burden in a preclinical AD cohort.
• To identify genetic factors influencing amyloid deposition in the brain.

Main Methods:

• Computed PRS for AD susceptibility and CSF biomarkers in 867 non-demented participants.
• Assessed PRS associations with amyloid burden (Centiloid) using linear regression, adjusting for covariates.
• Evaluated model performance via cross-validation and performed gene enrichment analysis on significant SNPs.

Main Results:

• PRS_amyloid at pT=1x10⁻⁵ showed the strongest prediction for frontal amyloid burden (R²=0.18).
• PRS_amyloid and PRS_Kunkle demonstrated comparable predictive performance across brain regions at stringent thresholds (pT=5x10⁻⁸, 1x10⁻⁵).
• Predictive performance was highest in the frontal cortex and showed higher predictive ability in males.

Conclusions:

• PRS effectively predict amyloid burden, especially in the frontal cortex, with PRS_amyloid and PRS_Kunkle showing similar performance.
• Genetic profiling holds potential for identifying individuals at risk for AD, with observed sex differences in predictive power.
• Findings contribute to understanding the genetic basis of amyloid pathology and highlight potential sex-specific genetic influences.