Polygenic pathways shape white matter vulnerability to Alzheimer's disease-related pathophysiological changes

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 (Aβ_1-42, p-Tau₁₈₁), polygenic risk scores (PRSs), and white matter (WM) structure in cognitively intact older adults.
• To examine how pathway-specific PRSs interact with Aβ_1-42 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-β_1-42 (Aβ_1-42) 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.