White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network

Abstract

Objective White matter hyperintensities(WMH) are areas of increased signal on magnetic resonance imaging(MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer’s disease(AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically-determined to develop AD. Methods The study comprised participants(n=299, age=39.03±10.13) from the Dominantly Inherited Alzheimer Network, including 184(61.5%) with a mutation that results in AD and 115(38.5%) first-degree relatives who were non-carrier controls. We calculated the estimated years from expected symptom onset(EYO) by subtracting the affected parent’s symptom onset age from the participant’s age. Baseline MRI data were analyzed for total and regional WMH. Mixed effects piecewise linear regression was used to examine WMH differences between carriers and non-carriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years prior to expected symptom onset. The effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years prior to estimated onset. Interpretation Autosomal dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMH are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.

Late-Life Vascular Risk Factors and Alzheimer Disease Neuropathology in Individuals with Normal Cognition

“…Increased HR can be a sign of cardiac problems, predicts incident cardiovascular events (50), and is not typically affected by aging. Therefore, some of the subjects in the sample may have experienced deterioration in overall cardiovascular health over time, potentially leading to cerebrovascular changes, a proposed core feature of AD (51). Increases in resting HR may also be capturing changes in HR variability (52), which may be sensitive to AD detection and severity (11).…”

Cerebral Hypoperfusion and the Energy Deficit in Alzheimer's Disease

“…The fact that the hypoperfusion actually damages the brain, even in preclinical or early disease, is well demonstrated on imaging of cerebral white matter in people with mutations that cause autosomal dominant forms of AD. A recent study showed that people with such mutations had a greater volume of white matter hyperintensities (WMH) several years before clinical disease, indicating that the hypoperfusion was severe enough to cause tissue damage (67). The increase in WMH was most pronounced in the parietal and occipital lobes; as noted above, this corresponds approximately to the distribution of early amyloid accumulation and reduced perfusion in the overlying cerebral cortex.…”

“…The authors found that amyloid burden, as assessed by measuring Aβ42 level in the CSF, was an independent predictor of total WMH volume. Lee and colleagues (67) found some correlation between WMH and the presence of microbleeds, suggesting a contribution from cerebral amyloid angiopathy. However, the increase in WMH remained significant after controlling for presence of microbleeds, which were calculated to account for 21% of the association between AD mutation status and WMH.…”

VEGFR1 and VEGFR2 in Alzheimer’s Disease

“…Cerebral blood flow (CBF) declines before cognitive decline or brain atrophy [1,8] and is associated with biochemical and MRI evidence of tissue damage [4,9]. Vessel wall abnormalities such as cerebral amyloid angiopathy (CAA) and arteriolosclerosis, may play a part in the hypoperfusion but its timing and distribution suggest that other factors are more important contributors.…”