Alpha-synuclein co-pathology in Down syndrome-associated Alzheimer's disease.
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Bernhardt Alexander Maximilian, Rodríguez-Baz Íñigo, Aldecoa Iban, Arranz Javier, Arriola-Infante José Enrique, Maure-Blesa Lucia, Carmona-Iragui Maria, Longen Sebastian, Trossbach Svenja Verena, Giese Armin, Matthias Torsten, Benejam Bessy, Videla Laura, Del Hoyo Soriano Laura, Barroeta Isabel, Sanjuan Aída, Fernández Susana, Vaqué-Alcázar Lídia, Rozalem Aranha Mateus, Morcillo-Nieto Alejandra O, Nübling Georg, Wagemann Olivia, Stockbauer Anna, Tondo Mireia, Bejanin Alexandre, Lleó Alberto, Alcolea Daniel, Molina-Porcel Laura, Fortea Juan, Levin Johannes
Аннотация
METHODS: We analyzed αSyn-SAA in cerebrospinal fluid (CSF) from 270 adults with Down syndrome, from the Down Alzheimer Barcelona Neuroimaging Initiative and from the AD21 cohort from the Department of Neurology at the University Hospital, Ludwig Maximilian University of Munich, Germany. Neuropathological examinations were conducted in 19 brain donors (five with ante mortem CSF). Participants were classified as asymptomatic or symptomatic (prodromal/dementia) Alzheimer's disease (AD). CSF Aβ1-42/1-40, CSF and plasma p-Tau181, and neurofilament light chain (NfL) levels were measured. Neuropathological evaluations assessed AD neuropathological changes and Lewy body pathology (LBP).
RESULTS: ΑSyn-SAA was positive in 9.2% of cases, independent of age or cognitive status. Symptomatic αSyn-positive cases exhibited higher plasma NfL levels than αSyn-negative cases (31 vs 21 pg/mL, p = 0.027). LBP was observed in 47% of necropsies. The individual with severe neocortical LBP was αSyn-SAA-positive.
DISCUSSION: These findings highlight LBP prevalence in DSAD but suggest current SAA may fail to detect limited αSyn deposition.
HIGHLIGHTS: αSyn-SAA positivity in DSAD is 9.2%, similar to ADAD but lower than sporadic AD. Misfolded αSyn was detectable from early ages in individuals with DS. Positivity rates did not vary with age or clinical status in DS. Plasma NfL levels are higher in symptomatic αSyn-SAA positive versus negative cases. CSF αSyn seeding activity was associated with high neocortical LBP at necropsy.