Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication

To report a triplication of the amyloid-β precursor protein ( ) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD). Four copies of the gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 duplication carriers. Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an locus triplication, which was consistent with the presence of 2 copies in the healthy mother and with the paternal medical history. Analysis of the mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in duplication carriers compared with controls. Increased copy number of is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.