Phenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy

Phenotypic and Molecular Characterisation of Early-onset Cerebral Amyloid Angiopathy

Cerebral Aβ amyloid angiopathy is a severe disease characterised by amyloid deposits in the cerebral vessels, manifested mainly by recurrent cerebral haematomas and cognitive impairment. Diagnostic criteria are based on brain imaging, but the usefulness of this imaging in predicting the course of the disease remains undetermined. The genetic component is largely understudied. Less than 5% of patients carry mutations or duplications of the APP gene. Susceptibility factors such as APOE genotypes and rare variants recently discovered in Alzheimer's disease within the SORL1, TREM2 or ABCA7, ABCA1 and ATP8B4 genes could play a role in the pathophysiology of cerebral amyloid angiopathy. There is currently no specific treatment available. Based on a national recruitment of patients with cerebral amyloid angiopathy, this project aims to assess the role of genetic variants in the diagnosis and progression of cerebral amyloid angiopathy. A better understanding of the mechanisms, particularly genetic, could help us to develop treatments in the era of gene therapy.

This research is carried out on the same blood sample taken during the treatment and sent to the Rouen University Hospital Genetics Laboratory for research into point mutations or duplication of the APP gene as part of the diagnosis of cerebral amyloid angiopathy (CAA). For each gene, the proportions of variant carriers will be compared between cases and controls using a Fisher exact test with R statistical software. To rule out any population stratification bias, the tests will also be carried out using logistic regression adjusted on the first PCA axes (principal component analysis) using the seqmeta function. A Bonferroni correction will then be used to adjust the significance threshold according to the number of genes tested.

Inclusion Criteria:

• Patients with a diagnosis of cerebral amyloid angiopathy (CAA) whose genetic samples are initially sent to the Rouen or Paris-Lariboisière genetics laboratories for molecular diagnosis of a genetic cause, thanks to national recruitment and for whom the patients consent to continuing genetic analyses for research purposes without feedback.
• Diagnosis of cerebral amyloid angiopathy (CAA) certain or probable according to the modified Boston diagnostic criteria (1) (except age)
• Age of onset of symptoms <66 years
• Absence of APP mutation/duplication (analysis must already have been carried out in the laboratory on receipt of the sample as part of routine care)
• Signed consent for research
• Patient covered by a social security scheme

Exclusion Criteria:

• Age at first neurological symptom > 66 years
• Minor patients
• Other differential diagnosis that better explains the clinical situation
• Identification of mutations or duplication of the APP gene
• AAC possible but not probable according to the revised Boston criteria
• Patient deprived of liberty by judicial or administrative decision