TY - JOUR
T1 - Investigating a genetic link between Alzheimer’s Disease and CADASIL related Cerebral Small Vessel Disease
AU - Dunn, Paul J
AU - Lea, Rodney A.
AU - Maksemous, Neven
AU - Smith, Robert
AU - Sutherland, Heidi
AU - Haupt, Larisa M
AU - Griffiths, Lyn R
N1 - Funding Information:
Open Access funding enabled and organized by CAUL and its Member Institutions This work was supported through the National Health and Medical Research Council of Australia (GNT1168601) Dora Lush Biomedical Postgraduate Research scholarship.
Funding Information:
Acknowledgement goes to the Australian National Health and Medical Research Council (NHMRC) for funding this project through the Dora Lush Biomedical Sciences Postgraduate Scholarship.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139197203&partnerID=8YFLogxK
U2 - 10.1007/s12035-022-03039-3
DO - 10.1007/s12035-022-03039-3
M3 - Article
SN - 0893-7648
VL - 59
SP - 7293
EP - 7302
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 12
ER -