Biomedical subjects

Nikolaos Scarmeas

Publications and source records attributed to Nikolaos Scarmeas.

3 recordsLinked to original sources

PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

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.

Journal Article↗

PubMed2026

Diet-responsive proteogenomic effects following short-term restriction of animal products in humans.

The effect of diet on genetic regulation in humans remains largely unexplored. Here, we investigate gene-diet interactions in a unique group of healthy individuals (N = 200) who alternate between omnivory and dietary restriction of animal products for religious reasons. Using longitudinal proteomic and genotype data, we identify diet-responsive cis-pQTLs and highlight regulatory effects on LBR and MSRA, proteins involved in cholesterol and methionine metabolism respectively. LBR-associated cis-pQTL rs74148404 colocalizes with obesity exclusively under dietary restriction, suggesting diet-dependent modulation of genetic risk. We also show that a diet-dependent cis-pQTL for metabolic regulator FGF21 colocalizes with eosinophil and platelet traits pointing to diet-sensitive immunometabolic signalling. By parallel profiling of a continuously omnivorous control group (N = 211), we uncover seasonally dynamic genetic regulation for proteins linked to apoptosis in immune system pathways (MAVS, CASP3, PDLIM7, IL12RB1), effects likely masked by animal product restriction. These findings reveal dynamic diet- and season-sensitive regulatory mechanisms with implications for precision nutrition and individualized disease prevention strategies, and underscore the need to integrate environmental context into genetic studies of health and disease.

Humans↗

PubMed2024

X-chromosome-wide association study for Alzheimer's disease.

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

Humans↗