Characterizing the emergence of amyloid and tau burden in Down syndrome

Zammit, Matthew D.; Betthauser, Tobey J.; McVea, Andrew K.; Laymon, Charles M.; Tudorascu, Dana L.; Johnson, Sterling C.; Hartley, Sigan L.; Converse, Alexander K.; Minhas, Davneet S.; Zaman, Shahid H.; Ances, Beau M.; Stone, Charles K.; Mathis, Chester A.; Cohen, Annie D.; Klunk, William E.; Handen, Benjamin L.; Christian, Bradley T.; ,

doi:10.1002/alz.13444

Cited by 13 publications

(5 citation statements)

References 75 publications

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“…Amyloid deposition increased in the parenchyma (amyloid PET) and in the vasculature (microbleeds) at ages 35 and 36 years, respectively. Increased tau deposition in early Braak regions was also observed at 35 years, which is consistent with previous studies showing tau deposition in adults with Down syndrome who were amyloid-negative but accumulating amyloid over time 35 , suggesting that the emergence of amyloid and tau pathology are tightly linked together in time 36 , 37 . Tau deposition in middle and late Braak regions were later at 39 and 37 years, respectively.…”

Section: Discussionsupporting

confidence: 91%

“…To investigate this somewhat unexpected finding, we ran a sensitivity analysis excluding one individual with a very low late Braak SUVR (< 0.5) at an older age, which may have biased the age trajectory after the inflection point lower and pushed the inflection point earlier; however, the estimated age inflection point in late Braak regions was very similar (37.5 [29.1, 45.9]). Longitudinal within-subject data in adults with Down syndrome demonstrated that middle Braak regions accumulate tau prior to late Braak regions according to the amyloid cascade 36 White matter hyperintensities emerged at 35 years old across the brain. The temporal ordering observed is consistent with previous work in late onset AD that demonstrated that greater WMH are associated with tau burden in middle and late Braak regions, but not early Braak regions 38 .…”

Section: Discussionmentioning

confidence: 99%

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Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Lao,

Edwards,

Flores-Aguilar

et al. 2024

Sci Rep

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Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer’s Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25–72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Lao,

Edwards,

Flores-Aguilar

et al. 2024

Sci Rep

Self Cite

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“…Indeed, the first clinical trial (NCT05462106) testing an Aβ vaccine in DS participants is underway [64], and there may be future trials testing Aβ immunotherapies already showing promising results in sporadic AD subjects. However, compared to sporadic AD, the formation of tau tangles is much more rapid following the deposition of Aβ plaques in DS [65,66], and thus effective therapeutics targeting pathological tau in DS will be required due to the condensed trajectory of AD pathogenesis. Given the intracellular localization of tau NFTs, immunotherapy approaches are unlikely to succeed, thus emphasizing the need to develop small molecule therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer’s Disease Fold

Ghosh,

Tse,

Yang

et al. 2024

Preprint

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Down Syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among the complex clinical features including musculoskeletal, neurological and cardiovascular disabilities, individuals with DS develop progressive dementia and early onset Alzheimer’s Disease (AD). This is attributed to the increased gene dosage of amyloid precursor protein (APP), the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here we characterized 4 DS cases spanning 36 to 63 years in age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures reveal paired helical (PHF) and straight filament (SF) conformations of tau that are identical to those determined from AD. The PHFs and SFs are made of two C-shaped protofilaments with a cross-β/β-helix motif. Similar to AD, most filaments adopt the PHF form, while a minority (∼20%) form SFs. For the youngest individual with no documented dementia samples exhibited sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we employed a novel “affinity grid” method involving a graphene-oxide surface derivatized with anti-tau antibodies. This improved isolation and revealed primarily tau PHFs and a minor population of SSPE type II-like filaments are present at this early age. These findings expand the similarities between AD and DS to the molecular level providing insight into their related pathologies and the potential for targeting common tau filament folds by small molecule therapeutics and diagnostics.

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“…Indeed, the first clinical trial (NCT05462106) testing an Aβ vaccine in participants with DS is underway [ 67 ], and there may be future trials testing Aβ immunotherapies that are already showing promising results in individuals with sAD. However, the formation of tau tangles after the deposition of Aβ plaques is much more rapid in DS than in sAD [ 68 , 69 ]; thus, effective therapeutics targeting pathological tau in DS will be required due to the condensed trajectory of AD pathogenesis. Given the intracellular localization of tau NFTs, immunotherapy approaches are unlikely to succeed, emphasizing the need to develop small-molecule therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold

Ghosh,

Tse,

Yang

et al. 2024

acta neuropathol commun

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Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer’s disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36–63 years of age by spectral confocal imaging with conformation-specific dyes and cryo–electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II–like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

show abstract

Characterizing the emergence of amyloid and tau burden in Down syndrome

Cited by 13 publications

References 75 publications

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Cerebrovascular disease emerges with age and Alzheimer’s disease in adults with Down syndrome

Cryo-EM Structures Reveal Tau Filaments from Down Syndrome Adopt Alzheimer’s Disease Fold

Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold

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