CASE REPORT article
Front. Neurosci.
Sec. Neurogenomics
An Unexpected Discovery of a Novel Potentially Pathogenic APP Gene Variant: A Case Report of Slowly Progressive Alzheimer's Disease with Prominent Cerebral Amyloid Angiopathy
Provisionally accepted
- 1Department of Neurology, Thomayer University Hospital, Prague, Czechia
- 2BrainBank, Third Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czechia
- 3Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czechia
- 4Department of Neurology, Faculty of Medicine, Hradec Kralove, Charles University, and University Hospital Hradec Kralove, Prague, Czechia
- 5Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czechia
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Amyloid precursor protein (APP) plays an essential role in brain function and development. Variants in the APP gene are associated with both familial Alzheimer's disease and cerebral amyloid angiopathy. We report a case of early onset, slowly progressive mixed dementia with a newly identified APP variant. The patient developed mild cognitive impairment at age 51, followed by neuropsychiatric symptoms, seizures, and progressive white matter changes. Despite a fluctuating clinical course, significant deterioration occurred later, culminating in death at age 77. Genetic testing revealed an APP c.2086G>A (p.Gly696Ser) variant, currently classified as a variant of uncertain significance (VUS). Postmortem examination showed definite AD neuropathologic changes, with fully blown amyloid pathology including amyloid deposits in plaques as well as in severe generalized cerebral angiopathy with concomitant advanced FTLD-tau pathology. In silico analysis of the variant's impact was performed, and the inconclusive results are discussed later.
Keywords: Alzheimer's disease, amyloid precursor protein, cerebralamyloid angiopathy, Mutation, neurodegeneration
Received: 11 Sep 2025; Accepted: 02 Dec 2025.
Copyright: © 2025 Sykora, Harmackova, Parobková, Rusina and Matej. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Radoslav Matej
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