Pediatric Von Willebrand Disease: Practice Essentials, Pathophysiology, Epidemiology
Trisomy 21
Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy, Down's SyndromeACMG/AMP Pathogenicity Criteria: PS1, PS2, PS3, PS4, PM1Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Down's SyndromeCoding/Non-Coding: BothDNA Change: DuplicationExpected RNA Consequence: DuplicationExpected Protein Consequence: DuplicationGenomic Region: Chromosome 21
The presence of three copies of chromosome 21, which harbors the amyloid precursor protein (APP) gene, is the most common genetic cause of Alzheimer's disease. Carriers of this alteration have Down syndrome (DS), a condition that results in cognitive disability, alterations in craniofacial morphology, increased risk of congenital heart defects, immune disorders, reduced sense of smell, and a very high risk of developing AD (Antonarakis et al., 2020). Most commonly, trisomy 21 arises because of meiotic nondisjunction in which a pair of chromosomes 21 fail to separate in either the sperm or egg. The frequency of this alteration is relatively high, approximately 0.001 worldwide, according to the World Health Organization.
Dating back to 1948, multiple studies have shown that middle-aged individuals with DS are likely to develop AD dementia and pathology, including amyloid plaques, neurofibrillary tangles, and neuronal loss (Jervis, 1948; for review see Lott and Head, 2019). Of note, the original description of amyloid β (Aβ) was in DS (Glenner and Wong, 1984) and contributed to the formulation of the Aβ hypothesis (Lott and Head, 2019).
Mean age at onset of AD in DS is 54.5 years (Rubenstein et al., 2024), with nearly all individuals with DS developing amyloid plaques by age 40, and more than 95 percent diagnosed with AD dementia by age 70 (Fortea et al., 2021). In a study of more than 130,000 adults with DS in the US, the probability of an incident AD diagnosis over 8 years was 0.63 (95% CI, 0.62-0.64) for those between 55 and 64 years of age when entering the study (Rubenstein et al., 2024). Indeed, AD is currently a leading cause of death in DS adults and may explain their shortened life expectancy (Iulita et al., 2022). Of note, both disease onset and death occurred, on average, later in White non-Hispanics than in Hispanics and Native Americans (Rubenstein et al., 2024).
Like AD in the general population, AD in individuals with DS is characterized by dementia and can also be accompanied by gait disturbance, sleep disruption, and seizures. The latter are particularly frequent in DS AD, commonly developing after the third decade of life and before the onset of dementia (Lott and Head, 2019).
Overall, AD in DS appears to be the same disease as AD in the general population. Although not identical (Carmona-Iragui et al., 2024), AD biomarker trajectories in DS are very similar to those in autosomal dominant AD and sporadic late onset AD, with very similar links to AD symptomology (Fortea et al., 2020; Hartley et al., 2024; Kac et al., 2024). In addition, as in sporadic and familial AD, APOE4 accelerates the onset of AD in individuals with DS (Bejanin et al., 2021; Jul 2021 news). Also, AD polygenic risk scores were associated with cognitive phenotypes and cerebrospinal biomarkers in DS adults, suggesting common pathways influence memory decline in both (Gorijala et al., 2023).
Interestingly, in the general population, trisomy 21 mosaicism in the brain—affecting only a subpopulation of cells—may contribute to AD and other neurodegenerative diseases (for review see Potter et al., 2016). The effects of mosaicism in individuals with the DS phenotype and trisomy 21 remains uncertain. For example, while one study reported lower plasma Aβ40 and Aβ42 concentrations and lower incidence and prevalence of dementia in mosaic DS individuals compared to non-mosaic DS individuals (Xicota et al., 2024), another found mosaic DS individuals were more susceptible to neurodegenerative conditions, including AD (Rubenstein et al., 2024).
NeuropathologyBiological EffectsClinical TrialsResearch Models
NeuropathologyAD neuropathology in DS surfaces at a young age. Amyloid plaques can start depositing in carriers as early as during the teen years and 20s (e.G., Lemere et al., 1996; Mori et al., 2002), and are seen routinely after age 30. After age 40, when virtually all DS individuals have AD neuropathology, amyloid accumulation ramps up at an exponential rate (Lott and Head, 2019).
