Alzheimer’s disease genetic risk variants show brain cell type‐specific associations with protein levels in cerebrospinal fluid

Background Neuronal dysfunction is central to the clinical manifestation of Alzheimer’s disease (AD). However, genome‐wide studies also suggest important roles for non‐neuronal brain cell‐types such as microglia and astrocytes. Our objective was to study whether brain cell type‐specific polygenic risk scores (PGRS) for AD, including single nucleotide polymorphisms (SNPs) of genes expressed in one brain cell type, showed relationships with levels of cerebrospinal fluid (CSF) AD markers in individuals across the clinical spectrum of AD. Method We selected 1,535 subjects (552 controls/709 mild cognitive impairment/274 AD‐dementia, age 71±8 years, 48%female) from the ADNI (N=617) and EMIF‐AD MBD (N=918) study, who had genetic data available. We labelled AD risk genes as specific for neurons, astrocytes, microglia, oligodendrocytes or endothelial cells when more than 50% of the gene expression was produced by one cell type (otherwise as ‘non‐specific’) according to the BRAIN RNASeq database (Zhang et al., 2014). We calculated cell type‐specific‐PGRS with cell type‐corresponding SNPs (P