Contribute Try STAT+ Today

It’s neuroscience’s oldest and most acrimonious debate. On one side, scientists who aver that blasting away toxic plaques called amyloid is the best path toward treating Alzheimer’s disease. On the other, frustrated skeptics ready to ditch the amyloid hypothesis once and for all.

But a parade of failed clinical trials has seeded a growing middle ground of agnostics and stoked a bevy of new research efforts, as “the field in general — and our pharma colleagues — are recognizing that they need to think beyond amyloid,” said Dr. David Knopman, a neurologist at the Mayo Clinic.

Here’s a look at some of the most interesting ideas from the beyond.


What about the immune system?

The memory-destroying effects of Alzheimer’s unassailably take place in the brain, but mounting research suggests that the body’s natural defenses, hardly infallible, are unwittingly contributing to the problem. Now scientists are on the hunt for ways to tinker with the immune system before it can mistakenly damage the brain.

The key lies in cells called microglia, which are the immune system’s foot soldiers in the central nervous system, tasked with clearing out infectious invaders and unnecessary cells. When microglia go astray, it leads to tissue inflammation, a reaction that could be driving the progression of Alzheimer’s.


“There’s clearly an inflammatory change” in patients with the disease, said George Perry, neuroscience professor at University of Texas at San Antonio and editor of the Journal of Alzheimer’s Disease. “Inflammation is critical to aging and plays an underlying role in the whole process.”

The outstanding question is just how to attack it. Two companies — Annexon Biosciences and Alector — are going after a protein called C1q, which acts like the flapping red cape to microglia’s on-charging bull. Synapses marked with C1q get attacked by immune cells, leading to the memory loss and brain atrophy at the heart of Alzheimer’s. In animal studies, blocking the protein directly spared healthy synapses, a result Annexon and Alector are hoping to replicate in humans.

NeuroTherapia, a startup spun out of the Cleveland Clinic, is targeting cannabinoid receptors in the brain with the same goal. The company’s drug, called NTRX-07, is meant to calm overactive microglia, and NeuroTherapia is angling to advance it into human trials in the next 12 months.

Alison Goate, a professor of neuroscience at Mount Sinai, is looking one step upstream, isolating the genes that pull the strings in microglial action. One, called TREM2, looks like it helps protect brain tissues from errant microglia; another, PU.1, seems to have the opposite effect when it’s overactive.

“Where we’re focusing our efforts right now is to try and figure out how these Alzheimer’s disease risk genes are all related to one another at a network level within a cell,” Goate said. “The question is: At which points within that network are there good druggable targets?”

It’s early days yet, but a drug that could stimulate TREM2 or tamp down PU.1 — or both — could be key in fighting neuroinflammation, she said.

Can epigenetics help?

Epigenetics is the fairly new and oddly controversial study of the many proteins and processes that regulate how genes express themselves, a sort of biological deep state that may play a role in a host of bodily functions. The untimely death of brain tissue is among them, and thus epigenetics has become a fertile field for Alzheimer’s research.

One promising target is an enzyme called HDAC2, which plays a role in regulating the genes that encode for production of new synapses. Too much HDAC2 stifles the brain’s ability to repair itself, and blocking the enzyme directly showed promise in improving mental function in animal studies, researchers at the Massachusetts of Institute of Technology found.

Rodin Therapeutics, a Cambridge, Mass., startup, is working to find safe HDAC2 inhibitors that can slip past the blood-brain barrier and replicate the effects seen in mice. Li-Huei Tsai, whose MIT lab published pioneering work on HDAC2’s relationship to Alzheimer’s, is taking a different tack. In preclinical research published this month, Tsai’s team targeted a protein called Sp3, which binds to HDAC2 in the brain, leading to deleterious gene suppression. With Sp3 knocked down, HDAC2 can find no quarter, leading to a synaptic renaissance in mouse brains.

“It shows that if we can reduce HDAC2 expression in Alzheimer’s disease models, we can reactivate the genes [that] actually rescue learning and memory,” Tsai said.

One company, based in Spain, is already in human trials with an epigenetic treatment. Oryzon Genomics (ORY) is at work on a drug that targets a pair of enzymes called LSD1 and MAOB in an effort to take the brakes off of synapse-bolstering genes. The drug, ORY-2001, proved itself safe in a study on healthy volunteers, the company said, and Oryzon is planning a trial in Alzheimer’s sufferers next year.

“That’s the leading program in the world for epigenetic therapy for Alzheimer’s,” said Dr. Howard Fillit, chief science officer of the Alzheimer’s Drug Discovery Foundation, which has funded Oryzon. “We’re very excited about that effort.”

What about machines?

When drugs fail — as they have time and again in Alzheimer’s — some researchers turn to machinery. And there’s growing evidence that targeted light, emitted by finely tuned devices, can ameliorate the symptoms and, possibly, treat the underlying causes of Alzheimer’s.

At the University of Texas, researchers are using laser light, beamed onto the skull and into the brain, in hopes of improving brain function. Led by neuroscience professor Francisco Gonzalez-Lima, the scientists are using targeted light to stimulate an enzyme that regulates oxygen consumption, hoping to bolster cognitive performance by energizing brain cells.

