Future Treatments for Alzheimer’s Disease: Where Are They Headed?

The past year has brought some disappointing results from clinical trials testing new Alzheimer’s drugs. On top of that, a handful of pharmaceutical companies have bowed out of Alzheimer’s drug development altogether.

While that seems scary, things are not as bad as they appear, according to neurologist Serge Gauthier, MD, a clinical trial expert who directs the Alzheimer Disease Research Unit at McGill University’s Research Centre for Studies in Aging in Montreal, Canada. At the 16th Annual Mild Cognitive Impairment Symposium held recently, he  reviewed the latest thinking about Alzheimer’s clinical trials and future treatment directions being explored.

One of the most important lessons research has taught us lately is that the great majority of Alzheimer’s is of mixed origin. In other words, rather than being driven by one cause, Alzheimer’s and related dementias are driven by a host of genetic and environmental risk factors that develop over decades.

The sheer variety of factors contributing to Alzheimer’s has made it difficult to select the right group of people for clinical trials, he said, meaning those most likely to benefit from treatment. While one drug can’t be expected to make a difference in all types, “there has been steady progress in our understanding of the various pathologies underlying Alzheimer’s disease (AD),” Dr. Gauthier said, “and this will be put to good use in the next generation of clinical trials.”

So no more ‘one-size-fits-all’ approach. Gauthier predicted that future drug trials will be more finely tuned and targeted to a defined group of patients in whom they’ll deliver the most promising results.

What’s Next?  Treatments to Slow or Stop Alzheimer’s’ Damage to the Brain

A quarter-century ago, Gauthier was a lead investigator in the trials to bring tacrine (Cognex™) to market, the first cholinesterase inhibitor (CI) approved by the FDA in 1993 for the treatment of Alzheimer’s symptoms.  CI drugs prevent the breakdown of acetylcholine, a chemical produced in the body that serves as a “neurotransmitter,” meaning it spurs communication between brain cells, which is how memories are made, stored, and retrieved.

Tacrine was pulled off the market for safety reasons in 2013. However, newer CIs, including donepezil (Aricept™), galantamine (Razadyne™) and rivastigmine (Exelon™), are widely used in the United States to improve memory and mental functioning in Alzheimer’s-related dementia.

What’s still needed, and what pharmaceutical development for Alzheimer’s has lately focused on, are drugs that slow Alzheimer’s progression. That includes drugs that target the biggest three causative factors of late-onset Alzheimer’s disease (LOAD)—amyloid beta, tau, and inflammation.

“The combination of all three of these leads to a gradual loss of synapses and neurons until symptoms become apparent,” Gautheir said. Currently, he said, the big effort is to design randomized controlled trials (RCTs) for drugs that target amyloid, tau, & inflammation “at the right stage of disease for the right patient.”

To treat someone for Alzheimer’s requires a diagnosis. Here, too, the field is moving ahead to develop biomarkers, which are substances that can be measured in the brain or body and serve as signals for the presence and/or worsening of Alzheimer’s disease (AD). Before too long, a single blood test or lumbar puncture to sample cerebrospinal fluid will yield as much information as expensive PET scans, and be able to accurately measure levels of proteins associated with AD, including amyloid beta (Aβ), tau, and alpha-synuclein, as well as inflammatory markers. Simultaneously, genetic risk factors and an expanding field of other risks that contribute to AD pathology, ranging from head injuries and micro-strokes to Lewy bodies pathology, are being studied. All these tools will make it easier and less expensive to screen for and diagnose AD at earlier stages.

As all of this knowledge converges, known risks and indicators “will guide treatment against each of these pathologies in people who are at a higher risk of progression to mild cognitive impairment (MCI) or dementia because of genetic or other factors,” Gauthier explained. He called the customized approach a type of “personalized medicine” that has been widely touted as a future trend in fighting disease.

As we head towards that goal, Gauthier believes we will learn much from the Dominantly Inherited Alzheimer’s Disease Network Trial Unit (DIAN-TU) studies funded by the National Institutes of Health. Because DIAN-TU enrolls people with inherited forms of AD, the hope is it will reduce “noise,” or multiple confounding factors that contribute to LOAD and in the past might have muddied clinical trial results. This will help make it possible to see if anti-amyloid therapies, and other strategies, truly work.

Currently, DIAN-TU is testing Lilly’s solanezumab, a monoclonal antibody targeting soluble amyloid beta, and Roche’s gantenerumab, an antibody that binds to Aβ plaques. Both investigational drugs are also being studied in large industry-sponsored trials.

