Neuroscientists Pinpoint Midlife Crisis In Brain Circuitry As Key To Brain Aging And Onset Of Alzheimer's Later In Life

Detailed in the January edition of the peer-reviewed journal Neurobiology of Aging, the model presents opportunities to explore how lifestyle changes, hormone replacement therapy, higher education or treatment with common medications in middle age might help brains remain healthy longer.

"This model embraces the human brain as a high-speed Internet rather than a computer. The quality of the Internet's connections is the key to its speed, fidelity and overall capability," said Dr. George Bartzokis, the author and visiting professor of neurology at UCLA's David Geffen School of Medicine. He also is director of the UCLA Memory Disorders and Alzheimer's Disease Clinic and Clinical Core director of the UCLA Alzheimer's Disease Research Center.

"Close analysis of brain tissue and MRIs clearly shows that the brain's wiring develops until middle age and then begins to decline as the breakdown of myelin triggers a destructive domino affect. Our time at the peak is short indeed," Bartzokis said. "The challenge for science and medicine is to figure out how to extend the brain's peak performance so that our minds function as long as our bodies."

The journal also published six commentaries on the model written by investigators from around the world, as well as a response by Bartzokis. The response expands on his findings to discuss the role myelin plays in overall brain function as well as its dysfunction in many other neuropsychiatric disorders that occur over the human lifespan.

Myelin is a sheet of lipid, or fat, with very high cholesterol content — the highest of any brain tissue. The high cholesterol content allows myelin to wrap tightly around axons, speeding messages through the brain by insulating these neural "wire" connections.

As the brain continues to develop in adulthood and as myelin is produced in greater and greater quantities, cholesterol levels in the brain grow and eventually promote the production of a toxic protein that attacks the brain. The protein attacks myelin, disrupts message transfer through the axons and eventually leads to the brain/mind-destroying plaques and tangles visible years later in the cortex of Alzheimer's patients.

Bartzokis' analysis of magnetic resonance images and post-mortem tissue data suggests that genetic factors coupled with the brain's own developmental process of increasing cholesterol and iron levels in middle age help degrade the myelin. The papers describe how complex connections that take the longest to develop and allow humans to think at their highest level are among the first to deteriorate as the brain's myelin breaks down in reverse order of development.

"The body was designed to myelinate through the natural lifespan. Medical advances, however, have expanded the lifespan well beyond the brain's natural capacity to operate in a healthy, efficient manner," Bartzokis said. "The process of adult brain development and becoming 'wiser' has this downside that evolution could not anticipate."

This new model of brain development and degeneration suggests that the best time to address the inevitability of myelin breakdown is when it begins, in middle age. By the time the effects of Alzheimer's disease become apparent in a patient's 60s, 70s or 80s, it may be too late to reverse the course of the disease.

Preventive therapies worth investigating include cholesterol- and iron-lowering medications, anti-inflammatory medications, diet and exercise programs and possibly hormone replacement therapy designed to prevent menopause rather than simply ease the symptoms. In addition, education or other activities designed to keep the mind active may stimulate the production of myelin. Finally, there may be ways to address genetic and environmental factors that accelerate the degeneration process.

Commentaries accompanying the paper were written by Drs. Francine M. Benes, Harvard Medical School; Heiko Braak and Kelly Del Tredici, Frankfurt/Main, Germany; James R. Connor, Penn State University College of Medicine, M.S. Hershey Medical Center; Terry L. Jernigan, University of California, San Diego; Mark Noble, University of Rochester Medical Center; and Gregory T. Whitman, and Carl W. Cotman, University of California, Irvine.

The UCLA Department of Neurology encompasses 260 teachers, researchers and clinicians, and 245 staff personnel involved in more than a dozen research, clinical and teaching programs. These programs cover brain mapping and neuroimaging, movement disorders, Alzheimer's disease, multiple sclerosis, neurogenetics, nerve and muscle disorders, epilepsy, neuro-oncology, neurotology, neuropsychology, headaches and migraines, neurorehabilitation, and neurovascular disorders. The department ranks No. 1 among its peers nationwide in National Institutes of Health funding, with $23.4 million in active research grants.

The Alzheimer Disease Research Center (ADRC) at UCLA, directed by Dr. Jeffrey L. Cummings, was established in 1991 by a grant from the National Institute on Aging. Together with grants from the Alzheimer's Disease Research Center of California and the Sidell-Kagam Foundation, the center provides a mechanism for integrating, coordinating and supporting new and ongoing research by established investigators in Alzheimer's disease and aging. The Memory Disorders and Alzheimer's Disease Clinic of the ADRC is an evaluation clinic for individuals over the age of 45 who are experiencing mild but gradually progressing cognitive or memory declines that are not related to other brain diseases such as strokes, tumors, infection, metabolic abnormalities, psychiatric disease or trauma.