WMH Volume Tied to Neurodegeneration in Sporadic and Autosomal Dominant AD

Increased white matter hyperintensity (WMH) in patients with Alzheimer disease (AD) is associated with neurodegeneration and amyloidosis of the parenchyma and vessels but is not associated with increased systemic vascular risk, according to study findings in JAMA Neurology.

Observing increased WMH is typically nonspecific and common among patients evaluated for AD. While WMH is typically indicative of small-vessel ischemic brain injury, the interpretation of this finding remains unclear. 

Researchers conducted a retrospective cohort study to determine the relationship between neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation. The researchers also sought to determine whether WMH is associated with intrinsic processes related to AD or if this finding is secondary to increased systemic vascular risk factors.   

The researchers collected patient data from 3 longitudinal cohort studies that were conducted at tertiary and community-based medical centers: the Dominantly Inherited Alzheimer Network (DIAN) observational study, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Harvard Aging Brain Study (HABS). 

The primary outcomes of this study were the associations of neurodegeneration, parenchymal amyloidosis, and vessel amyloidosis. Neurodegeneration was defined as a decrease in gray matter volume; parenchymal amyloidosis was assessed using amyloid positron emission tomography, and vessel amyloidosis was evident with the presence of cerebral microbleeds.

The researchers included a total of 3960 magnetic resonance imaging (MRI) sessions of 1141 participants in the study. Of these patients, 252 participants were from the DIAN cohort, 571 were from the ADNI cohort, and 318 were from the HABS cohort.

The baseline WMH was increased among patients with autosomal dominant AD (ADAD) who had at least 1 cerebral microbleed at baseline (t, 2.1; P =.03). These patients also tended to be older (t, 4.7; P <.001) and had lower gray matter volume (t, -2.3; P =.02).

Among patients who were ADAD pathogenic variant carriers, the researchers observed longitudinal increases in individuals with cerebral microbleeds compared to those without cerebral microbleeds (t, 3.2; P =.001). This finding was consistent in older adults with cerebral microbleeds compared with those without (t, 2.7; P =.008).

Factors associated with increasing WMH volume include higher gray matter volume rate of change (DIAN: t, -3.1; P =.002; ADNI: t, -5.6; P <.001; HABS: t, -2.2; P =.03) and older age (DIAN: t, 6.8; P <.001; ADNI: t, 9.1; P <.001; HABS: t, 5.4; P <.001).

However, longitudinal decreases in gray matter volume were not associated with systemic vascular risk (DIAN: t, 0.7; P =.40; ADNI: t, 0.6; P =.50; HABS: t, 1.8; P =.06) among patients with ADAD and late-onset AD (LOAD).

In patients without cerebral microbleeds at baseline, an increased WHM volume is associated with the development of cerebral microbleeds (hazard ratio [HR], 2.63; 95% CI, 1.72-4.03; P <.001).

“Importantly, these data support the further development of white matter-centric measures to serve as biomarkers in both Alzheimer’s disease and [cerebral amyloid angiopathy] CAA,” the researchers concluded. 

Study limitations include the differences in effect sizes, the potential inability to identify cerebral microbleeds, and the lack of investigation between WMH and tau burden.