Relationship between BrainAge Polygenetic Risk Score and plasma biomarkers in the A4/LEARN studies.

Area of Science:

• Neuroscience
• Genetics
• Biomarkers

Background:

• Alzheimer's disease (AD) pathology can be detected using plasma biomarkers.
• Genetic factors may influence brain aging and AD risk.
• Understanding genetic predisposition to accelerated brain aging is crucial for early AD detection.

Purpose of the Study:

• To investigate the association between genetic risk for accelerated brain aging and plasma AD biomarkers.
• To explore age- and sex-specific effects in these associations.

Main Methods:

• Analysis of 1994 cognitively unimpaired participants from A4/LEARN studies.
• Calculation of polygenic risk scores (PRS) for accelerated grey matter loss.
• Measurement of plasma pTau217, GFAP, and NfL levels.
• Statistical modeling to test associations and interactions with age and sex.

Main Results:

• BrainAge PRS significantly moderated the age-pTau217 association, with higher PRS linked to elevated pTau217 in older individuals.
• This association was significant in females but not in males.
• No significant associations were found between BrainAge PRS and GFAP or NfL levels.

Conclusions:

• Genetic predisposition to accelerated brain aging is associated with elevated pTau217 in cognitively unimpaired older females.
• These findings highlight a potential sex- and age-specific genetic link between brain aging and early AD pathology.