Researchers identified new genetic links to Alzheimer’s disease, shedding light on sex-specific pathways and the role of lipid metabolism in driving neurodegeneration in a study published in Acta Neuropathologica Communications.
Alzheimer’s disease (AD), the most common form of dementia, remains a formidable challenge for clinicians and researchers alike. Its diagnosis often relies on clinical assessments, which have a 24% misdiagnosis rate. In this study researchers tok a neuropathology-based approach abd examined post-mortem brain samples to pinpoint genetic factors directly linked to the characteristic plaques and tangles of AD.
The research integrated 14 datasets, covering 6960 individuals, and employed genome-wide association studies (GWAS) and multi-omics analysis. This comprehensive effort aimed to unravel the genetic complexity of AD and address the lack of sex-specific genetic studies, the researchers noted.
The study identified several novel genetic loci associated with AD neuropathology:
- BIN1, a gene previously linked to clinical AD, emerged as particularly significant in women. BIN1 influences processes such as amyloid-beta production and tau pathology propagation.
- Two new loci—QRFPR and SGCZ—showed strong female-specific associations. QRFPR, a receptor involved in circadian rhythm regulation and neuroprotection, and SGCZ, a gene linked to protein aggregation, both provide new targets for understanding and treating AD in women.
Notably, the study highlighted the critical role of lipid metabolism in AD progression. Through phenome-wide association studies (PheWAS) and Mendelian randomization, the researchers established a causal link between disrupted lipid metabolism, immune response dysregulation, and AD neuropathology.
Women face a higher risk of developing AD and tend to exhibit faster cognitive decline. This study underscored hormonal changes, particularly those involving luteinizing hormone (LH), as a possible driver of increased susceptibility. The findings connect AD neuropathology in women to pathways involving LH secretion, offering a biological basis for sex-specific differences.
By focusing on sex-specific pathways and the interplay between lipid metabolism and neurodegeneration, the researchers said this study could help to develop targeted therapies that address the unique vulnerabilities of women and men.
Moreover, the findings emphasized the importance of early detection. Pathological changes in the brain often precede clinical symptoms by decades, making biomarkers critical for intervention.
The study authors declared no competing interests.