INTRODUCTION: Multi-etiology dementia necessitates in vivo markers of copathologies including misfolded METHODS: Cerebrospinal fluid (CSF) was obtained from 420 participants in two AD risk cohorts (35% male
91% cognitively unimpaired
mean [standard deviation] age, 65.42 [7.78] years
education, 16.17 [2.23]) years). synSAA results were compared to phosphorylated tau (T), amyloid beta (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects. RESULTS: Syn positivity (synSAA+) co-occurred with T (in synSAA+ vs. synSAA-, 36% vs. 20% T+
Pp = 0.011) and with cognitive impairment (10% vs. 7% mild cognitive impairment
10% vs. 0% dementia
p = 0.00050). synSAA+ participants' cognitive performance declined ≈ 40% faster than synSAA- for Digit Symbol Substitution, but not other tests. DISCUSSION: Findings support prevalent syn copathology in a mostly unimpaired AD risk cohort. Relationships with progression should be evaluated once more have declined. HIGHLIGHTS: In a middle-aged sample, misfolded