In a series of studies, the most recent published in April, a once-weekly laser treatment improved reaction time and memory in healthy volunteers. The next step is testing the approach in older patients at risk of developing Alzheimer’s, Gonzalez-Lima said, hoping blasts of laser light can stave off the onset of neurodegeneration.

Tsai’s lab at MIT is taking a different approach. Inspired by the budding field of optogenetics, a team of researchers crafted an LED light show that might bolster cognition.

They started by inserting modified neurons into the brains of mice and using implanted fiber optics to make them fire at frequencies that promote memory and learning. The method worked as planned, but the idea of surgically implanting lights into people’s brains made it a non-starter for human development.

So Tsai’s team set out to replicate the effects with more pedestrian technology, buying LED lights from Amazon and programming them to blink at a particular frequency. And it worked: Testing the light show on mice engineered to express the symptoms of Alzheimer’s, they saw the same benefits observed with fiber optics, Tsai said. A startup called Cognito Therapeutics licensed the technology and is at work on a device that could test the nascent theory on humans.

Whether any of these approaches actually works is far from certain. The history of Alzheimer’s research is littered with verdant ideas that look promising in animals before amounting to nothing in human trials. Mice don’t naturally develop the disease, meaning that the best bet for modeling Alzheimer’s is breeding a creature to express a particular biomarker. And with scientists still debating which, if any, biomarkers actually correlate with Alzheimer’s, it’s a particularly fraught guessing game.

“Basically you’re running completely blind in terms of understanding how this will affect humans until you get to phase 2,” said James Hendrix, head of global science initiatives at the Alzheimer’s Association. “That’s years and millions and millions of dollars of not knowing whether you’re on the right track.”

But researchers are optimistic that something — whether based on inflammation, laser lights, or something else — will eventually make good, creating a springboard for new therapies that might better chip away at the advance of Alzheimer’s.

“We will see a day, I hope, where we see Alzheimer’s is most effectively treated by combination therapies the way other complex diseases are, like HIV/AIDS, tuberculosis, and cancer,” Hendrix said.

  • Hello Damian,

    Anavex has seen positive results in its Phase II clinical trial of Anavex 2-73. Why no mention?

  • My husband had Ceregene 110 implanted in his brain in a clinical trial at Georgetown University Dec. 2009. It worked, (yes!) then after 4 years the amyloid plaques began damaging the new cholenergic neurons grown by the gene therapy. After 6 years the trial closed just short of the required 50 patients. (48 or 49) So they did not gain FDA approval despite promising results. We were so disappointed. Based on our experience it would seem that scheduled periodic treatments (ie every 4 or 5 years) could dramatically change the Alzheimer’s outcome. This would give researchers time to work on engineering the gene to become resistant to the amyloid plaques.
    My husband developed symptoms in his late 40s and was finally diagnosed at age 52 (no family history). We are seeing more and more people diagnosed in their 50s, losing 1 to 2 decades of productive living while this disease steals their life and robs family members of a loved one.
    ANYTHING that can fight this disease would have great and lasting impact as the number of Alzheimer’s patients continues to grow, and in a younger population. This is no longer a disease of people in their 80s or 90s, but more and more often hitting in the ‘prime of life, 40s and 50s.
    Thank you to all of the researchers fighting this awful disease.

  • Dear Niles, before we throw everything at fixing the problem would it wise to first find out why and how it happens. Personally I do not fix anything before I find out what broke it as fixing the cause will stop it from happening again. Once known what started it might give a simpler way of fixing it as well.

  • We need more therapeutic opportunities for Alzheimer’s, with more targets and more compounds in the pipeline, whether or not the amyloid hypothesis is correct. Combination therapies, whether drug/drug or drug/lifestyle or both, are what is most effective against complex disease that are major killers. These (and other) new ideas must be thoroughly investigated.

  • My question is not how amyloid can be stopped from forming or attaching but what makes it attach. If there is no amyloid what is the key that should be or is looked for.

    • A great question with possibly countess answers.
      Amyloid function can active or inactive. Can be genetically inherited to be active by external factors.
      Each human might have a factor that might activate in a specific way or not.
      If it can be induced by certain substances or food consumed acting on protein via calcium channels; then i can not begin to imagine how many other interactions take place on each and every human. Mind the physicians diagnosing & never mind the mice!!!!!!! They have the gene in a different place.

  • We explained in 2006 that A beta and Tau hypotheses were only unspecific consequences not the causes of the disease. The “Tauists” did not reacted positively!!!!!

    Read my posts on linkedIn


  • Although I count myself as an amyloid hypothesis skeptic (I side with the endothelial dysfunction hypothesis), I know the counterarguments very well. Any alternative hypothesis must explain why all of the genetic forms of Alzheimer’s Disease affect either the amyloid precursor protein itself or the enzymes which process APP. Is familial AD a completely separate disease from sporadic AD? Are AD and vascular dementia really two separate diseases, or are they two regions on the same disease spectrum? My own view is that familial AD is a separate disease that strongly resembles sporadic AD because it strikes the same part of the brain, and AD and VAD are the same disease.

Comments are closed.