Misfolded α-synuclein co-occurrence with Alzheimer's disease proteinopathy

Abstract

Introduction: Multi-etiology dementia necessitates in vivo markers of copathologies including misfolded $\alpha$ -synuclein (syn). We measured misfolded syn aggregates (syn-seeds) via qualitative seed amplification assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD).

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 $\alpha$ -synuclein (syn) co-occurred with phosphorylated tau181 (T). syn+/T+ status was linked with higher levels of other cerebrospinal fluid biomarkers. syn+ individuals were more likely than syn- to be cognitively impaired. syn+ status was linked to faster decline on an executive function task.

Keywords: α ${{\alpha}}$ ‐synuclein; Alzheimer's disease; Lewy body dementia; amyloid; cerebrospinal fluid; seed amplification assay; tau.

FIGURE 1

Violin plots of robust prototype biomarkers from the NTK in groups defined by synSAA status and T status. One NfL observation whose value was > 35 times the median value was removed to aid in visualization. GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; Ng, neurogranin; NTK, NeuroToolKit; sTREM2, soluble triggering receptor expressed on myeloid cells 2; synSAA, α‐synuclein seed amplification assay status; T, phosphorylated tau 181 status; YKL‐40, chitinase‐3‐like protein 1.

FIGURE 2

Results of nested linear mixed‐effects models of cognitive tests associated with executive function (Trail‐Making Test Part B; Trail‐Making Test Parts B–A difference score; Digit Span Backward; Digit Symbol Substitution Test) and a global Preclinical Alzheimer Cognitive Composite (PACC‐3). Model‐predicted values and confidence bands derived from final models represented in Table 2. Predictors not shown directly in the graph have been set to their average value. The largest model examined the effect of binary synSAA, synSAA $\times$ age (centered at 60), and synSAA $\times$ $\mathrm{ag}{\mathrm{e}}^2$, controlling for sex, education, and prior exposure to the battery, alongside binary $\mathrm{A}\beta 42/40$ and $\mathrm{p}-\mathrm{ta}{\mathrm{u}}_{181}$ and their interactions with age and $\mathrm{ag}{\mathrm{e}}^2$. From this largest model, non‐significant interaction terms (p > 0.1) were removed. The spaghetti plot layer beneath represents individual participants’ measurements over time. Aβ, amyloid beta; p‐tau, phosphorylated tau; synSAA, $\alpha$‐synuclein seed amplification assay status.