Objective:

To describe the clinical phenotype of a rare case of Early Onset Alzheimer's Disease due to a pathogenic APP duplication and elucidate its management implications.

Background:

Alzheimer's Disease (AD) has intricate genetic underpinnings. A specific interest lies with the APP gene, especially in trisomy 21 individuals, where an additional copy leads to increased amyloid beta production. This overproduction frequently results in early Alzheimer's disease onset due to amyloid plaque deposition. Although APP gene duplications are seldom observed outside of trisomy conditions, their potential to replicate trisomy 21 phenotypes and catalyze early disease onset is of clinical interest.

Design/Methods:

We conducted an extensive clinical assessment encompassing neuropsychology tests, MRI brain scans, plasma and CSF biomarker analysis, and in-depth genetic evaluations.

Results:

Our patient, a 54-year-old Honduran American woman with a maternal history of early-onset Alzheimer's dementia, demonstrated a 4-year trajectory of intensifying executive neurocognitive deficits. Neuropsychological evaluations validated these clinical manifestations. Biomarker analyses revealed decreased CSF Abeta42/40 ratios and elevated p-Tau/Abeta42, Phospho-Tau (181P), and Total Tau levels. MRI results indicated progressive cortical atrophy paired with cortical/sub-cortical microhemorrhages. Critical to our diagnosis, genetic assessments confirmed a pathogenic APP duplication. Cumulatively, the findings were aligned with Early Onset Alzheimer’s Dementia and probable Cerebral Amyloid Angiopathy, adhering to the Boston Criteria V2 guidelines.

Conclusions:

Our study fortifies emerging literature in APP genetics, spotlighting the connections between pathogenic duplications, trisomy 21 phenotypes, and precocious disease emergence. This case accentuates the pivotal influence of genetic variables in Early Onset Alzheimer’s Disease and Cerebral Amyloid Angiopathy's presentation.