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.
Highlights
People with Down syndrome (DS) are at higher risk for developing Alzheimer disease (AD), which is thought to be primarily due to the overexpression of amyloid precursor protein [19, 46]
Atherosclerosis and arteriolosclerosis were frequently observed in the AD cohort and less so in the DS and control cohorts (Table 2, Fig 1)
The relative risks of each of these vascular outcomes are provided in Table 3 and suggest that the DS cohort was 1.21 times more likely to have cerebral amyloid angiopathy (CAA) relative to AD cases, and 4.6 times more likely to have CAA compared to control cases
Summary
People with Down syndrome (DS) are at higher risk for developing Alzheimer disease (AD), which is thought to be primarily due to the overexpression of amyloid precursor protein [19, 46]. Beta-amyloid (Aβ) plaques and neurofibrillary tangles are typically observed by 40 years of age Up to 55% of people with DS between 40 and 49 years of age develop dementia and the numbers rise to 77% in people 60–69 years of age (reviewed in [6]). The presence of cerebrovascular pathology may be a critical comorbidity that accelerates the age of onset of dementia and leads to faster disease progression. Cerebrovascular pathology resulting from atherosclerosis and arteriolosclerosis may serve as a “second hit”
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