Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer’s Disease and Frontotemporal Dementia: A Serbian Memory Clinic

Background/Objectives: Early-onset dementia (EOD), defined as symptom onset before 65 years of age, is a clinically and genetically heterogeneous group. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are its most common neurodegenerative causes. Methods: We investigated the family history, genetic spectrum, and diagnostic yield of targeted genetic testing in a consecutive Serbian cohort of 130 patients with early-onset AD (EOAD) and 78 with early-onset FTD (EOFTD). Results: Approximately one-third of patients had a positive family history of dementia or another neurodegenerative disorder. Pathogenic or likely pathogenic variants were identified in 3.8% of patients with EOAD, whereas pathogenic or likely pathogenic variants or pathogenic repeat expansions were identified in 9.0% of patients with EOFTD. In EOAD, the diagnostic yield increased to 9.5% in those with a positive family history and, in an exploratory subgroup analysis, was 33.3% in those with symptom onset before 51 years. In EOFTD, the diagnostic yield was 25.0% among those with a positive family history. PSEN1 and APP were the only disease-causing genes identified in EOAD, whereas C9orf72 repeat expansion was the predominant genetic cause of EOFTD, with additional pathogenic variants identified in GRN and VCP. Conclusions: These findings support the clinical value of targeted genetic testing guided by family history, age at onset, and clinical phenotype in patients with EOD. Genetically unresolved familial cases may reflect incomplete assessment of known genetic causes, including genes and variant classes not covered by the targeted testing strategy used in this study.