# 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

## TL;DR

A new APP gene variant was found in a patient with slowly progressing Alzheimer’s and severe brain amyloid buildup.

## Contribution

Identification of a novel APP variant linked to mixed dementia and cerebral amyloid angiopathy.

## Key findings

- The patient had early-onset dementia with prominent cerebral amyloid angiopathy and white matter changes.
- Postmortem analysis confirmed Alzheimer’s pathology and advanced FTLD-tau pathology.
- The APP c.2086G > A variant was identified but remains classified as a variant of uncertain significance.

## Abstract

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.