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

Abstract

Background and ObjectiveTo report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).MethodsFour copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.ResultsBeginning 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 APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.DiscussionIncreased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.

Cerebrospinal fluid amyloid precursor protein as a potential biomarker of fatigue in multiple sclerosis: A pilot study

“…The only disease in which APP has been previously studied is Alzheimers Disease, where APP is well known to play a part in the pathogenesis. The connection of increased APP levels and dementia is underlined by the fact that triplications of APP in humans and overexpression of APP in mice have been associated with early onset of cognitive impairment (Kreis et al, 2021;Grangeon et al, 2021). However, to the best of our knowledge, this study is the first to find lower APP levels in a patient group, and the first to investigate the relationship of APP and fatigue in any disease.…”

Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities

“…Increased expression of APP leads to Alzheimer’s disease, where Aβ directly contributes to pathologies. For example, three copies of APP in Down’s Syndrome ( Wisniewski et al, 1985 ) as well as local duplications ( Rovelet-Lecrux et al, 2006 ; Sleegers et al, 2006 ) and triplications ( Grangeon et al, 2021 ) are causative of dementia.…”

“…Trisomy of chromosome 21 in Down’s syndrome (DS) leads to three copies of APP and a concurrent high incidence of Alzheimer’s disease in DS patients ( Wisniewski et al, 1985 ). Additionally, duplications ( Rovelet-Lecrux et al, 2006 ; Sleegers et al, 2006 ) and triplications ( Grangeon et al, 2021 ) of the local APP gene territory cause fAD. In contrast, people living with one functional copy of APP are asymptomatic ( Klein et al, 2016 ) and mutations that reduce amyloidogenic processing of APP can be protective against AD ( Jonsson et al, 2012 ).…”

CRIA: An Interactive Gene Selection Algorithm for Cancers Prediction Based on Copy Number Variations

“…The Flierl research team found that the higher vulnerability of Parkinson's disease and stress sensitivity of neuronal precursor cells carry an α-synuclein gene triplication (Flierl et al, 2014 ). Grangeon et al ( 2021 ) discovered that early-onset cerebral amyloid angiopathy and Alzheimer Disease (AD) were related to an amyloid precursor protein (App) gene triple amplification. Breunis et al ( 2008 ) reported that the copy number variations of FCGR2C gene promoted idiopathic thrombocytopenic purpura.…”