CSF α-synuclein aggregation is associated with APOE ε4 and progressive cognitive decline in Alzheimer's disease

At autopsy, around half of the Alzheimer's disease (AD) brains exhibit Lewy body pathology, and the main component of Lewy body pathology is α-synuclein aggregates. This study investigated the prevalence of cerebrospinal fluid (CSF) α-synuclein aggregation and its association with demographic factors and cognitive decline among 1619 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), with the test for α-synuclein aggregation by seed amplification assay (SAA). This cohort consisted of 595 cognitively normal (CN) individuals, 765 with mild cognitive impairment (MCI), and 259 with AD dementia. The results showed a higher prevalence of positive α-synuclein aggregation status in the AD dementia group (37.07 %) and the MCI group (22.75 %) compared to CN controls (16.13 %). Additionally, APOE ε4 carriers exhibited a higher prevalence of α-synuclein aggregation compared to non-carriers: 20.12 % for APOE ε4-/- (non-carriers), 24.82 % for APOE ε4 + /-, and 30.92 % for APOE ε4 + /+ . Longitudinally, positive CSF α-synuclein aggregation associated with accelerated cognitive decline, especially in the MCI and AD groups. Notably, positive aggregation status did not significantly affect cognitive trajectories in CN individuals. Moreover, APOE ε4 carriers with positive CSF α-synuclein aggregation experienced more pronounced cognitive decline. This study provides evidence that CSF α-synuclein aggregation is associated with cognitive function and the APOE ε4 allele. These findings suggest that CSF α-synuclein SAA, in combination with APOE ε4 status, could serve as biomarkers for predicting cognitive decline in AD.