Genomic Advances Shape Precision Medicine for Neurodegenerative Diseases
Genomic technologies including whole-genome sequencing and polygenic risk scores are advancing precision medicine for neurodegenerative diseases like Alzheimer's and Parkinson's. Research reveals complex gene interactions in conditions like PTEN hamartoma tumor syndrome and sex-specific metabolic signatures in Alzheimer's disease. The integration of genomics with molecular neurobiology offers potential for more accurate diagnosis and treatment.
Recent advances in genomic technologies have greatly enhanced our understanding of neurodegeneration, with techniques like whole-genome sequencing, long-read sequencing, and large-scale population studies expanding the range of identified genetic risk factors and uncovering new disease mechanisms and biological pathways that could serve as therapeutic targets. These tools have led to the discovery of disease-related variants and broadened our understanding of how genotype relates to phenotype across a wide range of neurodegenerative syndromes, from single-gene disorders to complex, multifactorial diseases such as Alzheimer's disease, Parkinson's disease, and frontotemporal lobar degeneration.
Genomic technologies have revolutionized the study of neurodegenerative disorders. High-throughput sequencing methods, including whole-exome sequencing, whole-genome sequencing, and long-read sequencing, enabled the exploration of the human genome at an unprecedented scale and at remarkably low cost. Genetic information is increasingly shaping diagnosis and treatment decisions.
In Alzheimer's disease, which has a strong genetic predisposition, genome-wide association studies have identified multiple risk loci, yet many non-coding variants remain uncharacterized. Machine learning-based polygenic risk scores enhance prediction by modeling genetic epistasis and sex-specific risks. Research reveals sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease.
For PTEN hamartoma tumor syndrome, caused by germline PTEN variants, whole-genome sequencing of 599 individuals with PHTS and family members has shown that phenotypes are shaped by complex gene–gene interactions beyond PTEN alone. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 individuals (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in neurodevelopmental disorder-related genes, including DHCR7, POLG, and ARSA. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1.
The ongoing integration of genomics, molecular neurobiology, and data science offers great potential for more accurate, biologically informed diagnosis and treatment of neurodegenerative disorders. However, translating these genetic insights into clinical practice remains difficult because of challenges in interpreting variants and the limited functional validation of new discoveries. Improvements in variant classification, detection of structural variants and repeat expansions, and combining transcriptomic, proteomic, and functional data are helping to better determine variant pathogenicity.