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 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.

Figure 1. Development of pathology and dementia in AD-DS and Dup-APP

The graphs show the cumulative frequency of amyloid plaque deposition (measured using histological methods and positron emission tomography with Pittsburgh compound B (PiB), a radioactive analogue of thioflavin that binds to amyloid) and neurofibrillary tangle (NFT) development (measured using histological methods), and the cumulative frequency of dementia in people with Alzheimer disease and Down syndrome (AD-DS)^, and in individuals with familial AD induced by duplication of amyloid precursor protein (Dup-APP). As shown, people who have DS can live for many years with substantial amyloid deposition before the development of dementia. Solid lines are based on the data described in Supplementary information S1–S3 (tables). Dashed lines indicate hypothesized development of pathology for which there are currently no data available. Further pathological and clinical studies directly comparing these two populations are required to verify the apparent differences in clinical dementia onset and to determine whether the development of pathology differs from that proposed here. Aβ, amyloid-β.

Figure 2. Regions of chromosome 21 duplicated in Dup-APP EOAD and ICH

Schematic illustrating the genetic regions affected in reported cases of early-onset Alzheimer disease (EOAD) accompanied by duplication of amyloid precursor protein (Dup-APP)^–,. The minimal duplicated region is shown in blue: the only gene duplicated in all cases is APP. ADAMTS1, a disintegrin and metalloproteinase with thrombospondin motifs 1; ATP5J, ATP synthase-coupling factor 6; BACH1, BTB and CNC homologue 1; BTG3, BTG family member 3; C21orf91, chromosome 21 open reading frame 91; CCT8, chaperonin containing TCP1 8; CHODL, chondrolectin; CLDN17, claudin 17; CXADR, coxsackie virus and adenovirus receptor homologue; CYYR1, cysteine- and tyrosine-rich 1; GABPA, GA repeat-binding protein-alpha; GRIK1, glutamate receptor ionotropic, kainate 1; HSPA13, heat shock protein 70 kDa 13; ICH, intracerebral haemorrhage; JAM2, junction adhesion molecule 2; LIPI, lipase member I; LTN1, listerin E3 ubiquitin protein ligase 1; MAP3K7CL, MAP3K7 carboxy-terminal like; MRPL39, mitochondrial ribosomal protein L39; N6AMT1, N-6 adenine-specific DNA methyltransferase 1; NCAM2, neural cell adhesion molecule 2; NRIP1, nuclear receptor-interacting protein 1; PED, pedigree; POTED, POTE ankyrin domain family member D; RBM11, RNA-binding motif protein 11; RWDD2B, RWD domain-containing 2B; SAMSN1, SAM domain, SH3 domain and nuclear localization signals 1; TMPRSS15, transmembrane protease serine 15; USP, ubiquitin-specific peptidase.

Figure 3. Schematic of suggested mechanisms that are important in AD-DS and their related genes

Several genes may modulate processes that are relevant to the development of Alzheimer disease in people with Down syndrome (AD-DS); these include non-chromosome 21 genes, such as apolipoprotein E (APOE; which could alter disease by influencing cholesterol metabolism and possibly many other pathways), phosphatidylinositol-binding clathrin assembly protein (PICALM), sortilin-related receptor 1 (SORL1; which may influence disease via the endocytosis system and amyloid precursor protein (APP) processing) and microtubule-associated protein tau (MAPT). Tau aggregates to form neurofibrillary tangles (NFTs). Numerous chromosome 21 genes have also been suggested to influence the development of AD-DS, including genes that may influence APP processing and synaptic function via their role in the secretory–endosome system (including cystatin B (CSTB), DOPEY2, synaptojanin 1 (SYNJ1), intersectin 1 (ITSN1) and the microRNA gene mir-155), APP processing (including small ubiquitin-like modifier 3 (SUMO3), ETS2 and beta-site APP-cleaving enzyme 2 (BACE2)), cholesterol metabolism (including ATP-binding cassette G1 (ABCG1)), cellular signalling and tau phosphorylation (including dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and regulator of calcineurin 1 (RCAN1)), inflammation (including mir-155 and S100 calcium-binding protein beta (S100B)), synaptic function (including DOPEY2, SYNJ1, ITSN1, RCAN1 and mir-155), neurodevelopment (including ubiquitin-specific peptidase 16 (USP16), DYRK1A and DS cell adhesion molecule (DSCAM)) and oxidative stress (superoxide dismutase 1 (SOD1)). The relative importance of these processes to the development of dementia in AD-DS remains unclear and constitutes an area for future study. Chromosome 21 genes and gene products are shown in purple; non-chromosome 21 genes and gene products are shown in green. Aβ, amyloid-β.