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000283150 0247_ $$2doi$$a10.1002/alz70856_106390
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000283150 0247_ $$2ISSN$$a1552-5279
000283150 037__ $$aDZNE-2026-00046
000283150 041__ $$aEnglish
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000283150 1001_ $$aRodríguez-Baz, Íñigo$$b0
000283150 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283150 245__ $$aAlpha-Synuclein Pathology in Down Syndrome-Associated Alzheimer's Disease: Insights from Seed Amplification Assay and Neuropathology
000283150 260__ $$c2025
000283150 3367_ $$0PUB:(DE-HGF)1$$2PUB:(DE-HGF)$$aAbstract$$babstract$$mabstract$$s1767880869_14468
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000283150 520__ $$aDown syndrome (DS) is a genetic cause of Alzheimer's disease (AD), with virtually all individuals developing AD pathology by their fourth decade due to Amyloid Precursor Protein (APP) gene overexpression. In addition to amyloid beta (Aβ) plaques and hyperphosphorylated tau (p-Tau) aggregates, DS-associated AD (DSAD) often includes α-synuclein (αSyn) aggregates, contributing to Lewy body pathology (LBP). The αSyn Seed Amplification Assay (SAA) in cerebrospinal fluid (CSF) enables the in vivo detection of misfolded αSyn. While αSyn-SAA has revealed αSyn pathology in autosomal dominant (6%-11%) and sporadic (21%-45%) AD, its role in DSAD remains unexplored. This study investigates αSyn-SAA positivity in DSAD, linking in vivo findings to fluid biomarkers and neuropathology.We analyzed CSF of 270 adults with DS from the DABNI and AD21 cohorts by αSyn-SAA, encompassing asymptomatic and symptomatic AD stages (prodromal/dementia). Additional biomarkers included CSF Aβ1-42/1-40, CSF and plasma p-Tau181 and neurofilament light chain (NfL) levels. Neuropathological evaluations in 19 brain donors, including 5 with antemortem CSF, assessed AD neuropathology and LBP.As shown in Table 1, αSyn-SAA positivity was observed in 9.2% of participants, consistent across age groups (Figure 1) and cognitive stages. Symptomatic αSyn-SAA-positive individuals exhibited significantly higher plasma NfL levels compared to αSyn-SAA-negative individuals (31.0 vs. 21.1 pg/mL, p = 0.027). Neuropathological analysis revealed LBP in 47% of cases, with the amygdala and olfactory bulb being the most frequently affected regions (Table 2). Among the five donors with antemortem CSF, the only αSyn-SAA-positive case corresponded to an individual with severe neocortical LBP.This study examines the relationship between LBP and DSAD, identifying a prevalence of αSyn-SAA positivity comparable to autosomal dominant AD but lower than sporadic AD. A potential association was noted between severe neocortical LBP and αSyn seeding activity, while age and cognitive status did not significantly influence positivity rates. Misfolded αSyn was detectable from early ages in individuals with DS. Further research is required to elucidate the mechanisms underlying LBP in DSAD, assess its clinical impact on cognitive and motor symptoms, and explore relationships with other biomarkers.
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000283150 650_7 $$2NLM Chemicals$$aBiomarkers
000283150 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000283150 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000283150 650_7 $$2NLM Chemicals$$atau Proteins
000283150 650_7 $$2NLM Chemicals$$aNeurofilament Proteins
000283150 650_7 $$2NLM Chemicals$$aPeptide Fragments
000283150 650_2 $$2MeSH$$aHumans
000283150 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aMale
000283150 650_2 $$2MeSH$$aFemale
000283150 650_2 $$2MeSH$$aAlzheimer Disease: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000283150 650_2 $$2MeSH$$aalpha-Synuclein: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aAmyloid beta-Peptides: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aDown Syndrome: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aDown Syndrome: pathology
000283150 650_2 $$2MeSH$$aMiddle Aged
000283150 650_2 $$2MeSH$$atau Proteins: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aAged
000283150 650_2 $$2MeSH$$aAdult
000283150 650_2 $$2MeSH$$aNeurofilament Proteins: cerebrospinal fluid
000283150 650_2 $$2MeSH$$aCohort Studies
000283150 650_2 $$2MeSH$$aPeptide Fragments: cerebrospinal fluid
000283150 7001_ $$0P:(DE-2719)9002620$$aBernhardt, Alexander M$$b1$$udzne
000283150 7001_ $$aAldecoa, Iban$$b2
000283150 7001_ $$aArranz, Javier$$b3
000283150 7001_ $$aArriola-Infante, José Enrique$$b4
000283150 7001_ $$aMaure-Blesa, Lucía$$b5
000283150 7001_ $$aCarmona-Iragui, Maria$$b6
000283150 7001_ $$aLongen, Sebastian$$b7
000283150 7001_ $$aTrossbach, Svenja Verena$$b8
000283150 7001_ $$aGiese, Armin$$b9
000283150 7001_ $$aMatthias, Torsten$$b10
000283150 7001_ $$aBenejam, Bessy$$b11
000283150 7001_ $$aVidela, Laura$$b12
000283150 7001_ $$aHoyo, Laura Del$$b13
000283150 7001_ $$aBarroeta, Isabel$$b14
000283150 7001_ $$aHernandez, Aida Sanjuan$$b15
000283150 7001_ $$aFernandez, Susana$$b16
000283150 7001_ $$aVaqué-Alcázar, Lídia$$b17
000283150 7001_ $$aAranha, Mateus Rozalem$$b18
000283150 7001_ $$aMorcillo-Nieto, Alejandra O$$b19
000283150 7001_ $$0P:(DE-2719)9001761$$aNübling, Georg$$b20$$udzne
000283150 7001_ $$0P:(DE-2719)9001249$$aWagemann, Olivia$$b21$$udzne
000283150 7001_ $$0P:(DE-2719)9002610$$aStockbauer, Anna$$b22$$udzne
000283150 7001_ $$aTondo, Mireia$$b23
000283150 7001_ $$aBejanin, Alexandre$$b24
000283150 7001_ $$aLleó, Alberto$$b25
000283150 7001_ $$aAlcolea, Daniel$$b26
000283150 7001_ $$aMolina, Laura$$b27
000283150 7001_ $$aFortea, Juan$$b28
000283150 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b29$$eLast author$$udzne
000283150 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70856_106390$$gVol. 21 Suppl 2, no. S2, p. e106390$$nS2$$pe106390$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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