Testing a Polygenic Risk Score for Morphological Microglial Activation in Alzheimer's Disease and Aging

Area of Science:

• Neuroscience
• Genetics
• Gerontology

Background:

• Neuroinflammation and microglial activation are early indicators in Alzheimer's disease (AD).
• Direct in-vivo observation of microglial activation is currently not feasible.
• Polygenic risk scores (PRS) can index heritable predispositions for complex traits.

Purpose of the Study:

• To assess if a PRS for microglial activation (PRSmic) enhances the predictive capability of existing AD PRS for late-life cognitive impairment.
• To investigate the utility of PRSmic in predicting AD diagnosis and cognitive decline.

Main Methods:

• PRSmic was developed and optimized using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n=450).
• The predictive performance of PRSmic was validated in two independent population-based cohorts (total n=212,237).
• Associations between PRSmic and AD biomarkers (imaging and fluid) were examined within the ADNI cohort.

Main Results:

• PRSmic did not significantly improve the prediction of AD diagnosis or cognitive performance in external validation cohorts.
• Nominal associations between PRSmic and AD biomarkers were observed in the ADNI cohort, but with inconsistent directions of effect.
• The study found no substantial predictive enhancement from the PRSmic for AD-related outcomes.

Conclusions:

• Genetic scores for indexing neuroinflammatory risk in aging are valuable but require more robust genome-wide association studies.
• Future biobank-scale studies should incorporate phenotyping of proximal neuroinflammatory processes to refine PRS development.
• Current PRSmic approaches may not be sufficient for predicting AD risk or cognitive impairment due to limitations in microglial activation data.