Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40 to 100 years and conversion from mild cognitive impairment to AD dementia taking 2 to 20 years. Development of biomarkers for amyloid-beta (AB) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20 to 40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of AB; and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:AB42, 10% beyond tau PET, and 50% beyond CSF NfL in AB positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant AD mutation carriers. Most notably, YWHAG:NPTX2 positive individuals (top 25th percentile) are 15 times (HR=15.4 [10.6 to 22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2 negative individuals (bottom 25th percentile), and this rises to 19 times (HR=18.9 [10.83 to 32.9]) with additional stratification by AB and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of AB, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease