Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years

Hithersay, Rosalyn; Startin, Carla M.; Hamburg, Sarah; Mok, Kin Y.; Hardy, John; Fisher, Elizabeth; Tybulewicz, Victor L. J.; Nižetić, Dean; Strydom, André

doi:10.1001/jamaneurol.2018.3616

Cited by 116 publications

(125 citation statements)

References 39 publications

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“…From 20 to 40 years of age, the majority of individuals with Down syndrome appear to develop characteristic Alzheimer disease neuropathology such as amyloid‐β plaques and neurofibrillary tangles; however, not all will develop dementia, which has a clinical prevalence of 68 to 80 per cent by 65 years of age . Dementia is also strongly associated with early mortality in older (>36y) adults with Down syndrome . There are therefore multiple factors which may explain why individual differences exist across all levels of assessment: from gene expression, cellular responses, and subsequent brain development, to cognitive, motor, and behavioural phenotypes …”

Section: Individual Variabilitymentioning

confidence: 99%

“…[9][10][11][12] Dementia is also strongly associated with early mortality in older (>36y) adults with Down syndrome. 13 There are therefore multiple factors which may explain why individual differences exist across all levels of assessment: from gene expression, cellular responses, and subsequent brain development, to cognitive, motor, and behavioural phenotypes. 6,12,14 NEURODEVELOPMENT IN DOWN SYNDROME Variable but atypical behavioural and cognitive functioning emerges throughout the lifespan in Down syndrome.…”

Section: Chdmentioning

confidence: 99%

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New approaches to studying early brain development in Down syndrome

Baburamani

Patkee

Arichi

et al. 2019

Develop Med Child Neuro

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Down syndrome is the most common genetic developmental disorder in humans and is caused by partial or complete triplication of human chromosome 21 (trisomy 21). It is a complex condition which results in multiple lifelong health problems, including varying degrees of intellectual disability and delays in speech, memory, and learning. As both length and quality of life are improving for individuals with Down syndrome, attention is now being directed to understanding and potentially treating the associated cognitive difficulties and their underlying biological substrates. These have included imaging and postmortem studies which have identified decreased regional brain volumes and histological anomalies that accompany early onset dementia. In addition, advances in genome‐wide analysis and Down syndrome mouse models are providing valuable insight into potential targets for intervention that could improve neurogenesis and long‐term cognition. As little is known about early brain development in human Down syndrome, we review recent advances in magnetic resonance imaging that allow non‐invasive visualization of brain macro‐ and microstructure, even in utero. It is hoped that together these advances may enable Down syndrome to become one of the first genetic disorders to be targeted by antenatal treatments designed to ‘normalize’ brain development. What this paper adds Magnetic resonance imaging can provide non‐invasive characterization of early brain development in Down syndrome. Down syndrome mouse models enable study of underlying pathology and potential intervention strategies. Potential therapies could modify brain structure and improve early cognitive levels. Down syndrome may be the first genetic disorder to have targeted therapies which alter antenatal brain development.

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Section: Individual Variabilitymentioning

confidence: 99%

Section: Chdmentioning

confidence: 99%

New approaches to studying early brain development in Down syndrome

Baburamani

Patkee

Arichi

et al. 2019

Develop Med Child Neuro

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“…This association is bolstered by the brain pathologies evident in Down syndrome patients who have extra-copies of chromosome 21 on which the amyloid precursor protein (APP) is located; trisomy results in overexpression of APP (Mentis, 2016). Over two thirds of older adults with trisomy 21 die from dementia, and among them, the risk of premature death is increased by almost seven-fold in APO E4 isoform carriers (Hithersay et al, 2018).…”

Section: The Role Of Apo E4 In Admentioning

confidence: 99%

Alzheimer disease and Apolipoprotein E4: meningeal brain lymphatics point to new clues in pathogenesis

Mentis

Chrousos

2019

Preprint

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ABSTRACTThe role of the lymphatic system in brain function and/or dysfunction has long been an enigma. However, recent reports that meningeal lymphatic vessels exist within the mouse and human brain, as well as evidence that mouse meningeal lymphatic vessels play a role in clearing the toxic amyloid-beta peptide connected with Alzheimer’s disease (AD), may herald novel diagnostic and therapeutic avenues. Here, we explore new evidence connecting the lymphatic system of the brain with AD. In particular, we focus on new findings showing that meningeal lymphatic vessels play a role in drainage of cerebrospinal fluid and egress of immune cells from the brain, and that disrupting this vessel system leads to accumulation of amyloid - beta peptide and cognitive dysfunction. We also discuss the hypothesis that apolipoprotein E isoform e4 (APO E4) ─ the leading genetic risk for developing AD ─ is involved in meningeal lymphatic vessel function. By reanalyzing previously published RNA-Seq data, we show that APO E4 knock-in microglia cells express lower levels of genes representing lymphatic markers (a phenomenon we call “attenuated lymphaticness”) and of genes in which functional missense mutations are linked to lymphedema. Accordingly, we propose the hypothesis that APO E4 is involved in the shrinkage of lymphatic vessels. This notion could lead, if verified by additional anatomic and mechanistic data, to the concept that APO E4-related AD (such as in late onset AD or trisomy 21-related AD) is related to lymphosclerosis coupled with lymphedema.

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“…Non-DS (euploid) people inheriting triplication of the APP gene alone (DupAPP) develop AD symptoms by age 60 with 100% penetrance. Paradoxically, only ~70% of people with DS develop clinical dementia by age 60, suggesting the presence of other unknown chromosome 21-located genes that modulate the age of dementia onset 6,7 . A number of secretases participate in the physiological cleavage of APP 1,8 , generating various peptides involved in neuronal pathology.…”

Section: Introductionmentioning

confidence: 99%

“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”

Alić

Goh

Murray

et al. 2020

Preprint

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A population of >6 million people worldwide at high risk of Alzheimer's disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS.We demonstrate that this protective mechanism is mediated by BACE2-trisomy and crossinhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.These studies uncovered that BACE2 can cleave the product of β-secretase (APP β-CTF) between aa19 and aa20, generating a 1-19 fragment [13][14][15] , thereby potentially preventing the formation of amyloidogenic Aβ, and degrading the β-CTF that has been implicated in neuronal toxicity, and impairment of several neuronal functions, such as axonal transport and autophagy 16 .When offered synthetic Aβ40/42 peptides in solution, purified BACE2 protein can rapidly degrade them by cutting after aa20 and aa34, to generate the 1-20 and 1-34 peptide products, but only at very acidic pH (3.5-4). In this reaction, BACE2 is 150-fold more efficient than BACE1, which is also capable of this cleavage, upon conditions of increased enzyme concentration/time 12,14 . Neither of these two putative anti-amyloidogenic actions of BACE2 (the θ-secretase activity, generating aa1-19, or the Aβ-degrading-protease activity (AβDP or Aβ clearance) generating aa1-20 and aa1-34), have yet been demonstrated to be the functional role of BACE2 under physiologically fluctuating gene doses in vivo in the human brain. A naturally occurring form of gene overdose for both APP and BACE2 is DS, caused by the trisomy of human chromosome 21 (T21) that harbours both APP and BACE2 genes. As increased levels of soluble Aβ were observed already in foetal brains in DS 17 , we examined cerebral organoids grown from induced pluripotent stem cell (iPSC) generated by non-integr...

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Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years

Cited by 116 publications

References 39 publications

New approaches to studying early brain development in Down syndrome

New approaches to studying early brain development in Down syndrome

Alzheimer disease and Apolipoprotein E4: meningeal brain lymphatics point to new clues in pathogenesis

“Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain”

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