Identifying Missing Links - and Why Certain Drugs Don’t Work - in Alzhiemer’s

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A team at the University of California, San Diego developed a drug screening method to help determine why Alzheimer’s drugs fail. The system analyzes disease mechanisms in human neurons.

Before the U.S. Food and Drug Administration’s controversial approval of Biogen’s Aduhelm (aducanumab) for Alzheimer’s disease in June 2021, there were well over 200 failed clinical trials in the last twenty years for drugs to treat the disease. Part of the drug’s controversy is the alleged negligible improvement in Alzheimer’s symptoms. At the highest doses, which can be risky, Aduhelm appears to slow the progression of the disease in patients if caught early enough.

Aducanumab is an antibody that clears beta-amyloid in the brain, one of two proteins that accumulate abnormally in the disease. Although beta-amyloid is associated with the disease, it’s not the only factor, and researchers are making progress on understanding Alzheimer’s better and taking new approaches. Here’s a look.

Screening Approach to Why Alzheimer’s Drugs Fail

A team at the University of California, San Diego developed a drug screening method to help determine why Alzheimer’s drugs fail. The system analyzes disease mechanisms in human neurons. They published their research in Alzheimer’s & Dementia. The researchers note that sometimes drugs that clear amyloid don’t improve the disease but make it worse. With that as the focus, their drug screening method evaluates what endotypes, or disease mechanisms, are modified in the patient’s neurons from the treatment. They note that although amyloid plaque formation is one endotype, others should be targeted, including differentiation of neurons to an early “non-neuron” state, neuronal gene suppression and loss of synaptic connection.

“The key here is that we are using the endotypes that we discovered to see how current drugs fail,” senior author Shankar Subramaniam, Ph.D., said. “When drugs interact with human neurons, what endotypes do the drugs fix and what endotypes do they not fix in the process?”

Their technique requires taking human-induced pluripotent stem cells derived from patients with familial Alzheimer’s disease and transforming them into neurons. They then treat these cells with drugs and leverage genetic sequencing to determine what endotypes change pre-and post-treatment. They also do the same on neurons derived from healthy people.

In a test of two experimental Alzheimer’s drugs targeting amyloid, the researchers found the drugs only improved some endotypes, such as the formation of amyloid plaques, partly fixing some, while not fixing others.

“What we are seeing is that fixing amyloid plaque formation does not reverse the disease in any way,” Subramaniam said. “It turns out that this endotype is way downstream, so it is too late. Once neurons de-differentiate into non-neurons, they lose their synaptic connections, which leads to loss of memory and cognition and as a consequence, dementia.”

Targeting Alzheimer’s Earlier in the Process

Although amyloid and a second protein, tau, are linked to Alzheimer’s, with amyloid generally occurring earlier and tau later in the disease, some researchers are focused earlier. Qin Wang, MD, Ph.D., with the new Alzheimer’s Therapeutics Discovery program at the Medical College of Georgia, described amyloid and tau as like a gun in the brain: beta amyloid is the trigger and tau is the bullet. Wang is looking at why and how they interact.

“There’s a missing link there,” Wang stated.

Earlier in Alzheimer’s, a group of neurons in a part of the brain called the locus coeruleus seem to die first. Those nerves interact with norepinephrine, a neurotransmitter. Norepinephrine is involved in various processes, including fight or flight, arousal, attention and memory. They have connections throughout the brain and, Wang said, seem to be “hypersensitive” to amyloid beta and tau.

These cells have a special receptor that can both release, and are involved in receiving norepinephrine. Once turned on, the receptor controls the protein that creates beta amyloid. But once beta amyloid is formed, it can attach to the same receptor in a different location and begin creating more beta amyloid in what Wang describes as a vicious cycle.

“This is very important for the initial seeding of the (deposits) in the brain,” Wang said.

Wang noted that drugs that target amyloid remove about 60% at best, which isn’t nearly enough. Very little beta amyloid is needed to feed the cycle, with even 1% “still sufficiently activates this detrimental pathway.”

So Wang and her team are evaluating drugs that can prevent that cycle. Two are already on the market. One of them is an approved antidepressant, Idazoxan. Another is a blood pressure medication called clonidine that also activates the particular receptor in the brain.

“Hopefully in humans, if we can block those receptors, we will see the oppositive effect,” Wang said. “We can see an improvement in their cognitive function.”

NeuroNascent’s Neuron Regeneration Drug

NeuroNascent reported data from a Phase I trial of NNI-362 in Alzheimer’s disease. The drug demonstrated favorable safety and a significant decrease in a biomarker for Alzheimer’s disease. The drug appears to produce new neurons to replace lost neurons or improve their numbers in aging patients or neurodegenerative diseases, such as Alzheimer’s.

The drug is taken orally and data showed it to be well tolerated in healthy aged people after single and multiple daily dosing. Using a new test to detective Alzheimer’s biomarkers in blood plasma, the drug also significantly decreased p-tau181 levels compared to pre-treatment levels.

“This exciting early data, demonstrating our novel allosteric oral therapy, NNI-362, can normalize the plasma p-tau181 — a biomarker correlated with Alzheimer’s disease brain pathology and progression, supporting the need to further test NNI-362 in long-term trials,” Judith Kelleher-Andersson, Ph.D., founder and chief executive officer of Neuronascent, said. “Running of a Phase II trial in mild to moderate Alzheimer’s disease patients could assess longer-term amelioration of p-tau181 levels and to determine if this intervention could consequently improve quality of life for patient and caregiver.”