Phenotype associated with APP duplication in five families

Area of Science:

• Neurology
• Genetics
• Pathology

Background:

• Autosomal dominant early-onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA) have been linked to APP locus duplications.
• Identifying the specific phenotype associated with these duplications is crucial for diagnosis and management.

Purpose of the Study:

• To describe the clinical, neuropsychological, imaging, and neuropathological features of individuals with APP locus duplications.
• To characterize this newly identified genetic entity causing early-onset dementia and CAA.

Main Methods:

• Review of clinical, neuropsychological, imagery, and neuropathological data from five families with APP locus duplications.
• Analysis of phenotype variability and correlation with duplication size.

Main Results:

• Dementia was universal, with onset between 42-59 years.
• Intracerebral hemorrhage (ICH) occurred in 26% and seizures in 57% of patients.
• Neuropathology revealed Alzheimer's disease, severe CAA, and intraneuronal Abeta40 accumulation.

Conclusions:

• APP locus duplications define a distinct genetic cause of early-onset Alzheimer's disease and cerebral amyloid angiopathy.
• The phenotype includes dementia, ICH, and seizures, with characteristic neuropathological findings.
• Intraneuronal Abeta40 accumulation in the hippocampus is a notable feature.