ABSTRACT Background Alzheimer's disease (AD), the most prevalent form of dementia, is highly heritable, yet much of its genetic basis remains unexplained. Most genetic studies have focused on European populations, with limited data from under‐represented groups. Whole‐exome sequencing (WES) in the Han Chinese population may help identify novel rare variants and population‐specific genetic risk factors. Aims This study aims to use WES to identify potential candidate genes associated with dementia and AD in the Han Chinese population. Methods In this exploratory pilot study, we performed WES in 63 Han Chinese patients with dementia, including 43 with AD and 20 with non‐AD dementia (including one with dementia with Lewy bodies, one with Parkinson's dementia, four with frontotemporal dementia and 14 with mixed dementia), to identify rare coding variants. Gene‐based case–control burden analyses using public gnomAD controls were conducted in the overall dementia cohort and the AD subgroup. Protein–protein interaction, functional enrichment, weighted gene coexpression network analysis (WGCNA) and gene set variation analysis (GSVA) using single‐nucleus RNA sequencing (snRNA‐seq) datasets were performed to evaluate biological relevance and cell‐type‐specific activity. Cell‐type marker enrichment analysis was used to identify relevant neuronal subtypes. Multilevel evidence was integrated to prioritise candidate risk genes. Results We identified suggestive rare variant signals in genes involved in cilia‐related pathways, with stronger signals in the AD subgroup. These candidate genes were enriched in WGCNA modules associated with ageing, microtubule organisation and dementia pathology. GSVA showed increased activity of candidate genes in astrocytes using the snRNA‐seq dataset. Cell‐type marker analysis revealed strong enrichment in Ex6 excitatory neurons. Finally, integration of multilevel evidence prioritised 10 candidate genes. Conclusions This pilot study provides preliminary evidence that cilia‐related pathways may be involved in dementia, especially AD susceptibility in the Han Chinese population. Further validation in larger independent cohorts with ancestry‐matched controls and in functional experiments is required. Larger sample sizes for each dementia subtype will improve the detection of both dementia‐shared and subtype‐specific signals.
ABSTRACT Background Cognitive impairment is common in major depressive disorder (MDD) and is associated with impaired social functioning and an increased risk of relapse. Although sex differences in MDD are well documented, their specific role in subjective cognitive impairment (SCI) and related clinical correlates remains unclear. Aims This study aimed to examine sex differences in SCI and its associated clinical risk factors within a large cohort of Chinese patients with MDD. Methods This cross‐sectional study included 2298 adults with MDD (665 males, 1633 females; mean [standard deviation] age, 30.88 [10.33] years). Sociodemographic and clinical characteristics were collected electronically. Participants completed the Patient Health Questionnaire‐9 (PHQ‐9) for depressive symptoms, Generalised Anxiety Disorder‐7 (GAD‐7) for anxiety symptoms, 20‐item Perceived Deficits Questionnaire‐Depression (PDQ‐D‐20) for SCI and 20‐item Toronto Alexithymia Scale (TAS‐20) for alexithymia. Analysis of covariance and binary logistic regression were used to analyse sex differences in SCI and associated factors. Interaction analyses assessed whether these associations differed by sex, and sensitivity analyses used a more stringent SCI cutoff. The Benjamini–Hochberg false discovery rate (FDR) correction was applied to account for multiple testing. Results Of the 2298 participants, 67.9% ( n = 1561) met the criterion for SCI. Females had significantly higher PDQ‐D‐20 scores than males (adjusted mean, 31.65 vs. 30.06; F = 6.25, p = 0.013) and a higher prevalence of SCI (69.8% vs. 63.3%, χ 2 = 9.17, p = 0.002). In both sexes, SCI was associated with TAS‐20 scores (males: odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.05–1.10; females: OR = 1.07, 95% CI 1.06–1.09) and PHQ‐9 scores (males: OR = 1.17, 95% CI 1.11–1.24; females: OR = 1.12, 95% CI 1.08–1.16) (all p < 0.001; p ‐FDR < 0.001). GAD‐7 scores were associated with SCI only among female patients (OR = 1.05, 95% CI 1.01–1.09; p = 0.008; p ‐FDR = 0.014), and this finding remained robust in sensitivity analyses. No interaction with sex was significant in the primary analysis (all p > 0.05), but a significant sex × TAS‐20 interaction was observed under the more stringent cutoff (OR = 1.03, 95% CI 1.00–1.06; p = 0.024; p ‐FDR = 0.036). Conclusions This study identifies significant sex differences in SCI among Chinese patients with MDD. Female patients reported greater SCI, and anxiety symptoms were associated with SCI only in the female subgroup. These findings support further investigation of sex‐sensitive approaches to assessing and managing cognitive complaints in MDD.
