Phenotypic variability in early-onset dementia segregating with a novel APP (p.I718M) variant.
Level 4 - case-series / case-control
Familial case series with genetic segregation and cross-sectional biomarker comparison
PubMed 41327373 · doi:10.1186/s13195-025-01890-9
What was done
Five siblings from a multi-generational family presenting with cognitive impairment were assessed using clinical phenotyping, genetic analysis, and segregation analysis. The authors analyzed CSF biomarkers (Aβ38, Aβ40, Aβ42, t-tau, p-tau181, NfL) and plasma biomarkers (p-tau181, p-tau217, GFAP, NfL) cross-sectionally against non-carrier controls and other autosomal dominant Alzheimer disease (ADAD) mutation carriers. Brain MRI, amyloid PET, and neuropathological assessments were also conducted.
What was found
All five siblings carried the novel APP p.I718M variant, classified as likely pathogenic. The median age at onset was 53 years (range 47 to 67). Four siblings met criteria for probable Alzheimer disease and one met criteria for mixed Alzheimer disease and dementia with Lewy bodies (AD/DLB). Compared to controls, CSF Aβ42/40 and Aβ42/38 ratios were decreased, while the CSF Aβ38/40 ratio was increased. Plasma GFAP, NfL, and p-tau181 concentrations were elevated in carriers. Exact quantitative values for biomarker levels and control group sizes were not reported in the abstract.
Why it matters
The findings identify a novel likely pathogenic APP variant associated with early-onset ADAD and clinical phenotypic variability, expanding the known genetic spectrum of familial dementia.
Limits
The study is restricted to five affected siblings from a single family. Comparator group sample sizes and exact quantitative values were not reported in the abstract, and functional cellular assays to directly verify pathogenic mechanisms remain to be completed.
Cited by
- supports Monogenic dominant mutations in PSEN1, PSEN2, or APP account for less than 5%, and possibly as little as 1%, of Alzheimer's disease cases.