Biomarkers.

Background: White matter hyperintensities (WMH) are prevalent Alzheimer's disease (AD). However, the role of WMH in the etiology of AD is debated. Specifically, a key question is whether higher WMH is predictive of higher beta-amyloid (Aβ) and fibrillar tau accumulation. Here, we assessed whether a genetic predisposition to higher WMH (assessed via polygenic score [PGS] of WMH based on a large-scale population-based GWAS) is associated with higher rates of WMH volume and amyloid- and tau-PET accumulation in elderly individuals.

Methods: We included 338 participants within the AD spectrum defined by amyloid-PET positivity, encompassing 135 cognitively normal (CN Aβ+), 122 mild cognitive impairment (MCI Aβ+), 81 AD dementia, and in addition 287 amyloid-negative controls (CN Aβ-) from from ADNI. Flortaucipir-PET was available in a subset of 92 Aβ+ & 85 CN Aβ- participants. WMH were segmented via a deep learning-based algorithm on FLAIR images and partitioned into 5 lobar volumes. Based on GWAS in 35,000 individuals from the UKBiobank with global WMH volume as the dependent variable, we generated a PGS including 20 SNPs (p<5×10). Centiloids of global cortical amyloid-PET and temporal-meta ROI values of tau-PET SUVR were computed. All linear regression analyses were stratified by group (CN Aβ- vs pooled Aβ+) and controlled for age, sex, education, systolic blood pressure, BMI, APOE e4 genotype, and population genetic components.

Results: A higher PGS was associated with higher cross-sectional WMH volume in the frontal, parietal, and temporal lobes in both the CN Aβ- and the whole Aβ+ group (except for temporal WMH; Figure 1). Longitudinally, higher PGS was associated with faster increases in frontal WMH volume in CN Aβ- (β=0.18, p=.03) and in the temporal lobe in the Aβ+ group (β=0.18, p=.01, Figure 2) over 2.8 years on average. Conversely, neither PGS nor baseline WMH volume (or modifiable risk factors) predicted increase in amyloid- or tau-PET (mean follow-ups: 3.9 & 2.8 years).

Conclusion: Genetic predisposition to WMH was associated with higher WMH volume in a region-dependent manner, but the increases in WMH were associated neither with Aβ- nor tau-PET accumulation, suggesting that white matter lesions develop independently from AD pathologies.