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Why is it So Hard to Find Drugs That Prevent or Treat Alzheimer’s Disease?

Why is it So Hard to Find Drugs That Prevent or Treat Alzheimer’s Disease?

By Randolph Fillmore

On November 6, 2020 it was a big disappointment when a US Food and Drug Administration (FDA) advisory panel failed to approve aducanumab, Biogen’s candidate drug for treating Alzheimer’s disease (AD). In the end, the FDA’s advisory panel voted 10 to 1 against approving the drug because the evidence of its effectiveness fell short, said the panel majority. https://www.nytimes.com/2020/11/06/health/aducanumab-alzheimers-drug-fda-panel.html

Today, around one in 10 people over age 65 have AD. Between 2000 and 2015 the number of deaths resulting from Alzheimer’s increased by 123 percent. The last time a new medication was approved for Alzheimer’s was 15 years ago. https://elemental.medium.com/why-drugs-for-alzheimers-are-so-hard-to-find-52e8086f7a2a

Of 146 medicines being tested in clinical trials for Alzheimer’s in the period 1998 to 2017, only four new medicines were approved to treat the symptoms of Alzheimer’s disease. In other words, for every successful research project, about 37 failed to yield a new medicine – a 2.7 percent success rate. https://catalyst.phrma.org/new-report-details-the-setbacks-and-challenges-to-alzheimers-research?__hstc=46830328.c4a301e88339df05837e9caf590e78c7.1605441546859.1605441546859.1605449760882.2&__hssc=46830328.1.1605449760882&__hsfp=4248830902

Why is finding an Alzheimer’s disease treatment so difficult?

Alzheimer’s progresses over the course of years, not months, and patients can sometimes have the disease for 20 years before showing symptoms. This makes identifying clinical trial participants challenging. It is also difficult to find clinical trial participants for medicines that can potentially treat Alzheimer’s in its earliest stages because patients are usually not aware they are in the early stages of the disease. Subsequently, many clinical trials enroll healthy volunteers and randomize them to experimental treatment or nontreatment to see who eventually develops AD.

Another problem is that AD is so difficult to diagnose. Among the most common symptoms of the disease is memory loss, but memory loss also occurs with forms of  dementia that are not AD.

Amyloid plaques

Although AD’s biological pathways are not entirely understood, research has clarified much of the biology over the last decade. It has become clear that abnormal fragments of a protein called beta-amyloid accumulate to form “plaques” in the brain of individuals with Alzheimer’s, particularly in brain regions that support memory. Beta-amyloid is formed from the breakdown of a larger protein called “amyloid precursor protein.” One form, beta-amyloid 42, is thought to be especially toxic. With Alzheimer’s, abnormal levels of this naturally occurring protein bind together, collect between neurons, and disrupt cell function. Research currently aims at gaining a better understand this process and determining when and how the various forms of beta-amyloid influence the development Alzheimer’s.

Neurofibrillary tangles and Tau

Neurofibrillary tangles are abnormal accumulations of a protein called tau that collect inside neurons. Tau, one of the hallmarks of Alzheimer’s disease, is a protein contained within the axons of the nerve cells and helps form microtubules — essential structures that transport nutrients within nerve cells.

In a healthy brain, the tau protein helps these microtubules remain straight and strong. But with Alzheimer’s, tau collapses into aggregates called tangles. When this happens, the microtubules can no longer sustain the transport of nutrients and other essential substances in the nerve cells and eventually leads to cell death.

Until recently, scientists did not know why some tau tangles are longer than others or how they grow. New evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.

In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that join tangles inside neurons and hinder communication between neurons.

Inflammation

Research also suggests that chronic inflammation may be caused by the buildup of glial cells normally meant to help keep the brain free of debris. One type of cell, microglia, removes waste and toxins in a healthy brain. In Alzheimer’s, microglia fail to clear away waste, debris, and protein collections, including beta-amyloid plaques. Why this happens is an important question. 

Another complication involves a gene called TREM2, which normally tells the microglia cells to clear beta-amyloid plaques from the brain and in doing so helps fight inflammation in the brain. When TREM2 does not function normally, plaques build up between neurons. Astrocytes—another type of glial cell—are signaled to help clear the buildup of plaques and other cellular debris. These microglia and astrocytes collect around the neurons but fail to perform their debris-clearing function and release chemicals that cause chronic inflammation and further damage the neurons they are meant to protect.

