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

Abstract

Objective: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted 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 noncarrier 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 piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO.

Results: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset.

Interpretation: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939.

Figure 1

Correlation between total WMH volume and Aβ_1-42, plotted separately for mutation carriers and non-carriers. The relationship was significant (r=−0.26, p=0.0012) for carriers but not for non-carriers (r=−0.053, p=0.623). Shaded areas represent 95% confidence intervals. IHS=inverse hyperbolic sine transformation.

Figure 2

Association between estimated year from symptom onset and total WMH volume in mutation carriers and non-carriers. Mutation carriers had greater total WMH volume; differences in WMH volume between groups began increasing systematically approximately 6.6 years prior to estimated symptom onset (inflection point: −6.6 EYO, indicated by arrow on x-axis). Shaded areas represent 95% confidence intervals. Arrow indicates the inflection point in the analysis. IHS=inverse hyperbolic sine transformation.

Figure 3

Association between estimated year from symptom onset and regional WMH volumes and AD biomarkers in mutation carriers and non-carriers. In all cases, mutation carriers had more severe biomarker burden; the point at which differences between groups begin to increase systematically (i.e., inflection point) is indicated by an arrow on the x-axis. A: frontal lobe WMH volume (inflection point=−3.0 EYO); B: temporal lobe WMH volume (inflection point=−1.3 EYO); C: parietal lobe WMH volume (inflection point=−7.0 EYO); D: occipital lobe WMH volume (inflection point=−22.0 EYO); E: Aβ₄₂ (inflection point=−30.1 EYO); F: ptau181 (inflection point=−26.0 EYO). Shaded areas represent 95% confidence intervals. IHS=inverse hyperbolic sine transformation.

Figure 4

Examples of WMH distribution in mutation carriers (upper row) and non-carriers (lower row) across three EYO time points. The top row displays examples of T2-weighted FLAIR MRI scans from three mutation carriers at varying estimated years from symptom onset. The bottom row displays examples of MRI scans from non-carriers matched for estimated years from symptom onset (based on parental age of onset). All participants displayed in this figure had CDR scores of 0 at the time of MRI scan.