Background and ObjectivesAbnormal metabolism of β-amyloid (Aβ) and soluble phosphorylated tau (P-tau), as well as neurodegeneration, are key components of Alzheimer disease (AD), but it is unclear how these different processes are related to genetic risk factors for AD.MethodsIn the Swedish BioFINDER study, we tested associations between a priori defined polygenic risk scores (PRSs) for AD (excluding single-nucleotide polymorphism [SNP] within the APOE region in the main analysis) and biomarkers in CSF (total tau [T-tau] and P-tau181; Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-42/1-40; and neurofilament light [NfL]) in cognitively unimpaired (CU) individuals (n = 751), and in patients with mild cognitive impairment (MCI) (n = 212) and AD dementia (n = 150). Results were validated in the Alzheimer's Disease Neuroimaging Initiative data set with 777 individuals (AD = 119, MCI = 442, and CU = 216).ResultsPRSs with SNPs significant at p < 5e-03 (∼1,742 variants) were associated with higher CSF P-tau181 (β = 0.13, p = 5.6e-05) and T-tau (β = 0.12, p = 4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for Aβ status. Aβ pathology mediated 37% of the effect of this PRS on tau levels. Aβ-dependent and Aβ-independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF Aβ biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL.DiscussionGenetic pathways implicated in causing AD are related to altered levels of soluble tau through both Aβ-dependent and Aβ-independent mechanisms, which may have relevance for anti-tau drug development.