Input of exome sequencing in early-onset cerebral amyloid angiopathy

Abstract

Introduction: Genetics of cerebral amyloid angiopathy (CAA) remains understudied.

Methods: We assessed variants in Alzheimer's disease (AD) risk factor genes and differential diagnosis genes by performing exome sequencing among 78 patients with early-onset definite or probable CAA, after negative screening for APP mutation or duplication.

Results: Among 14 genes involved in non-Aβ CAA, or vascular leukoencephalopathies, we detected pathogenic NOTCH3 variants in two patients, who exhibited lobar hematomas at the ages of 58 and 65, leading to a diagnosis redirection toward CADASIL. Of the remaining 76 patients, 23.1% carried at least one apolipoprotein E (APOE) ε2 allele and 43.6% carried at least one APOE ε4 allele, known as CAA risk factors. A total of 15 out of 76 (19.7%) carried either a loss-of-function or a rare predicted damaging missense or known AD risk variant in SORL1, TREM2, ABCA7, ABCA1, and ATP8B4.

Discussion: Exome sequencing allowed the redirection toward CADASIL in two patients and suggested shared genetic factors between AD and CAA, beyond the APOE gene.

Highlights: The genetic component of cerebral amyloid angiopathy (CAA) remains understudied.Rare differential diagnoses such as CADASIL should be considered, even in cases of cerebral hemorrhage.Our study suggests shared genetic factors between AD and CAA, beyond the APOE gene.Rare variants in SORL1, TREM2, ABCA7, ABCA1 and ATP8B4 might be susceptibility factors in early-onset CAA.

Keywords: Alzheimer disease; CADASIL; cerebral angiopathy amyloid; genetic risk factors; intracerebral hemorrhage.

FIGURE 1

Summary of the study: CAA patients selected for WES and count of causative variants. CAA, cerebral amyloid angiopathy.

FIGURE 2

Scatterplots of CSF biomarkers (Aβ42, Aβ40, Tau, and phosphorylated Tau) levels in CAA patients (n = 45). CAA, cerebral amyloid angiopathy; CSF, cerebrospinal fluid.

FIGURE 3

MRI imaging of the two carriers ROU‐1149 (panel A) and EXT‐1182 (panel B) of a pathogenic NOTCH3 variant presenting with a history initially compatible with CAA. Panel A: Left and middle axial T2‐GRE weighted sequence showing several posterior lobar microbleeds and bilateral temporal ICH sequela; right: axial T2 weighted sequence showing mild periventricular white matter lesions of posterior topography and dilated perivascular spaces. Panel B: Left and middle axial T2‐GRE weighted sequence showing several posterior lobar microbleeds; right: axial FLAIR weighted sequence showing mild periventricular white matter lesions and previous thalamic stroke. CAA, cerebral amyloid angiopathy; ICH, intra‐cerebral hemorrhage; MRI, magnetic resonance imaging.