MAPT locus on Chromosome 17 Links Parkinson’s and Alzheimer’s Diseases

Dr. Rahul S. Desikan MD, PhD Department of Radiologoy University of California, San Diego School of MedicineMedicalResearch.com Interview with:
Dr. Rahul S. Desikan MD, PhD
Department of Radiologoy
University of California, San Diego School of Medicine

Medical Research: What is the background for this study? What are the main findings?

Dr. Desikan: The MAPT gene encodes the tau protein, which plays an integral role in Alzheimer’s disease (AD) neurodegeneration. Though a number of studies have investigated this issue, the role of the MAPT gene in Alzheimer’s disease is still unclear. In contrast, a number of studies have found a robust association between MAPT and increased risk for other ‘tauopathies’ like Parkinson’s disease (PD). In our study, rather than evaluating all possible genetic loci, we only assessed shared genetic variants between Alzheimer’s disease and PD. By using this type of approach, we were able to increase our statistical power for gene discovery in Alzheimer’s disease.

We found genetic overlap between Alzheimer’s disease and Parkinson’s disease at a locus on chromosome 17 within the MAPT region. Our findings demonstrate that this MAPT associated locus increases risk for Alzheimer’s disease, correlates with gene expression of MAPT and is associated with brain atrophy of the entorhinal cortex and hippocampus on longitudinal MRI scans.

Medical Research: What should clinicians and patients take away from your report?

Dr. Desikan: I think the main contribution of our work is showing the importance of tau and the need to focus additionally on tau-based diagnostic and therapeutic approaches.

A tremendous amount of prior work is being undertaken to identify and treat amyloid dysmetabolism. Comparatively little is known about the early involvement of tau in the Alzheimer’s cascade. Our findings suggest that individuals who are carriers of the deleterious MAPT allele may be at increased risk for developing Alzheimer’s neurodegeneration. Clinically, it will be important to identify and follow these individuals.

Microscopic image depicting plaques and tangles characteristic of Alzheimer’s disease. Credit: Image courtesy of Tom Deerinck, NCMIR, UC San Diego.

Microscopic image depicting plaques and tangles characteristic of Alzheimer’s disease. Credit: Image courtesy of Tom Deerinck, NCMIR, UC San Diego.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Desikan: I think it will be very important to have a better understanding of the entire MAPT region on chromosome 17. There are a number of loci within the larger MAPT region, including the CRHR locus that we identify, that demonstrate a strong correlation (linkage disequilbrium) with MAPT and it will be important to decipher whether these signals just tag MAPT or represent independent signals. It will also be important to see what happens functionally if you knockout/knockdown our identified locus: how does this correlate with tangle formation or memory decline? does this have any relationship with amyloid pathology? does possessing this locus increase the rate of progressing to Alzheimer’s disease in a survival analysis? finally, what is the relationship between MAPT carrier status and APOE carrier status?

Citation:

R S Desikan, A J Schork, Y Wang, A Witoelar, M Sharma, L K McEvoy, D Holland, J B Brewer, C-H Chen, W K Thompson, D Harold, J Williams, M J Owen, M C O’Donovan, M A Pericak-Vance, R Mayeux, J L Haines, L A Farrer, G D Schellenberg, P Heutink, A B Singleton, A Brice, N W Wood, J Hardy, M Martinez, S H Choi, A DeStefano, M A Ikram, J C Bis, A Smith, A L Fitzpatrick, L Launer, C van Duijn, S Seshadri, I D Ulstein, D Aarsland, T Fladby, S Djurovic, B T Hyman, J Snaedal, H Stefansson, K Stefansson, T Gasser, O A Andreassen, A M Dale. Genetic overlap between Alzheimer’s disease and Parkinson’s disease at the MAPT locus. Molecular Psychiatry, 2015; DOI: 10.1038/mp.2015.6

[wysija_form id=”1″]

MAPT locus on Chromosome 17 Links Parkinson’s and Alzheimer’s Disease (2015). MAPT locus on Chromosome 17 Links Parkinson’s and Alzheimer’s Disease MedicalResearch.com