👤 Arash Ghanbarian

Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults. We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E ( The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%). The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD. Show less

Hippocampal atrophy is a key marker of Alzheimer's disease (AD)-related neurodegeneration; however, hippocampal volume alone may not fully capture heterogeneity in cognitive decline. Hemispheric hippocampal asymmetry may provide complementary information, but its prognostic value for cognitive decline and clinical progression remains unclear. We studied 1,142 dementia-free participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with available baseline structural MRI, cerebrospinal fluid (CSF) amyloid-β (Aβ42) and phosphorylated tau (p-tau-181), and longitudinal cognitive follow-up. Total hippocampal volume (left + right) and hemispheric asymmetry (absolute left-right volumetric difference) were modeled simultaneously. Linear mixed-effects models examined associations with baseline performance and longitudinal change across memory, language, executive, and visuospatial domains. Cox proportional hazards models assessed risk of clinical progression to clinical dementia over up to 10 years of follow-up. All analyses adjusted for age, sex, education, APOE ε4 status, and CSF biomarkers, with stratification by amyloid status. The study cohort included 546 women (47.8%), with a mean age of 72.54 ± 6.98 years. Larger total hippocampal volume was consistently associated with better baseline performance and slower decline across all four cognitive domains, independent of amyloid and tau biomarkers. In contrast, greater hippocampal asymmetry was selectively associated with worse baseline memory performance and faster memory decline, independent of total hippocampal volume. In amyloid-stratified analyses, total hippocampal volume showed broad associations with cognition across all four domains among amyloid-positive participants and more limited, domain-specific associations among amyloid-negative participants, whereas hippocampal asymmetry was associated with memory only in amyloid-negative individuals. Regarding clinical progression to dementia, smaller total hippocampal volume was associated with higher risk of progression in the overall cohort and within both amyloid groups. In contrast, hippocampal asymmetry was associated with progression risk only among amyloid-negative individuals (hazard ratio per SD increase = 1.31, 95% CI: 1.03-1.65). Hippocampal total volume and asymmetry capture distinct aspects of neurodegeneration, with asymmetry providing additional prognostic information for memory decline and clinical progression in participants without detectable amyloid pathology. Show less

Gene-diet interactions may have an important role in the disparities between the lipid responses of individuals to diet. This study aimed to investigate whether polymorphisms (rs5882 and rs3764261) in the cholesteryl ester transfer protein (CETP) gene modify the association of diet with changes in serum lipid profiles. A total of 4700 individuals aged ≥18 years were selected from among participants of the Tehran Lipid and Glucose Study. After 3.6 years of follow-up, changes in serum lipid profiles were evaluated. Usual dietary intake was assessed using a validated food frequency questionnaire. DNA samples were genotyped with HumanOmniExpress-24-v1-0 bead chips (containing 649,932 SNP loci). No significant interaction was found between CETP polymorphisms and dietary patterns in changing lipid profiles. Mean changes of total cholesterol (TC) decreased in higher quartiles of fish intake in A allele carriers (Q1:8.02, Q4:5.58, P Our data demonstrated that minor allele carriers of rs5882 had a better TG value than AA homozygote individuals when consuming a low fat and high carbohydrate diet. Fish intake modifies the association of rs3764261with TC concentrations. Show less

RNA secondary structures in the 5'-untranslated regions (5'-UTR) of mRNAs are key to the post-transcriptional regulation of gene expression. While it is evident that non-canonical Hoogsteen-paired G-quadruplex (rG4) structures somehow contribute to the regulation of translation initiation, the nature and extent of human mRNAs that are regulated by rG4s is not known. Here, we provide new insights into a mechanism by which rG4 formation modulates translation. Using transcriptome-wide ribosome profiling, we identify rG4-driven mRNAs in HeLa cells and reveal that rG4s in the 5'-UTRs of inefficiently translated mRNAs associate with high ribosome density and the translation of repressive upstream open reading frames (uORF). We demonstrate that depletion of the rG4-unwinding helicases DHX36 and DHX9 promotes translation of rG4-associated uORFs while reducing the translation of coding regions for transcripts that comprise proto-oncogenes, transcription factors and epigenetic regulators. Transcriptome-wide identification of DHX9 binding sites shows that reduced translation is mediated through direct physical interaction between the helicase and its rG4 substrate. This study identifies human mRNAs whose translation efficiency is modulated by the DHX36- and DHX9-dependent folding/unfolding of rG4s within their 5'-UTRs. We reveal a previously unknown mechanism for translation regulation in which unresolved rG4s within 5'-UTRs promote 80S ribosome formation on upstream start codons, causing inhibition of translation of the downstream main open reading frames. Our findings suggest that the interaction of helicases with rG4s could be targeted for future therapeutic intervention. Show less