Alzheimer’s Disease: The Cholinergic Revival

Before the advent of the amyloid hypothesis in the 1990s, the cholinergic hypothesis offered key clues to the etiology of Alzheimer’s disease.

Concentrated in the basal forebrain and projecting extensively across the cerebral cortex and hippocampus, cholinergic neurons release the neurotransmitter acetylcholine and are critical to learning, information processing, and memory. Researchers in the 1970s and 80s discovered that a precipitous loss of these neurons occurred early in the disease course and was closely linked to cognitive decline.

These and other observations led to the development of cholinesterase inhibitors like donepezil and rivastigmine, which boost acetylcholine and for decades have served as the mainstay of Alzheimer’s disease treatment. Widely prescribed and moderately helpful in improving cognition, the drugs are not thought to slow the underlying neurodegenerative process, as is the hope for newer Alzheimer’s treatments that clear the brain of amyloid proteins. Because acetylcholine affects a range of bodily functions, cholinesterase inhibitors are also associated with a host of gastrointestinal (GI) and cardiovascular side effects, limiting their dosing.

Cholinergic neuron loss is now seen more as an effect of Alzheimer’s disease than a driver. But a handful of scientists who study cholinergic pathways never stopped aiming for drugs with more potent treatment effects and fewer side effects that could lessen behavioral and cognitive symptoms in Alzheimer’s disease and other central nervous system disorders. After being shelved for the better part of a generation, some of these agents are finally advancing through the pipeline.

A cholinergic agonist first developed in the 1990s for Alzheimer’s disease, xanomeline, was approved last year in combination with trospium chloride, a side-effect blocker, for the treatment of schizophrenia, offering a long-needed alternative to dopamine-targeting antipsychotics.

The combination, marketed as Cobenfy by Bristol Myers Squibb, is now being tested in patients with Alzheimer’s disease with psychosis. An experimental agent called VU 319, developed to improve cognition in both Alzheimer’s disease and schizophrenia, completed a successful phase 1 trial in 2024 and is being developed further by its license holder.

Paul Newhouse, MD, director of the Center for Cognitive Medicine in the Department of Psychiatry at Vanderbilt University Medical Center in Nashville, Tennessee, who designed and ran the phase 1 trial of VU 319, explained that the agent — part of a class of drugs called M1 muscarinic acetylcholine receptor positive allosteric modulators (M1 PAMs) — are more selective than any of the available cholinergic drugs, including xanomeline. “With the M1 PAMs, you’re not flooding the synapse with all of this acetylcholine but just making the existing acetylcholine work more effectively,” he said, resulting in a better therapeutic index and fewer side effects.

The cholinergic system has experienced a resurgence of interest in recent years, Newhouse said, “because we finally have better tools to study it with. Some of my work is investigating how cholinergic circuits in the brain change with these diseases. We’ve developed new PET tracers that can image the cholinergic projections in the human cortex.”

Newhouse said he views the M1 agents primarily as symptomatic, rather than disease-modifying, treatments. But there is some evidence to suggest that more effective stimulation of the cholinergic system might also stem neurodegeneration.

M1 agonists have been shown to modulate pathogenic amyloid processing in a transgenic mouse model of Alzheimer’s disease. Recently, an experimental M1 PAM similar to VU 319 was seen to slow neurodegeneration in mice with prion disease, and also reduce amyloid plaques and microgliosis — a reaction of brain immune cells — in mice with Alzheimer’s pathology.

“I’m excited about the reemergence of this pharmacology,” said Allan Levey, MD, PhD, a professor at Emory University in Atlanta, who like Newhouse has spent much of his career studying the cholinergic system.

Levey explained that while drug companies have long understood the promise of M1 receptors, “the tools were lagging” to synthesize agents that could target them selectively enough. The limitations of the cholinesterase inhibitors — modest clinical benefits combined with heavy side effects — also dampened enthusiasm. As the amyloid hypothesis of Alzheimer’s gained steam in the 1990s and 2000s, interest shifted to therapies that could demonstrate anti-amyloid activity. Yet these, too, have proven modest in their effects and with serious side effects that include brain swelling and bleeding.

In the 1990s, Levey helped conduct a randomized clinical trial of xanomeline in patients with Alzheimer’s disease. “What always stood out to me and my research coordinator was that there were patients and their families who cried when we told them they had to had to stop the drug. They felt like they were doing great. It’s an anecdote, obviously, but having done clinical trials my entire career, you don’t see that very often.” Besides the effects on cognition and functional abilities, xanomeline was associated with marked improvements in delusions, agitation, and disturbing behavior — findings that later led to its being developed as an antipsychotic.

A small incidence of syncope and difficulty tolerating GI side effects in that trial contributed to the company’s decision to not to take the drug further for Alzheimer’s disease. But in retrospect, Levey said, these effects seem a lesser threat than the brain edema and hemorrhaging associated with the approved anti-amyloid drugs.

Symptomatic Improvement vs Disease Modification

Both Newhouse and Levey said that even if the benefits of new cholinergic drugs result only in symptomatic improvements, it’s still a major step forward. The distinction between disease-modifying and symptomatic treatment may be a largely academic one for patients and their families.

“Symptomatic is critically important,” Newhouse said. “Symptoms are why people see the doctor. My mother had Parkinson’s disease, and she got tremendous symptomatic benefit from her drugs. She still died of Parkinson’s disease, but she had a decade of better functioning because of her symptomatic medications.”

Newhouse said he predicts that for now, both cholinergic drugs and anti-amyloid antibodies will continue to be used in Alzheimer’s disease. “Because we have to have something. We know that monoclonal antibodies don’t really help people who are in the moderate stage of disease. Cholinesterase inhibitors still have benefits even in those patients. Their effect is modest. But that’s because they have a narrow therapeutic index.” A cleaner cholinergic agent would be a game changer, he said.

A safe cholinergic agent that can help alleviate behavioral symptoms would be nothing short of a breakthrough, Levey said. Standard second-generation antipsychotics, used widely to control psychosis in people with Alzheimer’s disease, are modestly effective, cause sedation and falls, and come with black box warnings for dementia patients.

“That means that every time you prescribe one, you have to have a discussion with the family, saying the behavior is so bad, we’re going to have to try this because we don’t have other options,” he said. “But there’s a chance that it will kill the patient.”

With any neurologic or neurodegenerative disease, Levey said, symptoms don’t restrict themselves to specific domains. “The brain doesn’t work that way. Most patients with these diseases have psychiatric and cognitive and motor and other symptoms. Having a safe class of drugs that can address behavior and can be used across a range of disorders is really crucial.”

Levey served on the scientific advisory board of Karuna Therapeutics, which developed xanomeline/trospium chloride before being bought by Bristol Myers Squibb. Newhouse reported no relationships with commercial entities.

Jennie Smith is a freelance science writer.