UCSD. US: An international team of scientists, led by researchers at the
University of California, San Diego School of Medicine, has identified
the microtubule-associated protein tau (MAPT) gene as increasing the risk for developing Alzheimer’s disease (AD). The MAPT
gene encodes the tau protein, which is involved with a number of
neurodegenerative disorders, including Parkinson’s disease (PD) and AD.
These findings provide novel insight into Alzheimer’s neurodegeneration,
possibly opening the door for improved clinical diagnosis and
treatment.
The findings are published in the February 18 online issue of Molecular Psychiatry.
Alzheimer’s disease, which afflicts an estimated 5 million Americans,
is typically characterized by progressive decline in cognitive skills,
such as memory and language and behavioral changes. While some recent AD
genome-wide association studies (GWAS), which search the entire human
genome for small variations, have suggested that MAPT is
associated with increased risk for AD, other studies have found no
association. In comparison, a number of studies have found a strong
association between MAPT and other neurodegenerative disorders, such as PD.
“Though a tremendous amount of work has been conducted showing the
involvement of the tau protein in Alzheimer’s disease, the role of the
tau-associated MAPT gene is still unclear,” said Rahul S.
Desikan, MD, PhD, research fellow and radiology resident at the UC San
Diego School of Medicine and the study’s first author.
In the new Molecular Psychiatry paper, conducted with
collaborators across the country and world, Desikan and colleagues
narrowed their search. Rather than looking at all possible loci
(specific gene locations), the authors only focused on loci associated
with PD and assessed whether these loci were also associated with AD,
thus increasing their statistical power for AD gene discovery.
By using this approach, they found that carriers of the deleterious MAPT
allele (an alternative form of the gene) are at increased risk for
developing AD and more likely to experience increased brain atrophy than
non-carriers.
"This study demonstrates that tau deposits in the brains of
Alzheimer's disease subjects are not just a consequence of the disease,
but actually contribute to development and progression of the disease,"
said Gerard Schellenberg, PhD, professor of pathology and laboratory
medicine at the University of Pennsylvania, principal investigator of
the Alzheimer’s Disease Genetics Consortium and a study co-author.
“An important aspect was the collaborative nature of this work.
Thanks to our collaborators from the Consortium, the International
Parkinson’s Disease Genetics Consortium, the Genetic and Environmental
Risk in Alzheimer’s Disease, the Cohorts for Heart and Aging Research in
Genomic Epidemiology, deCODE Genetics and the DemGene cohort, we had
tremendous access to a large number of Alzheimer’s and Parkinson’s
genetic datasets that we could use to identify and replicate our MAPT finding,” said Ole A. Andreassen, MD, PhD, professor of biological psychiatry at the University of Oslo and a senior co-author.
Sudha Seshadri, MD, professor of neurology at the Boston University
School of Medicine, the principal investigator of the Neurology Working
Group within the Cohorts for Heart and Aging Research in Genomic
Epidemiology consortium and a study co-author added: “Although it has
been known since Alois Alzheimer’s time that both plaques (with amyloid)
and tangles (of tau) are key features of Alzheimer pathology, attempts
to prevent or slow down clinical disease progression have focused on the
amyloid pathway. Until this year no one had convincingly shown that the
MAPT (tau) gene altered the risk of AD and this, combined with
the greater ease of imaging amyloid in life, lead some researchers to
postulate that tau changes were secondary to amyloid changes. The recent
association of genetic variation in the MAPT gene with AD risk
and the emerging availability of tau imaging are now leading to a
recognition that perhaps tau changes are key in the pathophysiologic
pathway of AD and this pathway should be more intensively targeted.”
These findings underscore the importance of using a multi-modal and
multi-disciplinary approach to evaluating Alzheimer’s neurodegeneration.
“These findings suggest that the combination of genetic, molecular
and neuroimaging measures may be additionally helpful for detecting and
quantifying the biochemical effects of therapeutic interventions,” said
Anders M. Dale, PhD, professor of neurosciences and radiology and
director of the Center for Translational Imaging and Precision Medicine
at UC San Diego and the study’s senior author.
Co-authors include Andrew J. Schork, Linda K. McEvoy, Dominic
Holland, James B. Brewer, Chi-Hua Chen, Wesley K. Thompson, UCSD;
Yunpeng Wang, UCSD and Oslo University Hospital; Aree Witoelar, Ingun
Dina Ulstein, Srdjan Djurovic, Oslo University Hospital, Norway; Manu
Sharma, Thomas Gasser, University of Tubingen, Germany; Denise Harold,
Julie Williams, Michael J. Owen, Michael C. O’Donovan, Cardiff
University School of Medicine, Wales; Margaret A. Pericak-Vance,
University of Miami; Richard Mayeux, Columbia University; Jonathan L.
Haines, Vanderbilt University; Lindsay A. Farrer, Boston University
Schools of Medicine and Public Health; Peter Heutink, German Center for
Neurodegenerative Diseases; Andrew B. Singleton, Lenore Launer, National
Institute on Aging; Alexis Brice, Sorbonne University; Nicolas Wood,
John Hardy, University College London; Maria Martinez, INSERM; Seung Hoi
Choi, Anita DeStefano, Boston University; M. Arfan Ikram, Cornelia van
Juijn, Erasmus MC University Medical Center; Joshua C. Bis, Annette L.
Fitzpatrick, University of Washington; Albert Smith, Icelandic Heart
Association; Dag Aarsland, Karolinska Institute, Sweden; Tormod Fladby,
Akershus University Hospital, Norway; Bradley T. Hyman, Massachusetts
General Hospital; Jon Snaedal, University Hospital Reykjavik, Iceland;
and Hreinn Stefanson, Kari Stefanson, University of Iceland.
Funding for this research came, in part, the National Institutes of
Health (grants R01AG031224, K01AG029218, K02NS067427, T32 EB005970,
UO1AG032984, U24-AG041689, and R01 MH100351), the Research Council of
Norway, the South East Norway Health Authority, the Norwegian Health
Association and the KG Jebsen Foundation.