Progranulin Mutations as Risk Factors for Alzheimer Disease eInterview with Dr. David Perry
UCSF School of Medicine
Clinical Fellow in Neurology
675 Nelson Rising Lane
San Francisco CA 94158 What are the main findings of the study?

Dr. Perry: We described two patients with clinical syndromes and brain imaging patterns that are consistent with Alzheimer’s disease. Both were found to have mutations in GRN, which are typically associated with inherited frontotemporal dementia. They both showed evidence of underlying Alzheimer’s pathology, in one case through autopsy confirmation (demonstrating Alzheimer’s disease in addition to TDP-43 pathology), and in the other case from a positive amyloid PET scan. Were any of the findings unexpected?

Dr. Perry: GRN mutations have been previously described to cause a clinical syndrome suggestive of Alzheimer’s disease in a minority of cases (9-17%) but it has generally been thought that this syndrome is caused by FTLD-TDP rather than Alzheimer’s disease pathology. The fact that the young patients in this study (54 and 65 years old) had evidence of Alzheimer’s disease pathology as a cause of their syndrome raises questions about that assumption. What should clinicians and patients take away from your report?

Dr. Perry: As a case series this cannot determine the strength of the association between GRN mutations and Alzheimer’s disease. This study should suggest that clinicians consider screening for GRN mutations in patients with a family history of autosomal dominantly-inherited dementia, even if the patient has clinical Alzheimer’s disease rather than frontotemporal dementia. What recommendations do you have for future research as a result of this study?

Dr. Perry: Further research will need to confirm the risk of Alzheimer’s disease associated with GRN. Larger autopsy and biomarker studies in genetic neurodegenerative disease will demonstrate the strength of this association. We propose that GRN mutations may increase the risk of two different neurodegenerative diseases through common inflammatory pathways. Additional research can explore these molecular pathways with the hope of elucidating a common therapeutic strategy for both illnesses.


Progranulin Mutations as Risk Factors for Alzheimer Disease

Perry DC, Lehmann M, Yokoyama JS, et al.. JAMA Neurol. 2013;():1-5. doi:10.1001/2013.jamaneurol.393.

Last Updated on October 18, 2014 by Marie Benz MD FAAD