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2020 Alzheimer's Association Research Grant (AARG)

Clinical Relevance of a Widespread NOTCH3 Mutation for CADASIL Pathogenesis

Could variation in a specific gene explain the potential association between changes in the brain’s blood vessels and cognitive impairment?

Marina Ciullo, Ph.D.
Institute of Genetics and Biophysics
Naples, Italy


An inherited brain blood vessel disease called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (or otherwise known as CADASIL) may impact blood flow in brain blood vessels.  CADASIL is caused by certain variations of a gene called NOTCH3. Normally, NOTCH3 generates a protein designed to protect the structure of blood vessel walls. However, abnormal genetic variations of NOTCH3, may generate proteins that do not have the protective abilities.  This could be associated with blood vessel damage and cognitive impairment.

In southern Italy, Dr. Marina Ciullo and colleagues identified a particular genetic variation of NOTCH3 in a group of individuals diagnosed with CADASIL in 2002. This genetic variation of NOTCH3 has also been found in the general population, suggesting the possibility of a milder version of CADASIL that may be undiagnosed. Dr. Ciullo believes that the presence in such a long-studied community from southern Italy may offer researchers a chance to learn more about how the NOTCH3 gene may be associated with brain changes seen in CADASIL.

Research Plan

Dr. Ciullo and her team will further investigate the association between NOTCH3 and CADASIL in participants from the Southern Italian study. They will examine individuals with and without the genetic variation of NOTCH3 by collecting additional data on their brain, as well as their risk factors for blood vessel disease (factors such as high blood pressure). The researchers will also perform brain scans in individuals with the genetic variation of NOTCH3. Dr. Ciullo’s team will analyze these datasets to understand how the NOTCH3 gene may impact the development of CADASIL in individuals and whether other genetic factors may be involved in the disease.


The study results may provide further insights into the underlying biology of CADASIL, and an increased understanding between blood vessel disorders and dementia. The researchers can use this information to develop therapy strategies and tools for early diagnosis. 

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