👤 J Genius

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC). Global AD PRS, including and excluding the apolipoprotein E (APOE) gene, alongside five biologically informed pathway-specific PRS (amyloid, immune, external stimuli signaling, cholesterol efflux, lipoprotein metabolism) were computed. Generalized linear models including interaction by sex and stratified by sex and amyloid status (CSF Aβ42/40 < 0.071) assessed associations between PRS and cognitive change. In women, APOE-independent AD genetic risk predicted worse executive function, particularly via cholesterol efflux and external stimuli signaling pathways. Among Aβ + women, PRS also predicted lower memory performance, partially modulated by reproductive span. In Aβ - women, worse executive functioning performance was linked to amyloid, immune, and signaling pathways. In contrast, men showed associations between AD PRS and worse visual (Aβ-) and attentional (Aβ+) performance, independent of pathway-specific mechanisms. These findings reveal distinct, domain-specific cognitive vulnerabilities to AD genetic risk by sex and amyloid status, highlighting APOE-independent and mechanistic contributions to early and subtle cognitive changes. Results support the need for sex-aware, biologically informed genetic models in preclinical AD for risk stratification and early intervention. Show less

Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA receptor antagonist MK-801. Subsequently, we performed an expression study and identified 20 genes showing altered expression in the brain of these rats compared with untreated animals. We then explored whether the human orthologs of these genes are associated with schizophrenia in the largest schizophrenia genome-wide association study published to date, and found evidence for association for 4 out of the 20 genes: SF3B1, FOXP1, DLG2 and VGLL4. Interestingly, three of these genes, FOXP1, SF3B1 and DLG2, have previously been implicated in neurodevelopmental disorders. Show less