73: Family history and genetics in dementia

König T et al., Genetics in Medicine - A retrospective study of 701 memory clinic patients tested whether stratifying by age at onset and family history enriches for diagnostically relevant genetic findings. Using an adapted Goldman-score classification with exome sequencing and targeted genotyping in high-risk cases, the authors increased diagnostic yield and evaluated implications for APOE and C9ORF72 testing. Key terms: Alzheimer's disease, Exome sequencing, APOE, Genetic risk, Diagnostic yield. Study Highlights:In 701 dementia patients, 34–48% reported a positive family history depending on diagnosis. Applying an adapted age-at-onset (≤65 years) and Goldman-score stratification identified 51 high-risk patients, 38 of whom had complete genetic data. Among those 38, 39% carried diagnostically relevant variants including APP, PSEN1, MAPT, GRN, C9ORF72 repeat expansions and APOE4/4. Using a stricter ≤60-year cutoff increased yield but missed several APOE4/4 and one C9ORF72 case, showing trade-offs between sensitivity and specificity. Conclusion:A standardized classification by age at onset and family history improves selection for genetic testing in memory clinics, raising diagnostic yield to 39% among high-risk patients and supporting routine APOE and C9ORF72 testing while cautioning that overly strict onset cutoffs can miss clinically important cases. Music:Enjoy the music based on this article at the end of the episode. Article title:Assessing family history and approaches for identifying dementia patients with diagnostically significant genetic findings First author:König T Journal:Genetics in Medicine DOI:10.1016/j.gim.2025.101517 Reference:König T, Silvaieh S, Parvizi T, Wurm R, Goeschl S, Uhlik E, Farr C, Berger-Sieczkowski E, Untersteiner H, Zimprich A, Stögmann E. Assessing family history and approaches for identifying dementia patients with diagnostically significant genetic findings. Genetics in Medicine. 2025. https://doi.org/10.1016/j.gim.2025.101517 License:© 2025 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/family-history-genetic-dementia-s2e73 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Substantive audit of the transcript's presentation of the article's methods and results, including: AAO cutoff change (60→65) and its impact on yield; Goldman score integration; cohort/genetic testing approach (ES + APOE genotyping + C9ORF72 testing); key pathogenic variants; C9ORF72 repeat testing; APOE4/4 onset and t- transcript topics: Overview of dementia genetics and testing landscape; Goldman score and age-at-onset integration; Cohort design and sequencing approaches (ES, APOE, C9ORF72); C9ORF72 repeat expansions testing and limitations of ES; APOE4/4 genotype and age-at-onset interactions; Anti-amyloid therapies, ARIA risk, and regulatory considerations QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 8- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Cohort size: 701 dementia patients (490 AD spectrum,...