The following is a summary of “Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer’s Disease,” published in the October 2023 issue of Neurology by Shirzadi et al. 

White matter hyperintensity (WMH) volume is high in both autosomal dominant Alzheimer’s disease (ADAD) and late-onset Alzheimer’s disease (LOAD), but it is unclear whether this is due to Alzheimer’s disease (AD) itself or to vascular risk factors. Researchers performed a retrospective study to assess the associations of AD-intrinsic processes and systemic vascular risk with WMH accumulation. 

The study utilized data from three longitudinal cohort studies conducted at both tertiary and community-based medical centers: Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).

The primary outcomes of interest were the separate relationships between neurodegeneration (indicated by reductions in gray matter volume), parenchymal amyloidosis (evaluated through amyloid positron emission tomography), and vessel amyloidosis (identified by cerebral microbleeds [CMBs]) with both cross-sectional and longitudinal white matter hyperintensities (WMH). 

The study included data from 3,960 MRI sessions involving 1,141 participants, which included 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female).

Longitudinal increases in white matter hyperintensity (WMH) volume were more pronounced in CMBs individuals compared to those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]). These increases were associated with decreases in gray matter volume over time (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]). They were also more prominent in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]) and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD, after adjusting for age, gray matter volume, CMB presence, and amyloid burden.

In older adults without CMBs at baseline, greater WMH volume was linked to CMB development during follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).  

The study found that WMH volume in AD is associated with AD-intrinsic processes but not systemic vascular risk and may be an early sign of vessel amyloidosis. 

Source: jamanetwork.com/journals/jamaneurology/article-abstract/2810315