Alzheimer's Continues to Frustrate

Scientific American May 2020 pp30-36 “The Future of Medicine A New Era for Alzheimer’s”. “The Way Forward” “Our inability to come up with a good treatment for Alzheimer’s means it is time to reexamine the basic biology of the disease. Progress in five fundamental areas may lead to fresh hope”.

Alzheimer’s Disease is the sixth leading cause of death in American at ~40/100,000 (2017).

After decades of chasing Alzheimer’s Disease (AD) researchers are frustrated at being unable to leverage research to yield tangible improvements in preventing and treating AD. Understanding that AD is a problem of cell biology researchers are now focused on reexamining the underlying cellular and molecular mechanisms of AD by tapping into databases, clinical records, neuropsychologic profiles, brain imaging studies, blood and CSF biomarkers, gene studies, protein profiles, neuron recording and cell culture s systems. It’s a type of "back to basics" approach-sifting through potentially overlooked clues in hope of developing new theories, new models and new ways to combat AD.

Some basic assumptions.

Protein deposits consisting of Beta-Amyloid or Tau in the brain are hallmarks of AD. These deposits lead to loss of function, nerve cell death and a visible loss of brain mass and brain function. So far treatments that reduce these deposits haven't been effective in stopping or reversing the associated cognitive decline.

So, after all this time and effort, what are the most fruitful pursuits for new research?

All cells including nerve cells, or neurons as they are known, have ways to identify and remove proteins that are no-longer functional or useful. Often misfolded or misshapen these non-functional proteins create a foundation on which similar proteins gather and accumulate ultimately taking up space and disrupting normal cell function. AD is characterized by the accumulation of proteins known as Beta Amyloid and Tau. Do the accumulations or plaques result from a failure to recognize the problematic molecules or a failure to "digest" and exude them from the neurons? Are these proteins a cause of AD or a secondary phenomenon like parts strew across the highway after a collision? Why don’t the road crews arrive and remove the debris? This inability to remove plaques, referred to as senile plaques, consisting of clumps or Beta Amyloid or Tau residing within or between neurons is the central question of AD.

Is protein misfolding a primary cause of AD?

What's the role of genetics?

Is AD primarily caused an immune response gone awry?

Does an electrical disconnection between neurons result in AD?

Misfolding and Failure to Remove

There are two primary systems for removing abnormal cellular proteins; one for smaller proteins, like Tau and one for larger proteins, like Amyloid. Complicating matters for neurons is that the removal systems use the same "machinery" required for cell-to-cell signaling-the key function of neurons. Scientists are trying to elucidate the complicated sequence of events from misfolding, to identifying and removing these non-functional proteins. By understanding these "molecular and cellular mechanisms" researchers hope to logically develop therapies that prevent or remove plaques.

Genetic Influence

Familial or “early-onset” AD is rare but unlike non-familial forms some gene defects have been identified. Most AD is diagnosed in our aged population and is associated with gene variants each "carrying" a small but discernable risk for AD. It is thought that each of a dozen genes contribute in a small way to developing AD.

Immune Response

We know that while the immune response can vanquish microbial infections or emerging cancer cells it can also “over-do-it” resulting in autoimmune responses or general inflammation that inflicts damage to normal tissue. Similar to AD, inflammation increases as we age. Researchers are certain the immune-mediated tissue destruction in AD results mostly from non-specific actors of the innate immune system. Is it possible that this damage caused by inflammation prevents removal of misfolded proteins?

Electrical Disconnection

Biological systems tend to balance positive and negative influences not venturing far from homeostasis. Similarly, some neurons primarily stimulate while others primarily inhibit. As it turns out, Tau accumulates only in stimulatory neurons like those associated with deep sleep. As deep sleep declines the cells ability to remove damaging toxins including Amyloid is dimished.

It’s hoped that studying these basic mechanisms and leveraging modern tools and computing will reveal better strategies to combat AD.

See Youtube from The National Institute of Aging for a four minute update.