Assessing family history and approaches for identifying patients with dementia with diagnostically significant genetic findings.

Purpose: A significant proportion of the population reports a positive family history of dementia, which correlates with higher disease risk. As therapeutic advances raise awareness of genetic factors, memory clinics need clear guidelines for identifying patients who would benefit from genetic testing. We aimed to assess the proportion of patients with positive family history in our cohort and a method to improve identification of high-risk genes.

Methods: We analyzed 701 patients with dementia using an adapted classification scheme stratifying genetic risk based on family history and age of onset. Exome sequencing and genotyping data of patients with high-risk were assessed.

Results: A positive family history was reported in 42% of patients in the Alzheimer disease cohort, 48% of patients in the frontotemporal dementia cohort, and 34% in those with other dementia types. Of 51 patients with high-risk identified, 38 had complete genetic data with 38% carrying diagnostically significant variants, including APP, PSEN1, MAPT, PGRN, C9ORF72, and APOE4/4. Strict onset criteria (<60 years) missed 4 patients with APOE4/4 genotype and 1 with a C9ORF72 repeat expansion.

Conclusion: Our findings emphasize the need for improved genetic testing infrastructure in memory clinics. The proposed classification enhanced diagnostic yield to 39%, compared with 20% in routine practice. However, overly strict criteria may miss important findings crucial with the emergence of new anti-amyloid therapies.