Seed amplification assay‐determined alpha‐synuclein associates with Alzheimer’s pathology, clinical symptoms, and cognitive change

Abstract Background The high prevalence of mixed‐pathology dementias suggests that multi‐drug treatments may improve clinical outcomes; thus, in‐vivo biomarkers for co‐pathologies are needed. We investigated a novel assay for detecting seeds of misfolded alpha synuclein (αSyn) and explored its relationship to outcomes including Alzheimer’s disease (AD) biomarkers, clinical features, and cognitive trajectories, in two community‐based cohorts enriched for AD risk. Method Cerebrospinal fluid (CSF) obtained from participants in the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center (N=418 participants; 515 LPs; Table 1) was assayed using a clinically validated, qualitative Syn seed amplification assay (SAA; Amprion). Co‐occurrence of αSyn pathology (αSyn‐SAA+), and AD pathology (CSF amyloid, Aβ 42/40 and pTau 181 /Aβ 42 , and tau, pTau 181 , positivity), and clinical symptoms (neurological finding; Parkinsonian signs; etc) were examined with chi‐square tests. Cognitive trajectories were modeled retrospectively using separate mixed effects models of Trail‐Making Test B, Backward Digit Span, Digit Symbol Substitution, and a three‐test Preclinical Alzheimer’s Cognitive Composite (PACC‐3). Models included subject‐level random intercepts and age slopes and standard covariates (sex, education, and practice with the battery). For each outcome, we examined whether αSyn‐SAA+ modified age trajectories (centered; linear and quadratic terms; models 1A‐4A). In models 1B‐4B, we further examined effects of αSyn‐SAA+ after adjusting for age× and age× interactions. Nonsignificant quadratic interaction terms were removed (p>0.1). Result αSyn‐SAA+ co‐occurred with binary pTau 181 /Aβ 42 (p=0.048) and pTau 181 (p=0.0045), but not Aβ 42/40 (p=0.14). Among pTau 181 /Aβ 42 + participants, 20/119 (17%) were also αSyn SAA+, compared to 27/287 (9%) pTau 181 /Aβ 42 ‐ participants. For pTau 181 + and pTau 181 ‐, the proportions were 18/89 (20%) and 30/322 (9%), respectively. αSyn‐SAA+ participants had greater cognitive impairment (p=0.00050) and additional neurological findings (p=0.026), but did not differ (p>=.17) on Parkinsonian signs, REM behavior disorder, or depression. αSyn‐SAA+ participants declined faster in Digit Symbol performance after accounting for Alzheimer’s pathology (model 3B: = ‐0.20, p=0.045; Table 2; Figure 1). Conclusion Results suggest significant co‐pathology in an AD‐risk enriched cohort. Relationships with cognitive impairment provide evidence for the clinical utility of αSyn SAA in this population. Steeper age‐related decreases in Digit Symbol performance among αSyn SAA+ individuals suggest possible association with preclinical cognitive change.