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Basic Science and Pathogenesis.

Jorge Garcia Condado1,2,3, Colin Birkenbihl1, Hannah M Klinger1

  • 1Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

Genetic predisposition to accelerated grey matter brain aging is linked to elevated p-tau217, an early Alzheimer's disease biomarker, especially in older adults. This highlights genetic susceptibility interacting with age in AD pathogenesis.

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Area of Science:

  • Neuroimaging and Genetics
  • Biomarker Research
  • Alzheimer's Disease Pathogenesis

Background:

  • The BrainAge Gap quantifies brain age discrepancy via neuroimaging.
  • Polygenic Risk Scores (PRS) for BrainAge Gap estimate genetic predisposition to accelerated brain aging.
  • Understanding the link between genetic brain aging propensity and early Alzheimer's disease (AD) biomarkers is crucial for early detection and intervention.

Purpose of the Study:

  • To investigate the association between genetic propensity for higher or lower BrainAge Gap and plasma biomarkers of AD.
  • To explore how genetic factors influencing brain aging relate to early AD-related changes.
  • To enhance understanding of early AD mechanisms and risk factors.

Main Methods:

  • Analysis of 3014 cognitively normal participants from the A4 and LEARN studies.
  • Calculation of PRS for Grey Matter (GM), White Matter (WM), and Functional Connectivity (FC) BrainAge models.
  • Assessment of plasma biomarkers: p-tau217, GFAP, and NfL, using general linear models with interaction terms for age and PRS.

Main Results:

  • No significant differences in BrainAge PRS based on Aβ-PET status, APOEε4 carriership, age, sex, or education.
  • BrainAge GM PRS showed a positive association with p-tau217 levels (p=0.01), particularly in older adults (p=0.007).
  • No significant associations were found between any BrainAge PRS and GFAP or NfL levels.

Conclusions:

  • Genetic factors promoting accelerated grey matter brain aging are associated with p-tau217, a sensitive AD marker.
  • This genetic predisposition is more pronounced in older individuals, indicating age-related interaction.
  • The specific association with Grey Matter BrainAge PRS suggests its potential as an early marker for AD risk.