Evidence from European ancestry genome-wide association studies and a case-control study suggests several selenoproteins are linked to a decreased risk of Alzheimer's disease
Aug 2026· Journal of Alzheimer's Disease· Vol 113, pp. 1306 - 1319· 0 citations· 54 references
Medicine
TL;DR
Genetic and clinical evidence is provided that specific selenoproteins are associated with a decreased risk of AD and highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.
Abstract
Background Alzheimer's disease (AD) is a neurodegenerative disorder resulting from a complex interplay of multiple factors. Recent hypotheses suggest a potential role of selenium and selenoproteins in AD pathogenesis. However, the causality relationship between them remains to be elucidated. Objective This study investigates the causal link between selenoproteins and AD risk. Methods We analyzed the data by leveraging genome-wide association studies from European cohorts (90,338 AD patients and 1,036,225 controls) and expression quantitative trait loci (eQTLs) from eQTLGen (31,684 individuals) and GTEx v8 (838 individuals). Mendelian randomization and summary data-based Mendelian randomization were applied to assess the potential causal associations between selenoproteins and AD. To further confirm these genetic associations at the clinical level, we conducted a case-control study to evaluate the levels of four differentially expressed selenoproteins in peripheral blood in individuals with AD and cognitively normal controls. Results Our analysis revealed that four selenoproteins, including selenoprotein S (SEPH2) and selenoprotein M (SELENOM), glutathione peroxidase 4 (GPX4) and thioredoxin reductase 2 (TXNRD2), were correlated with a decreased risk of AD. The levels of GPX4, SELENOM, and TXNRD2 were found to be significantly downregulated in AD patients compared to controls in the case-control validation study, supporting the change identified in our genetic analysis. Conclusions This study provides genetic and clinical evidence that specific selenoproteins are associated with a decreased risk of AD. The findings highlight the potential role of these proteins in AD pathophysiology and suggest their promise as biomarkers or therapeutic targets, warranting further investigation.
Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 0 citations
Alzheimer’s disease (AD) and overlapping pathologies represent a growing worldwide health concern. With the first disease-modifying treatments on the rise, it becomes increasingly important to move research in this area forward. Genetic research is excellent at discovering novel contributors to disease mechanisms, which has been demonstrated by the discovery of over 75 disease loci associated with AD. However, classical large-scale genome-wide association studies (GWAS) use cohorts of individuals that have been assigned a case or a control status based on a clinical diagnosis. For AD, this can result in bias due to the complex nature of the disease profile. More specifically, on the neuropathological level, AD is multifaceted with co-morbid pathological lesions being the norm rather than the exception. Together with the substantial preclinical phase, this can lead to the introduction of type I and type II errors. An alternative to using large-scale clinical cohorts is to shift toward studying individuals where the disease diagnosis has been neuropathologically confirmed, or cohorts where an endophenotype is used which can directly reflect ongoing pathological processes in vivo. Such endophenotypes could entail biofluid or imaging-based biomarkers, but the most undiluted signal is obtained when employing neuropathological data. These data typically represent the presence or absence of a lesion or reflects the semi-quantitative burden of pathological features. Here, we review what this shift toward more detailed phenotypes has already contributed to the field by investigating the genetic background of AD hallmark lesions as well as commonly observed co-pathologies.
Celeste Laureyssen, D. Thal, K. Sleegers· Acta Neuropathologica· 0 citations
New SNPs linked to inflammatory biomarkers in a highly admixed Brazilian population are identified, including a missense variant in an olfactory receptor gene linked to MCP-1, which may be biologically important for inflammation and could affect the risk of cardiometabolic diseases.
J. Leite, G. F. L. Pascoal, G. B. S. Duarte et al.· Frontiers in Immunology· 0 citations
Aim: Alzheimer’s disease (AD) and migraine are both common and heritable neurological disorders. Epidemiological studies repeatedly report an association between migraine and an increased risk of AD. However, whether this co-occurrence reflects shared molecular etiology remains unclear.
Methods: We integrated large-scale genome-wide association study (GWAS) summary statistics, AD (Ncase = 21,982 and Ncontrol = 41,944), overall migraine (Ncase = 26,894 and Ncontrol = 374,605), migraine with aura (MA, Ncase = 11,757 and Ncontrol = 374,605), and migraine without aura (MO, Ncase = 9,690 and Ncontrol = 374,605), to perform genome-wide cross-trait meta-analysis (CPASSOC), functional annotation and transcriptome-wide association studies (TWAS) to elucidate the genetic etiology between AD and migraine in detail.
Results: Genome-wide cross-trait analysis revealed that 11 independent suggestive shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 0.05) and 3 significant shared loci (PCPASSOC < 5 × 10-8 and Psingle-trait < 5 × 10-3) for AD and migraine, with substantial subtype specificity. In addition, after global false discovery rate (FDR) correction across 49 tissues, we identified C2 as a highly significant shared pleiotropic gene in the brain cerebellar hemisphere, and TSBP1-AS1 in the thyroid for AD and MA. Finally, drug-target prioritization highlighted C2 as a candidate therapeutic target, while PheWAS analysis revealed no significant associations between C2 and major disease categories, supporting its limited phenotypic pleiotropy.
Conclusion: This study clarified the pleiotropic loci and shared genes underlying AD and migraine by integrating multi-omics. These findings provide important insights into the molecular mechanisms between AD and migraine, and potential candidate genes for further functional validation.
Tao Wang, Canteng Fang, Yunbao Liu et al.· Ageing and Neurodegenerative...· 0 citations
Progress in multi-omics technologies, disease models using induced pluripotent stem cells (iPSC), gene editing with CRISPR-Cas9, and artificial intelligence (AI) analysis are likely to speed up the implementation of precision medicine for early diagnosis, risk prediction, and treatment of Alzheimer's disease.
Sumithira George, Sharan Kumar, Sivakumar Subramaniyan et al.· Middle East Research Journal...· 0 citations
Household income exerts a protective causal effect on AD, which is predominantly mediated by cognitive performance, elucidate a key mechanistic pathway linking socioeconomic factors to neurodegenerative disease and highlight cognitive function as a potential interventional target, supporting the integration of socioeconomic considerations into AD prevention strategies.
