Investigating a Genetic Link Between Alzheimer’s Disease and CADASIL-Related Cerebral Small Vessel Disease

• Published in: Molecular neurobiology Vol. 59; no. 12; pp. 7293 - 7302
• Main Authors: Dunn, Paul J., Lea, Rodney A., Maksemous, Neven, Smith, Robert A., Sutherland, Heidi G., Haupt, Larisa M., Griffiths, Lyn R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2022; Springer Nature B.V
• Subjects: Alzheimer Disease - genetics; Alzheimer's disease; Amyloid; Apolipoprotein E; Biomedical and Life Sciences; Biomedicine; CADASIL - genetics; Cell Biology; Cerebral amyloid angiopathy; Exons; Genes; Genetic markers; Humans; Leukoencephalopathy; Mutation; Mutation - genetics; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Point mutation; Presenilin; Receptors, Notch - genetics; Signal transduction; Vascular diseases; CADASIL; Alzheimer’s disease; Whole exome sequencing; Burden test; Cerebral small vessel disease
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-022-03039-3

Monogenic forms of Alzheimer’s disease (AD) have been identified through mutations in genes such as
APP, PSEN1,
and
PSEN2
, whilst other genetic markers such as the
APOE
ε carrier allele status have been shown to increase the likelihood of having the disease. Mutations in these genes are not limited to AD, as
APP
mutations can also cause an amyloid form of cerebral small vessel disease (CSVD) known as cerebral amyloid angiopathy, whilst
PSEN1
and
PSEN2
are involved in
NOTCH3
signalling, a process known to be dysregulated in the monogenic CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The overlap between AD genes and causes of CSVD led to the hypothesis that mutations in other genes within the PANTHER AD–presenilin pathway may be novel causes of CSVD in a cohort of clinically suspicious CADASIL patients without a pathogenic
NOTCH3
mutation. To investigate this, whole exome sequencing was performed on 50 suspected CADASIL patients with no
NOTCH3
mutations, and a targeted gene analysis was completed on the PANTHER.
ERN1
was identified as a novel candidate CSVD gene following predicted pathogenic gene mutation analysis. Rare variant burden testing failed to identify an association with any gene; however, it did show a nominally significant link with
ERN1
and
TRPC3.
This study provides evidence to support a genetic overlap between CSVD and Alzheimer’s disease.