Polygenic predisposition to white matter hyperintensities does not contribute to amyloid or tau progression in Alzheimer’s disease

Abstract 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 −8 ). 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.