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 alpha-synuclein aggregates. This study investigated the prevalence of cerebrospinal fluid (CSF) alpha-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 alpha-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 alpha-synuclein aggregation status in the AD dementia group (37.07 %) and the MCI group (22.75 %) compared to CN controls (16.13 %). Additionally, APOE epsilon 4 carriers exhibited a higher prevalence of alpha-synuclein aggregation compared to non-carriers: 20.12 % for APOE epsilon 4-/- (non-carriers), 24.82 % for APOE epsilon 4 + /-, and 30.92 % for APOE epsilon 4 + /+ . Longitudinally, positive CSF alpha-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 epsilon 4 carriers with positive CSF alpha-synuclein aggregation experienced more pronounced cognitive decline. This study provides evidence that CSF alpha-synuclein aggregation is associated with cognitive function and the APOE epsilon 4 allele. These findings suggest that CSF alpha-synuclein SAA, in combination with APOE epsilon 4 status, could serve as biomarkers for predicting cognitive decline in AD.