CSF proteogenomics implicates novel proteins and humoral immunity in Alzheimer’s disease risk

Identifying causal genes at Alzheimer’s Disease (AD) GWAS loci requires tissue-relevant functional genomic data. Cerebrospinal fluid (CSF) interfaces directly with the brain and can be obtained from living individuals, providing a potential proxy for brain protein biology at scale; however, large-scale CSF proteogenomic studies have been limited to affinity-based platforms. Here, we used mass spectrometry to profile CSF proteins in 1,005 participants measuring 2,961 proteins, including 1,066 proteins not captured by other platforms. We mapped protein quantitative trait loci (pQTLs) in CSF, compared them with brain and plasma pQTLs, and integrated them with AD GWAS results. We identified 1,417 cis and 130 trans pQTLs, and uncover 24 candidate causal proteins – 10 novel, including 5 detected only by mass spectrometry. These proteins implicate lysosomal function, neurovascular remodeling, and immune response. Notably, three immunoglobulins (IGHG2, IGHV2-70, IGHV3-72) link humoral immunity to AD risk for the first time.