Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer's Disease and Frontotemporal Dementia: A Serbian Memory Clinic.
- 1Neurology Clinic, University Clinical Centre of Serbia, 11000 Belgrade, Serbia.
- 2Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
Abstract
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.
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BibTeX
@article{mandicstojmenovic2026genetic,
title = {{Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer's Disease and Frontotemporal Dementia: A Serbian Memory Clinic.}},
author = {Gorana Mandić-Stojmenović and Vladimir Kostić and Ana Marjanović and Ivana Novaković and Predrag Aleksić and Tanja Stojković and Elka Stefanova},
journal = {Diseases (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/diseases14100359},
url = {https://europepmc.org/article/MED/42929986},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic Spectrum, Family History and Diagnostic Yield of Targeted Genetic Testing in Early-Onset Alzheimer's Disease and Frontotemporal Dementia: A Serbian Memory Clinic.
AU - Gorana Mandić-Stojmenović
AU - Vladimir Kostić
AU - Ana Marjanović
AU - Ivana Novaković
AU - Predrag Aleksić
AU - Tanja Stojković
AU - Elka Stefanova
PY - 2026
DA - 2026/09/29
JO - Diseases (Basel, Switzerland)
DO - 10.3390/diseases14100359
UR - https://europepmc.org/article/MED/42929986
AB - 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.
SN - 2079-9721
ER -