CSF α-synuclein seed amplification assay positivity identifies a distinct soluble amyloid-β profile linked to fibrillar amyloid burden and structural neurodegeneration.

PURPOSE: To determine whether cerebrospinal fluid (CSF) α-synuclein seed amplification assay (SAA) positivity identifies a reproducible soluble amyloid-β (Aβ) configuration and whether its dimensions carry distinct information about downstream pathology and neurodegeneration. METHODS: In ADNI, 72 participants (13 SAA-positive [SAA+]) had same-day BACE1 activity, sAPPβ, and mass-spectrometry Aβ38/Aβ40/Aβ42. T captured common Aβ38/Aβ40 variation and D42 Aβ42 depletion relative to Aβ38/Aβ40. A one-factor measurement-error model tested common-factor compatibility. The pattern was then tested in 560 participant-disjoint individuals (131 SAA+), with T and D42 reconstructed de novo, and related to amyloid PET, clinical change, whole-brain MRI, and tau PET. RESULTS: In the proximal cohort, SAA + was associated with lower T (β=-0.549 SD, 95% CI -1.005 to -0.093), but this effect was compatible with the one-factor model (directional compatibility probability = 0.288). In the participant-disjoint cohort, SAA + was associated with lower T (β=-0.267 SD) and higher D42 (β = 0.206 SD); their direct contrast was - 0.473 SD. Higher D42 was associated with subsequent amyloid burden, faster 0-2.5-year clinical worsening, greater whole-brain loss, and subsequent tau burden; lower T independently predicted faster whole-brain loss. CONCLUSIONS: SAA positivity identifies a reproducible T-low/D42-high soluble-Aβ configuration. The preferential association of D42 with fibrillar amyloid, tau burden, and clinical worsening links the Aβ42-selective component to the AD pathological cascade, while the overall pattern points to altered post-β-cleavage APP/Aβ handling.