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.

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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.

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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, 29 FTD, 182 other/mixed).
- 51 high-risk patients identified; 38 had complete data and underwent genetic analysis.
- Among analyzed high-risk patients, 15/38 (39%) carried diagnostically relevant variants (APP, PSEN1, MAPT, GRN, C9ORF72, APOE4/4).
- C9ORF72 repeat expansions detected via specialized testing (two-step PCR and Southern blotting).
- 65-year AAO cutoff (instead of 60) increased capture of APOE4/4 cases; missed 4 APOE4/4 and 1 C9ORF72 with 60-year cutoff.
- APOE4/4 carriers had a later median onset (~68 years), illustrating semi-dominant effects and limits of a strict 60-year cutoff.

QC result: Pass.