Diagnostic Advancements Could Harbor Real Alzheimer Disease Treatments

The largest generation the nation has ever seen is 60-70 years old now, which means the United States is getting older—faster than it has ever gotten older before.

What the Baby Boomer generation is headed towards in the final decades of their lives is the greatest risk they will have of developing Alzheimer disease, dementia, or any number of cognition-affecting conditions.

And yet, there are few options to help them—at least none that are new. The US Food and Drug Administration (FDA) has not approved an Alzheimer disease therapy since 2003, and investigators are not close to presenting any novel drug right now.

But the key to developing new drugs for the disorder may actually be improved measures in actually diagnosing it at its earliest stages. Since 2010, advances in Alzheimer disease research have focused on pinpointing its characteristics out of a lineup of similar dementia symptoms, giving clinicians a shot to better treat the disease in this upcoming generation of senior citizens.

The key player in such advancements has been a powerful screening tool. Aaron Ritter, MD, director of clinical trials at the Cleveland Clinic’s Lou Ruvo Center, explained in an interview with MD Magazine® that in 2012, improvements were made to amyloid PET scans which has since allowed doctors to detect amyloid plaques in the brain.

It’s completely changed the timeline of disease identification, giving physician an earnest chance to track and combat the disease.

“So, it used to be that Alzheimer’s was purely a post mortem diagnosis, supported by clinical features, but now we can actually visualize amyloid plaque in the brain,” Ritter explained. “It really kind of took hold in probably the last 8 years with the licensing of amyloid.”

Alzheimer disease is an extremely challenging disease to diagnose, largely because it progresses very slowly, and the ability to measure brain activity is challenging. Traditionally, the best diagnostic testing for Alzheimer disease occurs in an autopsy once the patient has died.

When the decade began, most of the clinical trials involved testing medications that clear amyloid in the brain actually worked. But by applying the new amyloid PET scan to this patient population, researchers found only 70% to 80% of the patients in clinical trials that have Alzheimer disease actually have amyloid in their brain.

This could completely alter the process of identifying potential therapies.

There has also been breakthroughs in understanding the role of Alzheimer’s greatest symptom: dementia. Clinicians have uncovered in the last 10 years that it is not as great a tell as they previously thought—about 30% of patients with dementia have a different disease process.

Though the dearth of new drugs in the last 2 decades has made treating the disease in current patients particularly challenging, this decade has seen an increase in ongoing clinical trials which leave the field hopeful for eventual successes.

One of the tools helping investigators make progress is the Alzheimer's disease drug development pipeline, an annual comprehensive summary of all pharmacologic Alzheimer trials currently in development in the US.

As of December 2019, there are 132 agents currently in 156 clinical trials—28 of which are in 42 phase 3 trials; 74 in 83 phase 2 trials; and 30 in 31 phase 1 trials.

Currently in the Alzheimer disease pipeline are 19 agents in trials targeting cognitive enhancement, 14 treating neuropsychiatric and behavioral symptoms, and 96 agents in disease modification trials—of which 38 are focusing on amyloid, as either the primary target or as one of several effects.

Of the amyloid-targeting agents, 18 are small molecules, and 20 are monoclonal antibodies or biological therapies. Also in development are 7 small molecules and 10 biologics that have tau as either the primary target or as a combination target.

Ritter said the pipeline has grown steadily every year, while research funding has actually grown exponentially toward 2020.

Recent data from early stage clinical trials show that a disease-modifying therapy is on the precipice. Even Ritter predicts a drug will available sometime in the 2020s.

“The next decade will hopefully lead to finally these were called disease modifying effects medicines that slower stop the progression of the disease,” he said. “But if we hadn't made the advances in diagnosis, we would still be putting a lot of people in clinical trials who actually don't have Alzheimer's because the diagnosis was not sophisticated enough.”

Arjun Masurkar, MD, PhD, a neurologist and assistant professor in the departments of neurology and neuroscience & psychology at NYU Langone Health, told MD Mag the field has a model to follow in that set by oncologists: “the more trials that are done, the more research articles that are published, it really moves the needle forward towards a cure.”

“We really need to exponentially advance the number of trials that we have, as well as the participation of people out there in the general public, as well as a diverse population, so that we can really move forward with discovering therapy,” Masurkar said.

The greatest difference—and potentially the biggest issue—is average patient’s age. Christine Liu, MD, assistant professor of Medicine at Boston University focusing on geriatrics, explained to MD Mag that, despite some advancements in diagnostics and potential medications, the medical community is ill-prepared to handle the aging population.

“I think we're at the point where we can't handle it already, and we have been for a while, and it is just going to get worse,” Liu said. “What I often see in my own clinical practice is we get folks who were cared for by someone without geriatric background or training, and then they come and see us and we start peeling away things. We start talking about what’s their quality of life, and people are just so grateful.”

A goal-based approach could yield positive results in treating geriatric patients, particularly if some of the endpoint goals include quality-of-life improvements.

Still, some of the factors preventing better geriatric care are money and manpower. She said there are only 4000-5000 geriatricians in the field. Primary care, family practice, and internal medicine physicians are not as valued within their system as they may be in another specialty’s.

Liu added it is difficult for something as large as the US healthcare system to be able to adapt to the changing trends and demographics.

Indeed, the numbers point that growing problem. According to a Massachusetts Institute of Technology review, 16% of the US population is at least 65-years old, with the number expected to increase to 21% by 2035. At that time, senior citizens will outnumber children and adolescents combined.

Without advancements coming next in medicine, it will be difficult to handle that rate of patients. What helps somewhat is knowing the bar is still low for therapies.

“We don't have any good evidence of what will be 100% effective,” Liu said. “The way I think about dementia is we don't have a cure for it—we don't even really have any good treatments for it.”