Genome and epigenome wide studies of plasma protein biomarkers for Alzheimer's disease implicate TBCA and TREM2 in disease risk

The levels of many blood proteins are associated with Alzheimers disease or its pathological hallmarks. Elucidating the molecular factors that control circulating levels of these proteins may help to identify proteins causally associated with the disease. Here, genome-wide and epigenome-wide studies (nindividuals[≤]1,064) were performed on plasma levels of 281 Alzheimers disease-associated proteins, identified by a systematic review of the literature. We quantified the contributions of genetic and epigenetic variation towards inter-individual variability in plasma protein levels. Sixty-one independent genetic and 32 epigenetic loci were associated with expression levels of 49 proteins; eight and 24 of these respective findings are previously unreported. Novel findings included an association between plasma TREM2 levels and a polymorphism and CpG site within the MS4A4A locus. Through Mendelian randomisation analyses, causal associations were observed between higher plasma TBCA and TREM2 levels and lower Alzheimers disease risk. Our data inform the regulation of biomarker levels and their relationships with Alzheimers disease.