Origin of Alzheimer’s Could Differ from Accepted Theories

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Origin of Alzheimer’s Could Differ from Accepted Theories

Recent discussions of Alzheimer’s disease have centered around the controversial Biogen drug Aduhelm (aducanumab) and how its uptake has been much slower than expected. Sales have been disappointing, bringing in only $300,000 in the third quarter. The Health and Human Services (HHS) Inspector General’s Office is investigating the approval process. The price tag of $56,000 per patient per year threatens to bankrupt Medicare if it were more widely adopted.

However, several new studies have pointed to promising new approaches to treating and preventing Alzheimer’s disease and a deeper understanding of how the disease progresses.

No Single Point of Spread

Researchers with the University of Cambridge in the U.K. leveraged human data for the first time to quantify the speed of various processes in the brain that lead to Alzheimer’s disease. And to their surprise, it developed differently than expected. The original theory was that changes began from a single point in the brain, which sparked a chain reaction that led to brain cell death. Their research indicated that was not the case.

Using post-mortem brain samples from Alzheimer’s patients and PET scans from living patients, the research team tracked tau’s aggregation, one of the two abnormal proteins associated with Alzheimer’s. The other is amyloid beta. These proteins cause brain cells to die and the brain to shrink, leading to memory loss, changes in personality, and difficulty in cognition. They published their research in Science Advances.

“Tau isn’t the primary cause of Alzheimer’s, but it is thought to be the most closely correlated with the cascade of changes associated with the disease, including cognition,” Rebecca M. Edelmayer, Ph.D., senior director of scientific engagement at the Alzheimer’s Association, told Medical News Today.

“The thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Georg Meisl, Ph.D., from Cambridge’s Yusuf Hamied Department of Chemistry and first author of the paper. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”

The key discovery, said co-senior author Tuomas Knowles, Ph.D., also with the University of Cambridge’s Department of Chemistry, “is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied. This research shows the value of working with human data instead of imperfect animal models. It’s exciting to see the progress in this field—fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”

Why Some People Have Alzheimer’s “Brains” but No Dementia

Another research study, this one out of the Massachusetts Institute of Technology (MIT), delved into why some people’s brains show underlying signs of neurodegeneration, but they do not have cognitive issues. At one level, they found that education level and amount of time spent on intellectually stimulating activities can help prevent dementia.

The research identified a link between a gene family called MEF2 and what they are calling cognitive resilience. MEF2 controls a genetic pathway in the brain that seems to promote resistance to cognitive decline. They hope that enhancing MEF2 activity or its targets may be possible to protect against age-related dementia.

“It’s increasingly understood that there are resilience factors that can protect the function of the brain,” said Li-Huei Tsai, Ph.D., director of MIT’s Picower Institute for Learning and Memory. “Understanding this resilience mechanism could be helpful when we think about therapeutic interventions or prevention of cognitive decline and neurodegeneration-associated dementia.”

The study, published in Science Translational Medicine, began by determining how various environmental factors, such as education, employment type, languages spoken, and time spent on things like reading and crossword puzzles, affected the brain and led to higher cognitive resilience. They tested this in people and mouse models, and both led to MEF2 playing a critical role in resilience.

Source: BioSpace

Two Older Drugs Might Improve Cognition

Investigators at Rush University Medical Center in Chicago have been looking at how astrocytes, a star-shaped type of immune cell in the brain, may be the cause of the accumulation of amyloid beta, one of the two abnormal proteins that are associated with Alzheimer’s disease. Early studies in laboratory animals suggest that two older, already approved drugs—gemfibrozil (Lopid), used to lower cholesterol, and retinoic acid, a vitamin A derivative—seems to fend off the brain damage caused by Alzheimer’s disease.

Both drugs appear to target astrocytes and, when used in combination, result in astrocytes reversing the damage to the brain and decreasing amyloid beta, which causes improved cognitive function.

“From a therapeutic angle, these results suggest that low-dose [gemfibrozil and retinoic acid] might be repurposed as a treatment for reducing the plaque burden and improving cognition,” wrote Sumita Raha, Ph.D., first author of the study, which was published in Science Translational Medicine.

Earlier work by the same team found that the drug combination sped up the formation of lysosomes in mouse brain cells. Lysosomes are organelles in the membranes of cells that degrade and recycle cellular waste and are also involved in cellular signaling and energy metabolism. The new work found that the drug combo caused mouse astrocytes to activate PPAR alpha, which stimulated astrocytes to destroy beta amyloid. PPAR alpha regulates genes involved in fatty acid oxidation and also regulates energy balance. It is important in the elimination of amyloid beta.

Although down the road, the research team is working toward clinical trials of the drug combination.

BioSpace source:

https://www.biospace.com/article/alzheimer-s-studies-show-new-insights-and-possible-new-approaches