Exome sequencing of a Portuguese cohort of early-onset Alzheimer's disease implicates the X-linked lysosomal gene GLA.

Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD) and other dementias. Accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Additionally, common variants in COL4A1 and rare variants in HTRA1, NOTCH3, COL4A1, and CST3 have been associated with AD pathogenesis. We aimed to search for rare genetic variants in genes associated with monogenic small vessel disease in a cohort of Portuguese early-onset AD patients. We performed whole-exome sequencing in 104 thoroughly studied patients with early-onset AD who lacked known pathogenic variants in the genes associated with AD or frontotemporal dementia. We searched for rare (minor allele frequency < 0.001) non-synonymous variants in genes associated with small vessel disease: NOTCH3, HTRA1, COL4A1, COL4A2, CSTA, GLA, and TREX1. We identified 12 rare variants in 18 patients (17.3% of the cohort). Three male AD patients carried a pathogenic GLA variant (p.Arg118Cys). One of these patients had a definite neuropathological study, confirming the diagnosis of AD and showing concomitant Fabry pathology in CA1-CA4 and the subiculum. We also found several rare variants in other genes associated with cSVD (NOTCH3, COL4A2 and HTRA1), corroborating previous studies and providing further support for the possibility that cSVD genes may play a role in AD pathogenesis. The presence of the same GLA variant in 3 early-onset AD patients, with no other genetic cause for the disease, together with the colocalization of Fabry disease pathology in areas relevant for AD pathogenesis, suggest GLA may have a role in its pathophysiology, possibly parallel to that of GBA in Parkinson's disease, meriting further studies.