Phenotypic variability in early-onset dementia segregating with a novel APP (p.I718M) variant

Autosomal dominant Alzheimer disease (ADAD) is caused by pathogenic variants in the APP, PSEN1 and PSEN2 genes, but a substantial fraction of reported variants is of unknown clinical significance. Here we report a novel variant in the amyloid precursor protein gene (APP p.I718M). Five siblings from a family with a multi-generational history of cognitive disease were assessed for cognitive impairment at the memory clinic at Karolinska University Hospital. Data were included for genetic analysis, segregation analysis, phenotyping and fluid biomarker analysis. Biomarker analyses were performed in CSF (Aβ38, Aβ40, Aβ42, t-tau, p-tau181, NfL) and plasma (p-tau181, p-tau217, GFAP, NfL). CSF and plasma biomarkers were compared cross-sectionally to non-carrier controls or mutation carriers from other ADAD families. Also, amyloid PET, brain MRI and neuropathological data were included. The siblings fulfilled criteria of probable AD (N = 4) or mixed AD and dementia with Lewy bodies (AD/DLB) (N = 1). Median age at onset was 53 years (range 47 to 67). The genetic variant, APP p.I718M, classified as likely pathogenic based on segregation analysis, population frequency and in silico prediction of pathogenicity, was detected in all five siblings. CSF Aβ42/40 and Aβ42/38 ratios were decreased, and the CSF Aβ38/40 ratio was increased compared to controls. Additionally, elevated plasma concentrations of GFAP, NfL and p-tau181 were observed in APP p.I718M and other ADAD mutation carriers. The APP p.I718M variant is associated with ADAD. Also, concomitant Lewy body pathology was observed in one sibling. The increase in CSF Aβ38/40 suggests a shift in APP processing product-lines, but functional experiments are needed to characterize further cellular mechanisms of the APP p.I718M variant and to confirm its pathogenicity.