The spread of amyloid and tau pathologies in DSAD generally follows the pattern observed in sporadic AD, as do levels of biomarkers in cerebrospinal fluid and blood (e.G., Fortea et al., 2020; Janelidze et al., 2022; July 2022 news; Schworer et al., 2024a; Petersen et al., 2024). Also, the structure of tau fibrils—both paired helical and straight filaments—as well as Aβ42 filaments, appear to be very similar in the two conditions (Fernandez et al., 2024; Ghosh et al., 2024), although two Aβ40 filaments have been identified in DSAD that appear to be distinct from those found in sporadic AD (Fernandez et al., 2024). Moreover, similar amyloid plaque proteomes were identified in DS, early onset AD, and late onset AD, as described in a preprint (Martá-Ariza et al., 2024).
However, as reported in a paper that details the progression of AD pathology and symptoms in 167 DS adults, the time from Aβ positivity and tau deposition to initial cognitive decline and dementia is reduced in DSAD (Schworer et al., 2024b). Consistent with this shortened timeline, amyloid has been reported to accumulate particularly rapidly in DS, with tau neurofibrillary tangles emerging very soon after (Zammit et al., 2024). In addition, compared with autosomal dominant AD, tau pathology in DSAD appears to be moderately more widespread, more abundant for a given level of amyloid, and more strongly associated with amyloid accumulation (Wisch et al., 2024). Also, reductions in the thickness of the temporal and parietal cortices, which tracked well with disease stages, were more extensive and severe than those observed in autosomal dominant AD (Kennedy et al., 2025). Comparing levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrogliosis, to markers of amyloid and tau pathologies, one study suggested amyloid may stimulate astrogliosis, which in turn may play a role in fueling tau pathology in the compressed DSAD timecourse (Boerwinkle et al., 2024).
Of note, specific brain regions appear to be affected differentially. For example, in DS, PET imaging suggests the striatum is burdened with amyloid very early on and neurofibrillary tangles are particularly dense in DS brains compared with non-DS brains (Lao et al., 2016, Annus et al., 2016, Lachlan et al., 2024). Also, Aβ and tau pathologies in the locus coeruleus, a brain region affected very early in sporadic AD, differed from those observed in early onset AD (EOAD), and especially late-onset AD (LOAD) (Saternos et al., 2024). Oligomeric tau and Aβ levels in this brain region were particularly elevated in DS AD, with phospho-tau231 and neuronal tau staining being more similar in DSAD and EOAD than LOAD. Moreover, alongside the development of AD pathology, the cholinergic system of DS individuals appears to decline more quickly with age than in non-DS individuals (Russell et al., 2025).
Interestingly, the extent of cerebrovascular disease (CVD) in DSAD appears to correlate with the severity of amyloid and tau pathologies, suggesting it is a core feature of DSAD tied to AD progression (Aug 2023 conference news). This characteristic seems to be independent of conventional age-related vascular risk factors, such as hypertension and heart disease, which are less prevalent in DS individuals. A brain imaging study identified enlarged perivascular spaces and infarcts in the early 30s, before global amyloid and tau pathologies reached an inflection point at age 35 (Lao et al., 2024). Microbleeds and white matter hyperintensities surfaced in the 30s and 40s. A detailed study of microbleeds further showed that microbleeds in DS increase with age and AD clinical stage, are more common in APOE4 carriers, and are predominantly found in posterior, lobar brain regions (Zsadanyi et al., 2024). White matter hyperintensities also increased with age, surfacing 10 years before AD symptom onset with progression closely linked to AD pathology, particularly in periventricular regions, and frontal, parietal, and occipital lobes (Morcillo-Nieto et al., 2024). Also of note, in DS patients who had yet to develop AD, white matter hyperintensities were associated with plasma markers of astrocytosis (GFAP), tau pathology (phospho-tau 217), and neurodegeneration (neurofilament light chain) (Edwards et al., 2024; Rosas et al., 2024). Female gender, lower body mass index, hypertension, and carrying the APOE4 allele were associated with higher levels of cerebrovascular biomarkers for a given age (Lao et al., 2024).
