A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Abstract

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

Propagation of Aß pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

“…Mutations in the Aβ sequence itself can also favor aggregation as observed in the "Arctic" mutation (APP E693G). Triplication of the APP gene located on chromosome 21 as in Down's syndrome (Trisomy 21) [131], or in rare familial cases of AD with duplication of the APP gene [105] also lead to AD pathology [82]. A role for polymorphisms in the promoter region of the APP gene has been discussed [56].…”

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

“…Indeed, nearly all adults with DS evidence neuropathology of AD by their fourth decade of life (Mann & Esiri, 1989; Wisniewski, Wisniewski, & Wen, 1985) and more than half of adults with DS in their 60s exhibit clinical symptoms of AD (Coppus et al, 2006; McCarron et al, 2014). The early onset and increased incidence of AD in adults with DS is attributed to the overproduction of amyloid-β due to the triplication of chromosome 21, which contains the gene for the amyloid precursor protein (APP) (Wiseman et al, 2015). The accumulation of amyloid-β plaques, followed by neurofibrillary tangles of the protein tau, is an early event in the pathogenesis leading to clinical AD years to decades later (Hardy & Higgins, 1992).…”

Induction of Bax-dependent neuronal apoptosis by Amyloid-β Protein Precursor (AβPP) requires its localization to functional mitochondria

“…This suggests that other factors besides increased Aβ production contribute to the pathogenesis of sporadic AD. In this context, patients with Down Syndrome typically develop early onset AD that is most often attributed to expressing an extra copy of the AβPP gene which is localized to chromosome 21 [33][34][35][36]. The overexpression of AβPP has been shown to induce neuronal apoptosis in a variety of in vitro and in vivo models [16][17][18][19]37].…”