Cerebrovascular pathology in Down syndrome and Alzheimer disease

Elizabeth Head, Michael J Phelan, Eric Doran, Ronald C Kim, Wayne W Poon, Frederick A Schmitt, Ira T Lott, Elizabeth Head, Michael J Phelan, Eric Doran, Ronald C Kim, Wayne W Poon, Frederick A Schmitt, Ira T Lott

Abstract

People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD) with age. Typically, by age 40 years, most people with DS have sufficient neuropathology for an AD diagnosis. Interestingly, atherosclerosis and hypertension are atypical in DS with age, suggesting the lack of these vascular risk factors may be associated with reduced cerebrovascular pathology. However, because the extra copy of APP leads to increased beta-amyloid peptide (Aβ) accumulation in DS, we hypothesized that there would be more extensive and widespread cerebral amyloid angiopathy (CAA) with age in DS relative to sporadic AD. To test this hypothesis CAA, atherosclerosis and arteriolosclerosis were used as measures of cerebrovascular pathology and compared in post mortem tissue from individuals with DS (n = 32), sporadic AD (n = 80) and controls (n = 37). CAA was observed with significantly higher frequencies in brains of individuals with DS compared to sporadic AD and controls. Atherosclerosis and arteriolosclerosis were rare in the cases with DS. CAA in DS may be a target for future interventional clinical trials.

Keywords: Arteriolosclerosis; Atherosclerosis; Cerebral amyloid angiopathy; Trisomy 21; Vascular risk factors.

Conflict of interest statement

Ethics approval and consent to participate

Consent for autopsy was obtained from individuals enrolled in the study and was approved by the University of California Human Subjects Institutional Review Board.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Percentage of autopsy cases by severity of cerebrovascular outcome and cohort. Percentages for Atherosclerosis, Arteriolosclerosis, and Cerebral Amyloid Angiopathy (CAA) add to 100% within each cohort, separately. More moderate and severe CAA findings were associated particularly with the DS cohort
Fig. 2
Fig. 2
Age at autopsy across the three cohorts (DS, AD, Ctrl) showing that the DS cases were younger than the AD and Control (Ctrl) cases. Individual data points are shown in open circles, group means in solid, red circles. Error bars show plus-and-minus one standard deviation from the mean
Fig. 3
Fig. 3
Arteriolosclerosis as a function of age in DS, AD and Controls. Individual data points shown as open circles, group means as filled circles. Error bars show plus-and-minus one standard deviation from the mean
Fig. 4
Fig. 4
Atherosclerosis as a function of age in DS, AD and Controls. Individual data points shown as open circles, group means as filled circles. Error bars show plus-and-minus one standard deviation from the mean
Fig. 5
Fig. 5
Probability of CAA severity as a function of age-at-autopsy in DS cohort. Error bars show the upper and lower limits of the 95% confidence interval. The number of DS cases with no or mild CAA decreases with age. The number of people with DS with moderate CAA remains relatively stable but the numbers of cases with severe CAA increases with age
Fig. 6
Fig. 6
Probability curves for CAA severity based on age-at-autopsy in DS cohort. The age at which CAA shifts from mild, to moderate to severe are estimated based on age. Moderate to severe findings were more likely at upper ages

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