X-chromosome study reveals hidden genetic links to Alzheimer’s disease

Despite decades of research, the impact of the X chromosome on Alzheimer’s disease has been largely ignored until now. Discover how seven newly discovered genetic loci could revolutionize our understanding of the disease.

Study: X-chromosome-wide association study for Alzheimer’s disease. Image credits: nobeastsofierce / Shutterstock

Conventional research into the genetic factors contributing to the risk and progression of Alzheimer’s disease have ignored the role of the X chromosome, mainly due to technical analysis limitations. To address these knowledge gaps, a recent study was published in the journal Molecular psychiatry used comprehensive

The study considered three patterns of . Notably, the study identified seven loci with

Background

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory and cognitive decline. It remains the most common precursor to dementia in adults, for which there is currently no cure. Decades of research have identified several (>80) genetic contributors (loci) to AD risk. Unfortunately, traditional technical limitations have led to the X chromosome being largely excluded from these studies.

The X chromosome comprises 5% of the genome, with previous research showing that it contains up to 15% of known genes contributing to genetic intellectual disability. Significant sexual dimorphism (differences between males and females) in both X chromosome traits (females have two counterparts, while men show more rapid AD-associated cognitive decline) requires a better understanding of the role of the X chromosome in AD risk and progression.

About the study

The current study aimed to address the gaps in our understanding of the role of the X chromosome in AD risk and progression by using an in-depth X-Chromosome-Wide Association Study (XWAS). The research dataset is derived from 35 previous studies, two independent family cohorts and two biobanks (UK Biobank [UKB] and FinnGen). It included 115,841 AD cases (52,214 clinically diagnosed and 55,868 proxy cases), AD proxies (defined as ‘both parents showing dementia’ in women, and ‘mothers showing dementia’ in men) and 613,671 controls (55% women ), all of whom were of European descent.

A Key analyzes and b sensitivity analyses. Box colors indicate the approach: purple, green, orange, and blue represent r-XCI, s-XCI, e-XCI, and sex-stratified approaches, respectively. The red circled boxes are the main r-XCI, s-XCI and e-XCI analyses. *Fixed effect meta-analysis with an inverse variance weighted approach as implemented in METAL. **Sex-stratified models were adjusted for 1) principal components (PCs) and/or the genotyping center; 2) PCs, center and age; 3) PCs, Middle, Age and APOE.

After sensitivity analyses, 63,838 diagnosed AD cases and 806,335 controls were included for downstream analyses. The study further included biomarker analyzes of cerebrospinal fluid (Aβ42 and pTau) and assessments of cognitive impairment (Mini-Mental State Examination [MMSE]) in a subset of included participants (5,522 and 2,661, respectively). Notably, the study excluded pseudoautosomal regions from the analyses, mainly due to their exclusion from the genotyping chips of most participants.

Analytical calculations included association tests performed under three -XCI). Researchers additionally conducted sex-stratified analyzes to account for variability caused by XCI mechanisms, which could result in stronger-than-expected effect sizes in men. Stringent quality control measures and sensitivity analyzes were applied to ensure high reliability of the data and to limit potential false negatives due to biobank-specific methodological differences.

“To maintain the balance around allele dosage between the sexes, X chromosome inactivation (XCI) occurs in females. In this process, one is usually random (random XCI or r-XCI), but inactivation can also lead to a specific copy (skewed XCI or s-XCI). ‘escape’ inactivation and are expressed from both X chromosomes in female cells (escape XCI or e-XCI).

Finally, genetic colocalization calculations that compared study results (identified genetic loci) with pre-existing protein and expression quantitative trait loci (pQTL and eQTL, respectively) datasets were used to identify traits and biomarkers representative of cognitive decline.

Study findings

The [MAF] ≥ 1%). Notably, none of the approaches used identified genome-wide significant signals, suggesting that the non-pseudoautosomal regions of the X chromosome are devoid of common AD-associated genetic risk factors.

Seven loci with X-chromosome-wide significance thresholds were identified, including four common loci (Xp22.32, FRMPD4, DMD, and These loci are highlighted as targets for future research and may hold the key to discovering clinical, therapeutic and pharmacological interventions against the onset and progression of AD.

FRMPD4, a brain-expressed gene linked to cognitive reserve, showed particularly robust signals. In contrast, rarer variants such as those in PJA1 and DACH2 showed poor data quality (e.g., sparse variant coverage and lower imputation quality), underscoring the need for methodological optimizations in future research.

Conclusions

The current study represents the largest XWAS on AD to date, analyzing data from more than 115,000 cases and 613,000 controls. It presents the first attempt to account for the complexities of the X chromosome, such as the variability in female XCI patterns and the limitations of biobank-specific methods. Although no genome-wide significant associations were found, seven suggestive loci, including FRMPD4, DMD and WNK3, were identified. Together with gene expression and epigenetic research, this study may provide the basis for future clinical interventions against the risk and progression of AD.