Dementia is a general term that encompasses a set of symptoms associated with the progressive decline of cognitive functions such as memory, language, attention, reasoning, and orientation. When this decline becomes severe enough to interfere with activities of daily living, it can significantly affect a person’s independence and quality of life.
Alzheimer's disease is the most common cause of dementia, accounting for approximately 60 to 80 percent of cases. However, there are other types of dementia—such as frontotemporal dementia, Lewy body dementia, vascular dementia, and mixed forms—that may present with similar clinical manifestations and make differential diagnosis difficult.
For years, it was believed that most forms of dementia had a primarily environmental or multifactorial origin. It is now known that genetics plays a significant role in both familial and sporadic forms of these diseases. Although most cases are not caused by a single disease-causing genetic mutation, numerous genes have been identified that are associated with an increased risk or are directly involved in the development of certain forms of dementia.
It is now known that genetics plays a significant role in both familial and sporadic forms of dementia.
Among the most studied genes are APP, PSEN1, and PSEN2, which are responsible for hereditary forms of early-onset Alzheimer's disease; APOE, whose ε4 allele is the main genetic risk factor for sporadic Alzheimer's disease; and genes such as C9orf72, GRN, and MAPT, which are closely linked to various forms of frontotemporal dementia. Furthermore, variants in genes such as TREM2 have been associated with an increased risk of developing neurodegenerative diseases.
When is genetic testing recommended?
Genetic testing can be particularly useful in patients with a family history of dementia, cases of early-onset dementia (generally before age 65), atypical clinical presentations, or when there is diagnostic uncertainty between different neurodegenerative disorders.
Identifying a genetic variant associated with the disease can help confirm the diagnosis, guide clinical follow-up, facilitate genetic counseling for family members, and enable patients to participate in clinical trials or personalized medicine programs.
Targeted exome sequencing
The genetic heterogeneity of dementias means that, in many cases, analyzing just a few genes is not sufficient to identify the molecular cause of the disease. However, it is not always necessary to resort to a full exome analysis either. In this context, targeted exome studies represent an efficient strategy that combines the advantages of high-throughput sequencing with a clinically oriented approach.
This approach involves sequencing the patient’s entire exome and initially focusing the bioinformatics analysis on a set of genes selected for their known association with dementias or with the observed clinical phenotype. This makes it possible to arrive at a more accurate interpretation and reduce the likelihood of identifying incidental findings or variants that are not clinically relevant to the reason for the study.
The use of targeted exome sequencing offers several advantages in the genetic diagnosis of neurodegenerative diseases:
- It allows for the simultaneous analysis of a large number of genes associated with different types of dementia, including Alzheimer's disease, frontotemporal dementia, and other hereditary neurodegenerative disorders.
- It facilitates the diagnosis of patients with atypical symptoms or with clinical features common to different diseases.
- It allows for the gradual expansion of the analysis to include new genes when initial results are inconclusive, without the need to repeat the sequencing.
- It allows for the reinterpretation of the data in the future as new genes associated with dementia are discovered.
- It reduces the time and costs associated with conducting multiple genetic studies sequentially.
Thanks to this flexibility, targeted exome sequencing has become a particularly useful tool for diagnosing genetically complex diseases, allowing the analysis to be tailored to each patient’s needs and making the most of the information obtained through sequencing.
DG Dementia
Targeted exome sequencing that analyzes genes associated with Alzheimer's disease and other types of dementia. Analysis of SNVs, Indels, and CNVs:
Conclusion
Advances in sequencing technologies and genomic analysis are making it possible to identify new genes involved in neurodegenerative diseases and to better understand the role of genetics in their development. As new associations between genetic variants and disease are discovered, the ability to make more accurate diagnoses and better characterize patients with hereditary or early-onset forms of these diseases is increasing.
Although most forms of dementia have multifactorial causes, identifying genetic variants associated with the risk of or onset of the disease can provide valuable information for diagnosis, family genetic counseling, and the design of future therapeutic strategies based on precision medicine.
Therefore, when a neurodegenerative disease of possible hereditary origin is suspected or there is a relevant family history, it is essential to seek the advice of professionals specializing in clinical genetics who can evaluate each case individually and recommend the most appropriate diagnostic strategy.
BIBLIOGRAPHY
- Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics. 2022;54(4):412-436.
- Wightman DP, Jansen IE, Savage JE, et al. A genome-wide association study involving 1.1 million individuals identifies new risk loci for Alzheimer’s disease. Nature Genetics.
- Swift IJ, Sogorb-Esteve A, Heller C, et al. Genetic testing in dementia: a practical guide for clinicians. Lancet Neurology. 2024;23(3):278-292.
- Vogrinc D, Kocijan R, Koritnik B, et al. Clinical utility of exome sequencing in neurodegenerative disorders: a systematic review. Journal of Neurology.
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