Study Suggests Earliest Brain Changes Associated With The Genetic Risk Of Alzheimer’s Disease: May Have Implications for the Development of Prevention Therapies

30 November 2010

Glendale, Arizona—What are the earliest brain changes associated with the risk of developing Alzheimer’s disease? A scientific report published in the October Journal of Alzheimer’s Disease finds reduced activity of an energy-generating enzyme in deceased young adult brain donors who carry a common genetic risk factor for Alzheimer’s disease—before the protein changes or microscopic abnormalities commonly associated with the disease and almost five decades before the age at which they might have developed memory and thinking problems.

Arizona researchers studied tissue from a vulnerable part of the brain in 40 young adults who had died and donated their brains for research. 15 of the brain donors carried a common genetic risk factor for Alzheimer’s disease, known as APOE4, and 25 of the brain donors did not. With the exception of a person with two copies of the APOE4 gene, none of the deceased young adults had the microscopic abnormalities or elevated amyloid protein levels long associated with Alzheimer’s disease. However, the activity of an enzyme known as cytochrome oxidase, an energy-making enzyme found in the power-packs of the brain cells, was slightly reduced in the group at increased genetic risk for Alzheimer’s disease.

A team of researchers from several institutions in the Arizona Alzheimer’s Consortium had previously used a brain imaging technique called PET to detect reduced brain activity in living young adults at genetic risk for Alzheimer’s disease. They had also shown reductions in cytochrome oxidase activity and the expression of energy-making genes in deceased brain donors with Alzheimer’s symptoms. Based on these findings, they had proposed that individuals at genetic risk for Alzheimer’s disease might have alterations in energy utilization, or some other abnormality in the mitochondria (the power packs inside each cell) long before the progressive brain changes associated with Alzheimer’s disease had even started.

“Our findings suggest that mitochondrial brain changes contribute to the risk of Alzheimer’s disease,” said Jon Valla, Assistant Professor of Biochemistry at Midwestern University and the study’s lead author. He conducted the cytochrome oxidase activity analysis at the Barrow Neurological Institute. “While our findings do not suggest ways in which to predict or reduce a person’s risk at this time, they provide a foundation for studies seeking to do just that.”

This study was supported by the State of Arizona, the Barrow Neurological Foundation, and the National Institute on Aging.  The study authors include Eric Reiman and Roy Yaari (Banner Alzheimer’s Institute and University of Arizona), Andrew Wolf and Yael Kusne (Arizona State University and Barrow Neurological Institute), Thomas Beach and Alex Roher (Banner Sun Health Research Institute), Jason Corneveaux and Matthew Huentelman (Translational Genomics Research Institute), and Richard Caselli (Mayo Clinic in Arizona). Brain samples were provided by the National Institute for Childhood Disorders-supported Tissue Bank for Developmental Disorders at the University of Maryland in Baltimore.


Valla J, Yaari R, Wolf AB, Kusne Y, Beach TG, Roher AE, Corneveaux JJ, Huentelman MJ, Caselli RJ, Reiman EM (2010) Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer’s susceptibility gene. Journal of Alzheimer’s Disease 22, 307-313, 2010.

Midwestern University is a graduate degree-granting institution specializing in the health sciences with seven colleges and two campuses. The Illinois campus, located on a 105-acre site in Downers Grove, is home to 2,160 students and three colleges: the Chicago College of Osteopathic Medicine, the Chicago College of Pharmacy, and the College of Health Sciences.  The Arizona campus, located on a 144-acre site in Glendale, is home to 2,464 students and five colleges: the Arizona College of Osteopathic Medicine, the College of Pharmacy-Glendale, the College of Health Sciences, the College of Dental Medicine-Arizona, and the Arizona College of Optometry. The University is accredited by The Higher Learning Commission, a Commission of the North Central Association of Colleges and Schools.

