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Genetic risk pathways influence Alzheimer's disease (AD) brain changes. Specific pathways modify the impact of amyloid-β (Aβ) and phosphorylated-Tau (p-Tau) on white matter integrity, offering targets for intervention.

Keywords:
Alzheimer’s diseaseDiffusion magnetic resonance imagingFixel-based analysisPolygenic pathwaysPolygenic risk scoresWhite matter

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Area of Science:

  • Neuroscience and Genetics
  • Alzheimer's Disease Research
  • Brain Imaging and Structural Analysis

Background:

  • Alzheimer's disease (AD) is biologically defined by amyloid-β (Aβ) and phosphorylated-Tau (p-Tau) accumulation, but symptom onset varies significantly.
  • Genetic factors and their interactions with proteinopathies may explain heterogeneity in AD progression among cognitively intact individuals.
  • Understanding these genetic influences on brain structure is crucial for early detection and intervention strategies.

Purpose of the Study:

  • To investigate the association between AD-related pathophysiological changes (Aβ1-42, p-Tau181), polygenic risk scores (PRSs), and white matter (WM) structure in cognitively intact older adults.
  • To examine how pathway-specific PRSs interact with Aβ1-42 and p-Tau181 to affect WM micro- and macrostructural properties.
  • To identify specific genetic pathways that contribute to AD risk and influence brain integrity.

Main Methods:

  • Utilized data from 803 cognitively intact individuals from the European Prevention of Alzheimer Dementia (EPAD) cohort with available CSF biomarkers, genotyping, and MRI data.
  • Calculated pathway-specific PRSs for six functional clusters (immune activation, signal transduction, inflammation, lipid, amyloid, clearance) from 85 AD-related genetic variants.
  • Employed fixel-based analysis of diffusion MRI to assess fiber density (FD) and fiber cross-section (FC) in WM tracts, analyzing interactions with PRS and biomarker levels.

Main Results:

  • Phosphorylated-Tau181 (p-Tau181) was associated with increased fiber density (FD), while the lipid pathway PRS correlated with greater FD and fiber cross-section (FC).
  • The clearance pathway PRS moderated the effect of amyloid-β1-42 (Aβ1-42) on FD, showing a positive association in Aβ-positive individuals.
  • The immune activation pathway PRS moderated the effect of p-Tau181 on FD, with a negative association observed in p-Tau-positive individuals.

Conclusions:

  • Pathway-specific genetic vulnerability to AD is directly linked to WM alterations and modulates the impact of AD biomarkers.
  • Integrating AD-associated genetic risk into diagnostic frameworks can facilitate targeted screening and interventions for preclinical AD.
  • Findings highlight the importance of considering genetic pathways in understanding AD heterogeneity and developing personalized therapeutic strategies.