Boosting brain protein may slow cognitive decline

• A main theory behind the cause of Alzheimer’s disease is the build-up of the protein amyloid-beta in the brain.
• Researchers from the University of Cincinnati provide evidence suggesting it’s the lessening of amyloid-beta in the brain that is behind cognitive decline.
• Scientists believe that boosting brain protein amounts may offer cognitive benefits.

Now, researchers from the University of Cincinnati provide evidence suggesting it’s the lessening of amyloid-beta in the brain that is behind cognitive decline and boosting brain protein amounts may offer cognitive benefits.

“We observed that most of those in the population with amyloid plaques do not develop Alzheimer’s,” Alberto Espay, MD, professor of neurology in the UC College of Medicine and director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute at the University of Cincinnati, and lead author of this study explained to Medical News Today.

“By the age of 85 years, only one fifth of those with amyloid plaques develop Alzheimer’s disease. We discovered that what keeps people with amyloid plaques cognitively normal is (not) the level of the plaques in the brain but the extent to which individuals are able to produce enough Aβ42, an important protein for brain health, to keep those levels within a normal range,” he said.

The study was recently published in the journal Brain.

For this study, researchers analyzed data from about 26,000 people enrolled in 24 randomized clinical trials for new monoclonal antibody treatments that have been approved for treating Alzheimer’s disease.

Espay and his team decided to focus on these new treatments as they noticed they were unintentionally increasing levels of Aβ42 in the brain.

“Aβ42 is a protein that reacts to a variety of toxic and infectious exposures, in the process of defending the brain,” Espay explained. “In that process, Aβ42 transforms into amyloid plaques and ceases to function. The plaques can be viewed as the tombstones of Aβ42.”

“I wanted to find out if any cognitive benefits could be explained by the increases in Aβ42 as much as by the decreases in amyloid plaques,” he continued. “The data was ready to be harvested from the supplementary material of all the monoclonal antibody trial reports.”

After analyzing the study data, researchers discovered that higher levels of Aβ42 after monoclonal antibody treatment were independently associated with slower cognitive impairment and clinical decline.

“I was not surprised by this finding since prior studies from our group have shown that cerebrospinal fluid Aβ42 levels above a certain threshold of compensation are associated with normal cognition no matter how high the levels of amyloid plaques are,” Espay said. “Even in those with genetic forms of Alzheimer’s disease, higher baseline Aβ42 levels predict a lower progression to dementia.”

“Alzheimer’s is a process of loss (of Aβ42) not of gain (of amyloid),” he continued. “The brain does not swell but continues to undergo atrophy no matter how many plaques it has. Future medications should aim at increasing Aβ42 directly, not indirectly such as what these antibodies do. We are evaluating therapies that have the potential to increase Aβ42 as a form of rescue therapies.”

After reviewing this study, David Merrill, MD, PhD, a board certified geriatric psychiatrist at Providence Saint John’s Health Center in Santa Monica, CA, and Singleton Endowed Chair in Integrative Brain Health, told MNT it seems as reasonable as anything that an increase in Aβ42 explains the marginal benefit of the new drugs.

“Perhaps more important is to start looking above and beyond amyloid for causes of Alzheimer’s disease,” Merrill continued. “The processing of amyloid precursor protein into both soluble and non-soluble fragments of amyloid depends on many modifiable health factors.”

“Thanks to the work of hundreds of research groups cited by the Lancet Commission on Alzheimer’s disease, including our own showing that exercise slows brain atrophy, we now know that at least 14 modifiable factors contribute to causing at least 45% of all cases,” he continued. “Adopting healthful habits and addressing modifiable risk factors may also lower plaque loads in the brain while increasing soluble Aβ42 while improving cognitive function over time.”

For the next steps in this research, Merrill said it would be great to see more support of research elucidating the mechanisms of modifiable risks known to decrease dementia risk.

“Does soluble Aβ42 increase with treatment of hearing and vision loss?” he detailed. “With treatment of diabetes and hypertension? What non drug approaches could give the same benefits without risking brain bleeding and swelling as seen with the new drugs?”

MNT also spoke with Karen D. Sullivan, PhD, ABPP, a board-certified neuropsychologist, owner of I CARE FOR YOUR BRAIN, and Reid Healthcare Transformation Fellow at FirstHealth of the Carolinas in Pinehurst, NC, about this study.

“Their findings are a sea-change from the currently accepted theory that Alzheimer’s disease is caused by an accumulation of amyloid-beta plaques,” Sullivan said. “The authors are asking us to consider that the complete opposite of this prevailing belief may be true in that increased levels of amyloid-beta results in less cognitive decline.”

“To consider that an increase in amyloid-beta plaques levels as an unintended effect of the new anti-monoclonal antibody class of drugs may actually be part of the helpful mechanism of action will be a shock to most in the neuroscience community,” she continued. “It will be interesting to see the response of the Alzheimer’s community to this study. It has the potential to spark some very heated discussions.”