Understanding the genetics of neurodegenerative diseases has already opened promising avenues for early diagnosis, risk prediction, and targeted therapeutic interventions. These results stem from the application of different genetic technologies enabling the investigation of both rare and common variants within the genome.
Interestingly, the application of exome and genome sequencing to the study of neurodegenerative diseases across various populations has revealed not only novel genes linked to these conditions but also an extensive array of pleiotropic phenomena. TREM2 is a prime example of this: initially identified as the causative genetic factor for the mendelian Nasu-Hakola disease, subsequent research revealed its role in familial frontotemporal dementia within an understudied population. More recently, it has emerged as one of the most significant genetic risk factors for Alzheimer's disease across diverse populations. The same type of pleomorphic risk can be seen for other genes and phenotypes, often crossing from monogenic to complex diseases.
The presence of shared genetic factors among distinct clinical conditions and phenotypes introduces an added layer of complexity to the diagnostic process. It also offers insights into common molecular mechanisms and potential shared drug targets across these diseases. Equally vital is recognizing the substantial contribution of genetic studies in underrepresented populations, which have significantly enriched our comprehension of Alzheimer's disease, dementia, and other neurodegenerative disorders.
In summary, the convergence of genetic insights obtained across the spectrum from rare to common variants, populations, and phenotypes has the potential to give us an integrated roadmap to fully understand the genetic architecture of neurodegenerative diseases.