Cerebrovascular contributions to aging and Alzheimer's disease in Down syndrome

Abstract

Down syndrome (DS) is a common cause of intellectual disability and is also associated with early age of onset of Alzheimer's disease (AD). Due to an extra copy of chromosome 21, most adults over 40 years old with DS have beta-amyloid plaques as a result of overexpression of the amyloid precursor protein. Cerebrovascular pathology may also be a significant contributor to neuropathology observed in the brains of adults with DS. This review describes the features of cardiovascular dysfunction and cerebrovascular pathology in DS that may be modifiable risk factors and thus targets for interventions. We will describe cerebrovascular pathology, the role of comorbidities, imaging studies indicating vascular pathology and the possible consequences. It is clear that our understanding of aging and AD in people with DS will benefit from further studies to determine the role that cerebrovascular dysfunction contributes to cognitive health.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal‐dominant Alzheimer's disease

“…There are no previous studies assessing the mBCAA criteria or any of its component neuroimaging features in DS. CAA is also consistently observed in DS pathological studies [5,28], but it had been proposed that other genetic factors in DS might protect these subjects from the ICH [29]. We found 38.5% of frequency for lobar microbleeds in symptomatic DS and, more importantly, a frequency of 15.4% for ICH.…”

“…The mBCAA were more frequent in DS and ADAD, suggesting a more severe CAA, as shown in pathological studies [5,25]. The most frequent CAA neuroimaging feature was the presence of lobar microbleeds, as previously described [26].…”

“…Previous neuropathological studies have suggested a more severe CAA in ADAD than in sporadic Alzheimer's disease [4]. CAA in some APP mutations or duplication carriers drives the clinical presentation [4], and is also consistently observed in subjects with DS [5]. The modified Boston criteria for CAA-related hemorrhage (mBCAA) have been validated to attribute in vivo an ICH to CAA based on several neuroimaging features, and are frequently used in clinical practice [6].…”

Calcineurin proteolysis in astrocytes: Implications for impaired synaptic function

“…Vascular pathology is highly co-morbid with AD pathology and likely exacerbates cognitive decline with the progression of AD [41–47]. Mounting evidence suggests that microinfarcts are among the most common and insidious contributors to vascular cognitive impairment and dementia (VCID) [48, 49].…”

“…Microinfarcts, in particular, are increasingly recognized as a key mechanism for dementia [48, 49]. Though etiologically distinct from AD pathology, microinfarcts and other forms of vascular pathology show high comorbidity with AD, where they appear to exacerbate neurodegenerative processes and hasten cognitive decline [41–47]. Microinfarcts are often defined by extensive gliosis surrounding the core, including profound astrocyte activation [50, 51].…”