White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer's disease that emerge prior to dementia

Abstract

Background: To promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer's disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer's disease, in relation to age and symptom severity.

Methods: This is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer's Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.

Results: The mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.

Conclusions: The volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer's disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer's disease that is closely related to the progression of clinical symptoms.

Keywords: Autosomal-dominant Alzheimer’s disease; Cerebral microbleeds; Cognition; Dementia; PSEN1; White matter hyperintensities.

Fig. 1

Associations of age with A global normalized white matter hyperintensity volume (WMH) in PSEN1 E280A mutation carriers and non-carriers; B relative differences in lobe-specific normalized WMH volume in PSEN1 E280A mutation carriers; C relative differences across quantified biomarkers in PSEN1 E280A mutation carriers. All regression curves were fitted with a quadratic model and the 95% confidence intervals. In plots B and C, Z-scores reflecting relative differences were obtained using the mean of non-carrier individuals. Cortical amyloid (PET), measure of global cortical amyloid accumulation from positron emission tomography (PET) expressed in standardized uptake value ratio (SUVR); CSF, cerebrospinal fluid; ptau, phospho-tau; Aβ, amyloid-beta; SPL CT, superior parietal lobe cortical thickness; nWMH, normalized white matter hyperintensity volume. The dashed vertical line represents the median age of symptom onset in this clinical sample (i.e., 44 years) and the two vertical dotted lines represent 95% confidence intervals (i.e., 95% C.I. = 43, 45 years)

Fig. 2

Associations between normalized white matter hyperintensity (WMH) volume, A the Mini-Mental State Exam (MMSE) score, and B the CERAD Word List Learning Composite score in PSEN1 E280A mutation carriers (red) and non-carriers (gray)

Fig. 3

Bar graphs representing the relative contribution of each biomarker to the overall explained variance in performance of PSEN1 E280A mutation carriers on A the Mini-Mental State Exam (MMSE) score and B the CERAD Word List Learning Composite score. The relative contribution of each regressor is quantified using the LMG metric computed with the R package “relaimpo” (U. Grömping, 2006). Lines represent 95% confidence intervals after 1000 bootstrapping replications. CSF, cerebrospinal fluid; ptau, phospho-tau; SPL CT, superior parietal lobe cortical thickness; nWMH Vol., normalized white matter hyperintensity volume. *p < 0.05, **p < 0.01, ***p < 0.001