β-Amyloid-Dependent and -Independent Genetic Pathways Regulating CSF Tau Biomarkers in Alzheimer Disease

Background and Objectives Abnormal metabolism of beta-amyloid (A beta) 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. Methods In 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; A beta 1-38, A beta 1-40, A beta 1-42, and A beta 1-42/1-40; 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). Results PRSs with SNPs significant at p < 5e-03 (similar to 1,742 variants) were associated with higher CSF P-tau181 (beta = 0.13, p = 5.6e-05) and T-tau (beta = 0.12, p = 4.3e-04). The associations between PRS and tau measures were partly attenuated but remained significant after adjusting for A beta status. A beta pathology mediated 37% of the effect of this PRS on tau levels. A beta-dependent and A beta-independent subsets of the PRS were identified and characterized. There were also associations between PRSs and CSF A beta biomarkers with nominal significance, but not when corrected for multiple comparisons. There were no associations between PRSs and CSF NfL. Discussion Genetic pathways implicated in causing AD are related to altered levels of soluble tau through both A beta-dependent and A beta-independent mechanisms, which may have relevance for anti-tau drug development.

Automated summary

This study investigated the associations between genetic risk factors for Alzheimer's disease (AD) and biomarkers in cerebrospinal fluid (CSF). The results showed that the genetic risk scores were associated with higher levels of soluble phosphorylated tau, and these associations were partly mediated by beta-amyloid pathology. The study identified Aβ-dependent and Aβ-independent subsets of the genetic risk scores. The findings have implications for the development of anti-tau drugs.