Individuals with DS appear to have a higher frequency and severity of cerebral amyloid angiopathy (CAA) and have a unique neuroinflammatory phenotype possibly due to serum proteins infiltrating the brain via microbleeds. Indeed, microbleeds correlate with CAA in postmortem cortical tissue from individuals with DS beginning in the mid-30s, mirroring the rise in amyloid plaques (Helman et al., 2019). Also of note, cortical microinfarcts, mostly clustered in the parietal lobes, were found in 12 percent of DS patients and may be tied to a specific ischemic CAA phenotype (Aranha et al., 2024). Despite these pathologies, compared with CAA in carriers of other APP duplications limited to APP with or without a few neighboring genes, CAA in DS appears to be less severe and individuals with DS have a lower frequency of cerebral hematoma (Mann et al., 2018). This may be due to carriers of APP duplications having higher brain levels of total Aβ and shorter Aβ peptides than individuals with DS (Aug 2023 conference news).
DSAD can present with other neurodegenerative pathologies as well. A post-mortem study of 33 DSAD cases, for example, detected Lewy body pathology in the amygdala of 55 percent of individuals between the ages of 41 and 59, and in 75 percent of individuals aged 61 to 72 (Wegiel et al., 2022). In some cases, the distribution of Lewy pathology is atypical (Ichimata et al., 2022). Moreover, TDP-43 pathology has been reported in 6 to 18 percent of DS patients (e.G., Lippa et al., 2009; Davidson et al., 2011; Ichimata et al., 2022; Wegiel et al., 2022) and hippocampal sclerosis in 6 percent (e.G., Davidson et al., 2011). In one DSAD case, posterior cortical atrophy presented at an early age (Rodríguez-Baz et al., 2024).
AD and associated neuropathologies have also been reported in individuals with trisomy 21 mosaicism. A man with 10 percent mosaicism in his peripheral lymphocytes, died at age 64 with severe AD neuropathology after being diagnosed with early onset dementia starting at age 55 (Ngo et al., 2024). Pathology included widespread astrogliosis, CAA, perivascular space widening, and Lewy bodies in the amygdala. The extent of mosaicism in the brain was not reported.
An international consortium of brain banks—the Down Syndrome Biobank Consortium—has been established to collect and distribute brain tissue from individuals with DS throughout their lifespan (Aldecoa et al., 2024). It includes 11 sites in Europe, India, and the US.
Biological EffectAPP overexpression and the accumulation of Aβ in the brain is considered the primary driver of dementia in individuals with trisomy 21 (for reviews see Wiseman et al., 2015; Lott and Head, 2019). Consistent with this, at least two individuals with partial trisomy 21, carrying three copies of some parts of chromosome 21 but only two copies of APP, have lived past the age of 70 without developing either dementia or AD pathology (Prasher et al., 1998, Doran et al., 2017). Conversely, families with small chromosome 21 duplications consisting of only a few genes including APP have been reported to suffer from early onset AD. Indeed, there are AD families in which APP is the only gene present within the disease-associated duplication or triplication (APP Duplication 1104 [APP-APP]; see also APP Triplication [APP-APP]). Data from mouse models of DS also support accumulation of Aβ as playing a critical role in DSAD (e.G., Chen et al., 2024; Staurenghi et al., 2024).
Consistent with the clinical and genetic findings described above, increasing evidence at the cellular and molecular levels indicate DSAD is mechanistically very similar to AD in the general population. For example, a study that merged spatial transcriptomics and single-nucleus RNA-seq analyses of cortical samples from patients with sporadic AD and DSAD reported broad similarities between the two conditions (Miyoshi et al., 2024; Dec 2024 news), and a transcriptomic analysis of microisolated DSAD cortical neurons revealed alterations predicted to be relevant to sporadic AD (Alldred et al., 2024). Also, a pathway involving the binding of APP β-CTF to a lysosomal proton pump appears to lead to lysosomal dysfunction in both AD and DSAD (Jul 2023 news, Im et al., 2023).
