Alzheimer's Research Moves Ahead with Whole Blood Exchange, Tau Revelations

Alzheimers concept

Many Alzheimer’s clinical trials researchers express optimism that they are entering a new era. An op-ed published in the Journal of Prevention of Alzheimer’s Disease by Dr. Howard Fillit, M.D., and Yuko Hara, Ph.D., with the Alzheimer’s Drug Discovery Foundation, outlined why they think so. 

Although the researchers of the op-ed point out that antibodies against amyloid are still considered an essential approach to treating Alzheimer’s, “the leading risk factor for sporadic AD is aging.” And that both amyloid plaques and tau tangles start accumulating decades before cognitive problems appear. However, researchers are now going broadly toward other factors known to be involved, including inflammation, impaired proteostasis, vascular dysfunction, mitochondrial/metabolic dysfunction, epigenetic dysregulation, and synaptic dysfunction.

“Thus,” they wrote, “a combination of drugs to address many of these defects may be necessary to effectively treat AD. In recent years, an increasing number of drugs targeting these biological processes have emerged in the drug development pipeline for AD.”

 And as of January 2022, there were 143 compounds in clinical trials for the disease, with 119 classified as disease-modifying agents. And more of them target inflammation (23) than amyloid (20) or tau (13).

They also note that the development of biomarkers to identify early diagnosis and help pick patients for trials has improved significantly in the last decade. Prior to 2012, Alzheimer’s could only be accurately diagnosed with a brain autopsy after death. 

In 2012, the U.S. Food and Drug Administration approved florbetapir, a positron emission tomography (PET) ligand, that more accurately diagnoses the disease. And in late 2020, the first blood test for Alzheimer’s, PrecivityAD, became available. There are additional tests as well that are now available.

They conclude that given how complex the disease is, it’s unlikely that a drug for a single aspect of Alzheimer’s (such as Aduhelm) will have enough efficacy to treat AD in “a clinically meaningful manner. However, if incremental benefits are observed with some agents, combination trials should be considered.”

New Research

Routinely, new research into Alzheimer’s is published. Here are two recent studies:

Whole Blood Exchange

Researchers with UT Health Houston theorized that although amyloid plaques in the brain were associated with Alzheimer’s, the components of it were found in the blood. So that by using a form of dialysis to filter the blood, they might be able to slow or halt the development of the disease. They tested this in mice using a series of whole blood exchange treatments to partially replace blood in mice who showed Alzheimer’s disease-causing amyloid precursor proteins. The research was published in Molecular Psychiatry.

“This article provides a proof-of-concept for the utilization of technologies commonly used in medical practice, such as plasmapheresis or blood dialysis, to ‘clean’ blood from Alzheimer’s patients, reducing the buildup of toxic substances in the brain,” Claudio Soto, Ph.D., who led the research. Soto is a professor in the Department of Neurology with McGovern Medical School at UTHealth Houston, said. “This approach has the advantage that the disease can be treated in the circulation instead of in the brain.”

After multiple blood transfusions, the development of cerebral amyloid plaques in the mice was decreased by 40% to 80%. The mice also demonstrated improved spatial memory and lower rates of plaque growth over time.

How Tau Transforms Negatively

While amyloid is involved with Alzheimer’s, another abnormal protein, tau, is also associated with the disease. Broadly speaking, beta-amyloid appears earlier in the condition, while tau tangles appear later. New research published by researchers at Flinders University in the journal Science Advances describes how tau becomes modified, which causes its toxic accumulation in the brain.

“Alongside a small peptide called amyloid-beta, the tau protein is a central factor in Alzheimer’s disease,” Arne Ittner, Ph.D., senior research fellow in neuroscience at the Flinders Health and Medical Research Institute and senior author of the study, said. “Tau is necessary for the toxic effects on brain cells that then result in impaired memory function.”

Although tau was heavily modified during the disease, it wasn’t clear how this happened. Still, the new research solves at least part of the mechanism. They ran a large experiment that evaluated up to 20 different tau changes and 12 enzymes and found that one change in tau makes it easier for another change to occur. They also identified “master sites” in tau that control subsequent changes at most other sites.

 “By modifying these master sites, we were able to drive modification at multiple other spots within tau, leading to a similar state seen in the brains of Alzheimer’s patients,” Ittner said.

One of their findings was that mice with a version of tau that lacked one of the master sites did not develop memory problems compared to mice with the traditional version of tau. The next step is to determine how to apply this to people. The authors also note that this process may be applicable to other tauopathies, such as Parkinson’s disease and concussion-induced chronic brain injury and stroke.

 “Slowing down the changes at master sites of tau in these diseases may put the brakes on tau toxicity and dementia,” Ittner said.

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