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Alzheimer’s is a frustratingly complex disease of mixed origins that expresses itself in different ways. At least 70 percent of its variation remains unexplained. In an age when so much about Alzheimer’s disease is still unknown, a depth and range of funded topics is a necessity.  Numerous routes of discovery must be explored.

Scientists recognize that it’s unlikely one magic drug will prevent, postpone, or cure Alzheimer’s. Instead, a combination approach, or “cocktail” of different drugs may be necessary to modify or slow the progression of this complicated disease. That makes it all the more important that scientists explore various pathways and stages of the disease to find feasible drug targets.

Alzheimer’s Disease Research (ADR), a program of the BrightFocus Foundation, is currently funding nearly 100 research projects worldwide, an investment totaling more than $22 million. 

Here’s an overview of some of the Alzheimer’s topics engaging researchers in that program today.

Stopping Alzheimer’s by understanding how it starts

Our understanding of what causes Alzheimer’s disease remains incomplete, but we learn more each day. We know that a major turning point in the disease is when proteins in the brain—including tau and amyloid beta (AB)—go from “normal” to “diseased” and cause neuron death.  These proteins undergo molecular changes and take on altered shapes, causing them to collect into tangles, plaques, and vascular deposits that are toxic to surrounding tissues.

This picture is complicated by the fact that some neurons will develop tau tangles, while others next to them remain healthy, for reasons we don’t understand. Some researchers are pursuing an exhaustive cell-by-cell comparison, to see what makes some neurons more vulnerable or resistant than others.

Two examples here and here.

Regulating immune factors and clearance mechanisms

One unifying theory about Alzheimer’s disease is that it may be triggered, in part, by a breakdown in the brain’s immune system.  Normally our brain has ways of clearing damaged cells and other unwanted particles and disposing them into the cerebrospinal fluid and bloodstream, akin to “taking out the garbage.” But a chronic rise in unwanted debris, including toxic AB and tau proteins, can short-circuit the immune system. 

When cells in the central nervous system, known as microglia, malfunction, they lead to tissue inflammation.  Researchers are looking at what causes the immune response to become unbalanced, and whether there are ways to help the brain’s immune system do a better job of fighting Alzheimer’s.

Two examples here and here.

Looking at blood vessels and inflammation

Most Alzheimer’s disease is “mixed,” meaning that in addition to amyloid plaques and tangles, there are changes in the brain’s blood vessels that interfere with normal circulation. Amyloid can deposit in vessels, and Alzheimer’s-related inflammation can cause immune cells to become “sticky” and adhere to the sides of capillary blood vessel walls, stalling blood flow and depriving neurons of oxygen and vital nutrients. Even a tiny percentage of stalled brain vessels can result in up to a 30 percent reduction in blood flow, contributing to dementia.  One team funded by BrightFocus has developed an innovative, crowd-sourced game called Stall Catchers, allowing members of the public to help researchers shorten the time needed to document stalls.  

Other scientists are looking at the role of the blood-brain barrier (BBB), a protective layer that selectively regulates what passes back and forth between the peripheral bloodstream and the brain, in Alzheimer’s. The BBB’s tight seal may become leaky and compromised, weakening brain metabolism and contributing to cognition loss and dementia. Some researchers are exploring how to temporarily disrupt the intact BBB to deliver drugs at earlier stages of disease

Examples of currently-funded research are here and here.

Preserving the brain network in Alzheimer’s

Neuronal axons form connections known as synapses with other nerve cells, creating an incredible communications network through which our body talks to our brain, and vice versa. Over this network travel simple sensations as well as visual images and information that makes up short and long-term memories. 

Despite the loss of individual neurons in Alzheimer’s, it isn’t until the brain’s entire communications network malfunctions that we experience Alzheimer’s most typical symptoms—things like forgetting common words, or becoming lost in familiar places.  Even then, the brain is amazingly adaptable and “plastic,” meaning it actively remodels itself to meet new demands. If a part of the network becomes too damaged to connect with other neurons by the most direct route, it will form new connections known as indirect neural pathways.

BrightFocus grantees are devising new ways to study how this networks works and preserve its function for as long as possible, even after the onset of Alzheimer’s disease.

Two examples are here and here.

Understanding lifestyle factors and Alzheimer’s

The factors contributing to late-onset forms of Alzheimer’s begin to develop throughout middle age, when conditions such as diabetes, cardiovascular disease, sedentary lifestyle, and declining mental activity may begin to take their toll. Heart disease, lipid disorders, and sleep dysregulation are being investigated as contributing factors to this disease.

Conversely, factors that may have likely benefits on disease onset or severity are exercise and diet, focusing on lipid and cholesterol lowering; and cardiovascular health. (The old cliché proves true: what’s good for the heart is good for the brain.) Even gut bacteria (microbiome) may have positive benefits.

Two examples here and here.

Pioneering ways to look at the brain

Scientists suspect that Alzheimer’s changes happen slowly, a few decades before symptoms show. Researchers are pursuing advances in imaging that would permit earlier detection as well as a better understanding of changes over time.

Solving Alzheimer’s requires knowing as much as possible about how the brain’s tissue and circuitry are ravaged by the disease. Thanks to advanced imaging techniques being developed or tested by our grantees, the Alzheimer’s brain no longer has to be visualized “in theory,” or through postmortem examination, but can be observed in real time through live imaging.

Our grantees are adapting these techniques and creating new tools to support earlier diagnoses, before symptoms occur, and to help doctors track and better-detect changes in AB and tau, brain circuitry (i.e., synapse loss), depression, and other signs of Alzheimer’s progression. They are building new tools to monitor drugs and combination therapies on the horizon. Ultimately, we hope the imaging techniques studied today will help us monitor brain health tomorrow, and track the progress of cures.

Two examples here and here.

Drug discovery and new treatment approaches

In the search for feasible drug targets, we are funding new projects, like looking at ways to control genetic risk factors for late onset Alzheimer’s; to intervene with AB-induced damage to nutrient transport in and out of cells; and to manipulate an enzyme regulating AB production. On the protective side, our researchers are hoping to harness the body’s built-in protections that might assist with rescuing memory and stimulating the brain’s ability to remove toxic proteins.

As noted earlier, experts do expect that someday there will be a “cocktail” of drugs—a combination therapy—that will modify and slow the disease’s course. Scientists are using high-tech methods to find molecules capable of stopping or slowing Alzheimer’s disease changes, and these discoveries will be used to develop new drugs. Additionally, the search continues for opportunities to use already-approved drugs in novel ways to stop Alzheimer’s (drug repurposing).

Three examples are here and here and here

Conclusion

Alzheimer’s has long been one of the most vexing challenges for scientists, and for the families affected by the disease. However, there is promising research underway across a wide range of scientific approaches, and great hope for a future in which we will be able to slow, treat, and eventually cure this disease.

For more information, visit www.BrightFocus.org

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