DSAD may have unique aspects, however, stemming from the overexpression of non-APP genes on chromosome 21, numbering over 200 (see Lott and Head, 2019 for review). For example, increased expression of DYRK1A—which encodes a kinase that phosphorylates many proteins including tau, and splicing factors that modulate tau mRNA splicing resulting in imbalanced 3R-tau and 4R-tau expression—appears to accelerate the emergence of neurofibrillary tangles, along with increased RCAN1, which regulates calcineurin. DYRK1A also phosphorylates APP and its elevation has been reported to increase APP levels as well (e.G., Ferrer et al., 2005, Ryoo et al., 2008, Garcia-Cerro et al., 2017). Additional DSAD-specific changes have been identified by proteomic and transcriptomic analyses of DSAD brains, including upregulation of ApoE compared with euploid individuals with EOAD or LOAD, as reported in a preprint (Farrell et al., 2025). APOE expression was elevated in a subset of astrocytes, endothelial cells, and pericytes.
Some genes on chromosome 21 may delay AD pathology. Age at onset for DSAD varies widely, with many individuals suffering from cognitive decline only after age 55, later than the mean age of onset (~52 years) for APP duplication carriers (Wiseman et al., 2015). One study identified a subregion of chromosome 21 that decreases Aβ accumulation in mouse brain (Mumford et al., 2022). This region included BACE2, previously reported as protective against AD pathology (Feb 2020 news, Alić et al., 2021) and, paradoxically, DYRK1A.
In addition to genetic modifiers of Aβ and tau pathologies, other factors likely modulate the expression of AD in DS individuals. For example, trisomy 21-associated alterations in brain structure, elevated incidence of epilepsy, and disruptions of the immune system that arise during development might increase susceptibility to AD (Lott and Head, 2019). Studies of how gene expression is altered in DS brains may reveal additional DS vulnerabilities, such as observed disruptions in RNA splicing that affect cytoskeletal proteins and axonal polarization (Rastogi et al., 2024).
Interestingly, some individuals with DS remain cognitively stable despite developing AD neuropathology (Liou et al., 2025). These cases could provide insights into AD resilience both in DS and in the general population. Indeed, as described in a preprint, a trisomy 21-linked genetic variant in the microglial-expressed CSF2RB gene was identified as potentially neuroprotective (e.G., Jin et al., 2024).
Therapeutics
Several efforts to better understand and therapeutically tackle AD in DS individuals are underway. Biomarkers and cognitive evaluations for early AD detection, monitoring of progression, and assessment of therapeutic outcomes are being investigated (e.G., Petersen et al., 2024; García-Alba et al., 2025: Krinsky-McHale et al., 2025).
Moreover, the use of anti-amyloid antibodies in DSAD is being explored. Prescribing criteria are being adapted for these patients (Hillerstrom et al., 2024) and guidelines for amyloid-targeting trials are being developed (Geerts et al., 2024; Krasny et al., 2024). Importantly, these include strategies to mitigate the risk of amyloid-related imaging abnormalities (ARIA) associated with these treatments, a risk which is elevated in individuals with CAA (Aug 2023 conference news) and microbleeds (Zsadanyi et al., 2024), pathologies often found in DS AD. Indeed, a study of postmortem brain tissue from 15 DS patients revealed that the anti-amyloid antibody lecanemab labeled amyloid plaques, indicating potential target engagement, but it also labeled brain blood vessels extensively, indicating a potential safety hazard (Liu et al., 2024).
Pre-clinical evaluations of other therapeutic candidates are also ongoing. For example, γ-secretase modulators have been tested in DS mouse models (Chen et al., 2024) and the effects of APP antisense oligonucleotides on astrocytes derived from patient induced pluripotent stem cells (iPSCs) have been examined (Thirumalai et al., 2025).
Moreover, clinical trials for DS are in the works (May 2021a news), including trials for the anti-amyloid vaccine ACI-24.060 (May 2021b news) and subdermal pulses of gonadotropin-releasing hormone (Sep 2022 news).
Research Models
Multiple rodent models of DS have been generated (Herault et al., 2017), with a subset being particularly relevant to AD-DS (Farrell et al., 2022; the following are in the Alzforum Research Models database: Ts65Dn; Dp1Tyb, Dp9Tyb, Dp(16)1Yey/+, TcMAC21). The models have been used for in vivo studies, as well as experiments using cultured cells and organotypic slice cultures. In addition, human iPSCs with trisomy 21 have been used to create cerebral organoids that model the early pathology of AD (Fertan et al., 2024).