Germs - viruses and bacteria?

Leslie C. Norins, M.D., Ph.D. is convinced that Alzheimer’s is caused by germs https://alzgerm.org/whitepaper/

“From a two-year review of the scientific literature, I believe it’s now clear that just one germ—identity not yet specified, and possibly not yet discovered—is the root cause of most AD,” says Norins. “I’m calling it the ‘Alzheimer’s Germ.’ I purposely use the umbrella term “germ” so as to not exclude any possibility, such as bacterium, virus, fungus, parasite, prion, or something new.”

Norins suggests that too few researchers have been looking in the right places to solve the AD puzzle and only a few of the many classic and newer techniques for germ and immune response detection have so far been brought to bear. For Norins, there has also been too little collaboration between experts in Alzheimer’s research and those investigating infectious diseases. He suggests they work more closely.

Vascular contributions to AD

People with dementia seldom have only Alzheimer’s-related changes in their brains. Any number of problems that affect blood vessels, such as beta-amyloid deposits in brain arteries, atherosclerosis, and mini-strokes – called TIAs – may also be important.

Vascular problems may lead to reduced blood flow and oxygen to the brain, as well as a breakdown of the blood-brain barrier (BBB), which usually protects the brain from harmful agents while allowing in glucose and other necessary factors. In Alzheimer’s, the compromised BBB prevents glucose from reaching the brain, preventing the clearing away of toxic beta-amyloid and tau proteins. This results in inflammation, which adds to vascular problems in the brain. Because it appears that Alzheimer’s is both a cause and consequence of vascular problems in the brain, researchers are seeking new drug interventions to disrupt this complicated and destructive cycle. 

AD and your Zip Code

Recent research suggests a correlation between where you live and your Alzheimer’s disease risk.

Researchers in the field of aging looking at certain geographical locations and common risk factors associated with Alzheimer’s. Data has shown that AD prevalence in the U.S. is more highly concentrated in the Southeast and in the Gulf Coast states, including Florida and Texas, compared with Western states, such as Colorado and Arizona. Granted, age is a risk factor for AD and the southern states have increasingly more seniors.

Geographical location is itself not the main factor; rather, social conditions, such as income, education and access to health care and nutritious food in certain locations, could be determining factors. 

A recent report released by UsAgainstAlzheimer’s (https://www.usagainstalzheimers.org/) and the Urban Institute revealed that three groups have the highest prevalence of Alzheimer’s disease, with 13.8% of Blacks, 12.2% of Latinos and 10.3% of whites diagnosed with Alzheimer’s or other dementias. Prevalence among Asian and Pacific Islanders, American Indians and Alaska Natives is less than 10%. 

“Until we find an effective cure, the most we can do and best we can do is to try to change some of the factors that might contribute to the onset of dementia,” said Stipica Mudrazija, a senior research associate at the Urban Institute who worked on the UsAgainstAlzheimer’s report.

In another study released earlier this year, researchers at the University of Wisconsin School of Medicine and Public Health found that, based on autopsies, people who lived in the poorest neighborhoods at the time of their death were about twice as likely to have brain changes typical of Alzheimer’s disease as people who lived in the wealthiest neighborhoods. Researchers used the Neighborhood Atlas, a map developed by the University of Wisconsin that charts neighborhoods by socioeconomic status.

Considering the unknowns about AD, difficulties in recruiting for clinical trials, and the difficulty in setting study endpoints, the outlook for finding a reliable drug to prevent or stop the process of AD is not encouraging.

The Alzheimer’s Association’s 2020 Alzheimer’s Disease Facts and Figuresreport finds nearly nine in 10 primary care physicians (87%) expect to see an increase in people living with dementia during the next five years. Half of those responding say the medical profession is not prepared to meet this demand (https://www.alz.org/news/2020/primary-care-physicians-on-the-front-lines-of-diag

EDITOR'S NOTE: 

November is National Alzheimer's Disease Awareness Month. See our "sidebar" of open and enrolling Alzheimer's clinical trials in Florida, also in the CCM Blog.

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