SUCLG2 identified as both a determinator of CSF Aβ1–42 levels and an attenuator of cognitive decline in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a complex disorder in which severalpathways contribute to pathology and clinical phenotype. Delineationof each pathological pathway and identification of thefactors which modulate them are crucial for the developmentof effective treatment. Information on individual pathologicalpathways is provided by biomarkers. In AD, cerebrospinalfluid (CSF) levels of Ab1–42 and phosphorylated Tau (pTau)reflect cerebral amyloid deposition and tau-related neurodegeneration,respectively. However, many of the biological factorsthat influence these core AD pathways remain elusive.Research has shown that AD risk genes contribute to CSFmarker variance (1–4). However, genes may also exist thataffect CSF markers without conferring disease susceptibility.These genes may be promising candidates for modulation ofthe disease process.The aim of the present study was to identify genetic factorsrelated to heterogeneity in pathological pathways involved inamyloid deposition and tau-related neurodegeneration—asmanifested through CSF Ab1–42 and pTau levels—and whichmight influence the clinical course of AD. To achieve this, weperformed a four-step investigation involving analysis andmeta-analysis of data from genome-wide association studies(GWASs) of these two CSF biomarkers; replication of our topfindings in an independent sample; and specific analyses andfunctional experiments to follow-up promising findings. In contrastto previous GWAS of CSF biomarkers (1,4,5), the presentGWAS was restricted to patients with dementia secondary toAD only in order to enrich for genetic effects occurring afterdisease onset.