This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.
PS1-MSame amino acid change as a previously established pathogenic variant regardless of nucleotide change. Trisomy 21: Includes an extra copy of APP like multiple APP duplications known to be pathogenic.
PS2-SDe novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PS3-SWell-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PS4-SThe prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
PM1-SLocated in a mutational hot spot and/or critical and well-established functional domain (e.G. Active site of an enzyme) without benign variation. Trisomy 21: Mutation encompasses the APP gene, a mutational hotspot and a gene known to play a well-established functional role in AD.
Pathogenic (PS, PM, PP) Benign (BA, BS, BP) Criteria Weighting Strong (-S) Moderate (-M) Supporting (-P) Supporting (-P) Strong (-S) Strongest (BA)Assessing Gene Therapy Approaches For Down Syndrome
Decades ago, researchers showed that Down syndrome (also known as trisomy 21), was caused when individuals carried an extra copy of chromosome 21. Down syndrome is also the most common genetic cause of cognitive dysfunction. But little research has explored how gene editing tools could potentially be used to treat this condition. A new study reported in PNAS Nexus sought to do that, even though the applications of gene therapy in humans are still quite limited.
In this proof-of-principle study, the researchers aimed to cut or cleave the extra copy of chromosome 21 with CRISPR-Cas9 gene editing tools. They did so in cell lines such as skin fibroblasts and pluripotent stem cells.
One challenge with this approach is that the researchers could not simply eliminate one of the copies of chromosome 21; they had to take one away such that one from each parent remained in the cells.
The study showed that this was possible, and that duplicated chromosomes could be removed from both types of cells. This method was more efficient and more of the duplicated chromosomes were removed when the researchers also suppressed a cellular pathway that repairs chromosomal DNA damage.
Gene expression was shown to be normal after the removal of the duplicate chromosome, and the cells appeared to function normally as well.
This is still a long way from clinical application, and CRISPR-Cas9 is still not used in human patients in many situations. It is still illegal and considered unethical to apply this technology to human embryos that will continue through advanced stages of development. There are also still challenges to overcome as well, since this method can affect other chromosomes that are left in the cell. It is not that unusual for CRISPR-Cas9 to lead to unintended or off-target effects.
Although there is a wide range in how Down syndrome may present in different patients, it can sometimes be a devastating disease. There are no treatments for the condition. This work has shown that it may one day be possible to treat it by using gene editing in certain cell types such as neurons, or prevent Down syndrome from happening by applying a gene therapy technique at the right time during development.
Source: PNAS Nexus
Gene Editing Shows Promise For Treating Trisomy At Cellular Level
Gene editing techniques may eventually allow trisomy to be treated at the cellular level, according to an in vitro proof-of-concept study. Down syndrome is caused by the presence of a third copy of the 21st chromosome. The condition occurs in approximately 1 in 700 live births and is relatively easy to diagnose at early stages of development.
However, there are no treatments. Ryotaro Hashizume and colleagues use the CRISPR-Cas9 gene editing system to cleave the third chromosome in previously generated trisomy 21 cell lines derived from both pluripotent cells and skin fibroblasts. The technique is able to identify which chromosome has been duplicated, which is necessary to ensure the cell does not end up with two identical copies after removal, but instead has one from each parent. The authors were able to remove duplicate chromosomes from both induced pluripotent stem cells and fibroblasts. Suppressing chromosomal DNA repair ability increased the rate of duplicate chromosome elimination.
The authors show that the chromosomal rescue reversibly restores both gene expression and cellular phenotypes. The approach is not yet ready for in vivo application, however, in part because the current technique can also change the retained chromosomes. According to the authors, similar approaches could eventually be used in neurons and glial cells and form the basis of novel medical interventions for people with Down syndrome.
Source:
Journal reference:
Hashizume, R., et al. (2025) Trisomic rescue via allele-specific multiple chromosome cleavage using CRISPR-Cas9 in trisomy 21 cells. PNAS Nexus. Doi.Org/10.1093/pnasnexus/pgaf022.
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