The Journal of Alzheimer's Disease ( is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease and clinical trial outcomes. The Journal of Alzheimer's Disease has an Impact Factor of 3.83 according to Thomson Reuters' Journal Citation Reports 2009 Science Edition. The Journal is published by IOS Press (

Barrow Neurological Institute of St. Joseph's Hospital and Medical Center in Phoenix, Arizona, is internationally recognized as a leader in neurological research and patient care and is consistently voted as among the Top 10 hospitals for neurology in the United States. Barrow treats patients with a wide range of neurological conditions, including brain and spinal tumors, cerebrovascular conditions, and neuromuscular disorders. Barrow's clinicians and researchers are devoted to providing excellent patient care and finding better ways to treat neurological disorders.

Banner Alzheimer’s Institute is an outpatient treatment and research facility dedicated to fight against Alzheimer’s disease. Its three-part mission: to find demonstrably effective treatments to end Alzheimer’s disease without losing a generation, as exemplified by its proposed Alzheimer’s Prevention Initiative; to set a new standard of care that more fully addresses the medical and non-medical needs of patients and families; and to help forge a model of collaboration in biomedical research, as reflected by its role in the Arizona Alzheimer’s Consortium. Banner Alzheimer’s Institute is owned and operated by Phoenix-based Banner Health, one of the nation’s largest nonprofit health care organizations and named in 2010 as one of the Top Ten Hospital Systems by Thomson Reuters.  For more information, visit

Banner Sun Health Research Institute, part of nonprofit Banner Health, has been a leader nationally and internationally for 24 years in the effort to find answers to disorders of aging including Alzheimer’s disease, Parkinson’s disease and arthritis. The institute, together with its Arizona Alzheimer’s Consortium partners, has been designated by the National Institutes of Health as one of just 29 Alzheimer’s Disease Centers in the nation. The institute’s Cleo Roberts Center for Clinical Research takes laboratory discoveries to clinical trials that foster hope for new treatments. Banner Health is Arizona’s leading health care provider and second largest private employer. For more information, visit

Mayo Clinic is a non-profit worldwide leader in medical care, research, and education for people from all walks of life. For more information, visit and

The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the translational process. TGen is affiliated with the Van Andel Research Institute in Grand Rapids, Michigan. For more information, visit:

The University of Arizona is one of the nation's leading public universities, with a long history of academic excellence, research innovation and a student-centered approach. A member of the prestigious Association of American Universities, the UA is ranked 16th among public universities by the National Science Foundation with total research expenditures of more than $600 million. With more than 39,000 students, the UA is on the forefront of discoveries – from the depths of space to the medical and genetic mysteries of life, from emerging trends in climate change to the broad complexities of the human condition.  For more information, visit

Arizona State University is a New American University, a major public educational institution, a premier research center and a leader in innovation. Our vision is described by our three core principles: excellence in scholarship, access to education and impact in our global community. As a New American University, ASU is intellectually vibrant, socially conscious and globally engaged. For more information, visit:

The Arizona Alzheimer’s Consortium (AAC) capitalizes on the complementary resources of its seven member institutions to promote the scientific understanding and early detection of Alzheimer's disease and find effective disease-stopping and prevention therapies. Established in 1998, the Consortium also seeks to educate Arizona’s residents about Alzheimer’s disease, research progress in the state and the resources needed to help patients, families, and professionals manage the disease. The AAC is comprised of both the NIA-funded Arizona Disease Core Center (ADCC) and the state-funded Arizona Alzheimer’s Research Center (AARC).  The AAC's member research institutions include Arizona State University, the Banner Alzheimer’s Institute, the Barrow Neurological Institute, Mayo Clinic Arizona, Sun Health Research Institute, the Translational Genomics Research Institute (TGen) and the University of Arizona.

Media contacts:
Tony Johns
Midwestern University
19555 North 59th Ave, Glendale AZ  85308
Ph: 623-572-3792

Lynne Reaves
Barrow Neurological Institute
350 W. Thomas Rd, Phoenix, AZ  85012
Ph: 502-406-4734

Principal Investigator:
Jon Valla, Ph.D.
Midwestern University
Ph: 623-572-3729