Biomarkers.

Background: The buildup of brain amyloid-beta and tau protein aggregates do not sufficiently explain the heterogeneity in cognitive impairment in Alzheimer's disease (AD).

Method: To elucidate drivers of cognitive impairment, we measure the levels of 7,000 proteins, in addition to amyloid-beta-42 (Ab42) and phospho-tau-181 (PTau181), from the cerebrospinal fluid of 2,000 individuals from healthy to severe dementia.

Result: We identify synapse proteins as the strongest correlates of cognitive impairment. We use machine learning methods to derive a cognitive impairment signature, provided as the ratio between YWHAG and NPTX2, which increases with impairment severity (r=0.57) and explains resilience versus susceptibility to AD pathology. We find YWHAG:NPTX2 also increases with age in healthy individuals before PTau181:AB42 and increases 25 years before symptom onset (as early as PTau181:AB42) in autosomal dominant AD.

Conclusion: Our work reveals that synapse alterations precede and coincide with AD pathology accumulation and are the arbiters of cognitive decline. Additionally, we propose the CSF YWHAG:NPTX2 ratio as a biomarker for monitoring synapse health and predicting future cognitive decline in living people.