textlessptextgreaterAlthough our understanding of Alzheimer9s disease (AD) has greatly improved in recent years, the root cause remains unclear, making it difficult to find effective diagnosis and treatment options. Our understanding of the pathophysiology underlying AD has benefited from genomic analyses, including those that leverage polygenic risk score (PRS) models of disease. In many aspects of genomic research the use of functional annotation has been able to improve the power of genomic models. Here, we leveraged genomic functional annotations to build tissue-specific PRS models for 13 tissues and applied the scores to two longitudinal cohort studies of AD. The PRS model that was most predictive of AD diagnosis relative to cognitively unimpaired participants was the liver tissue score: n = 1,116; odds ratio (OR) (95% confidence interval [CI]) = 2.19 (1.70-2.82) per standard deviation (SD) increase in PRS; P = 1.46 x 10$^textrm-9$. After removing the APOE locus from the PRS models, the liver score was the only PRS to remain statistically significantly associated with AD diagnosis after multiple testing correction, although the effect was weaker: OR (95% CI) = 1.55 (1.19-2.02) per SD increase in PRS; P = 0.0012. In follow-up analysis, the liver PRS was statistically significantly associated with levels of amyloid (P = 3.53 x 10$^textrm-6$) and tau (P = 1.45 x 10$^textrm-5$) in the cerebrospinal fluid (CSF) (when the APOE locus was included) and nominally associated with CSF soluble TREM2 levels (P = 0.042) (when the APOE locus was excluded). These findings provide further evidence of the role of the liver-functional genome in AD and the benefits of incorporating functional annotation into genomic research.textless/ptextgreater