Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Misfolded α-synuclein co-occurrence with Alzheimer's disease proteinopathy.
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Jonaitis Erin M, MacLeod Karen, Lamoureux Jennifer, Jeffers Beckie, Studer Rachel L, Middleton John, Wilson Rachael E, Chin Nathaniel A, Okonkwo Ozioma C, Bendlin Barbara B, Asthana Sanjay, Carlsson Cynthia M, Gallagher Catherine L, Hermann Bruce, McEvoy Sean, Kollmorgen Gwendlyn, Zetterberg Henrik, Concha-Marambio Luis, Johnson Sterling C, Lebovitz Russ M, Langhough Rebecca E
Аннотация
INTRODUCTION: Multi-etiology dementia necessitates in vivo markers of copathologies including misfolded α ${{\alpha}}$ -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 α ${{\alpha}}$ -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.
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 α ${{\alpha}}$ -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.