Up ahead, DIAN-TU investigators plan to test another type of drug, called a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, to block production of excess Aβ peptides in developing AD. The director of the DIAN-TU studies, Randall Bateman, MD, of Washington University in St. Louis, is a noted leader in the field and 2017-20 grantee of BrightFocus' Alzheimer’s Disease Research program.

Another promising anti-amyloid treatment is Biogen’s aducanumab, an immunotherapy that targets amyloid aggregates (or plaques).  Early clinical trial results have shown it can reduce amyloid deposits in several regions of the brain.

Work also is moving ahead on drugs that inhibit neuroinflammation. PET imaging makes it possible to visualize activation of the brain’s resident immune cells, called microglia. Gauthier said that up ahead, we will see drug trials aimed at blocking microglial activation through non-steroidal anti-inflammatory drugs (NSAIDs) and other agents.

Also ahead in the Alzheimer’s field will be trials designed to take a “second look” at the use of older drugs in highly targeted select populations, Gauthier said. These may include drugs that have failed in previous trials. New tools of statistical analysis make it possible to look at subsets of earlier data, to see if there are hints of whether the same drug might work in more selective populations. “I would argue they might be effective,” Gauthier said.

In addition, drugs already approved to treat other diseases are being evaluated for selective use in Alzheimer’s. These include angiotensin receptor blockers, angiotensin converting enzyme (ACE) inhibitors, and insulin-enhancing drugs; biologic agents used in autoimmune diseases, such as rheumatoid arthritis; and rho-kinase inhibitors used to treat stroke.

Success Will Bring New Challenges

Once a drug is proven effective at delaying the onset of MCI, a condition that can be an early stage of AD), or in delaying or stopping progression to AD, “there will be interest in combining them to achieve larger therapeutic effects,” Gauthier said.  Already combination therapies are widely used to fight cancer and to prevent AIDS in HIV-positive individuals. “We should learn from other fields, such as oncology and infectious disease, about optimal trial designs to demonstrate additive benefits,” Gauthier said.

He also urged the field to “think through how you will use any of these drugs” if and when it’s approved. For example, with a drug like aducanumab, which is delivered to the brain by injection, “would the plan be to set up injection clinics?,” Gauthier wondered aloud.  And since it’s a bioengineered drug that will be costly to manufacture, would it mainly be targeted it to ApoE4 carriers (ie, those with the strongest genetic risk factor for LOAD) and others at greatest risk?  Gauthier also called for clearly defined start and stop rules, including time periods for gauging a drug’s effect, as a way to prepare for optimal use of new drugs.

Finally, even as new therapies advance and bring hope, Gauthier feels it’s important to place a major emphasis on Alzheimer’s prevention. Non-pharmacologic interventions such as diet and exercise, “have shown encouraging results,” he said, and need to be part and parcel of the effort to meet Alzheimer’s challenges.

He called the ongoing FINGER study (ie, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability”) “a classic,” the largest RCT of Alzheimer’s prevention. Conducted in Finland, FINGER enrolled thousands of 60-77 years who had risk factors for memory disorders and treated them with a structured program of lifestyle counseling and interventions focused on diet, exercise, treatment for medical risks like CVD and mood disorders, and social engagement.

One and two-year results showed these interventions helped prevent cognitive decline by a modest amount, averaging about 20-25 percent, compared to controls (Ngandu et al, Lancet, 2015; Rosenberg et al, Alzheimers Dement, 2017). Recently, a FINGER subgroup showed that these benefits hold true even in APOE4-positive individuals (Solomon et al, JAMA Neurology, 2018). Five-year results from FINGER are expected in 2020.

FINGER’s principal investigator, neurologist Miia Kivipelto, MD, of Sweden’s Karolinska Institute, has advocated that FINGER’s interventions should be adapted to various populations worldwide, including in the United States, as part of formulating global dementia prevention strategies. Now that’s happening with the World Wide FINGERS initiative, an effort to launch new clinical trials like FINGER to see if that helps prevent AD in diverse populations with a variety of geographical and cultural backgrounds.

Other researchers, including many funded by BrightFocus, continue to investigate the effects of cardiovascular disease, diabetes, diet and the microbiome, sleep, exercise, mood disorders, head injuries, metabolism, and other factors on Alzheimer’s risk. The knowledge that’s gained will lead to new treatments and also to risk reduction strategies which, if started in middle age or earlier, may help protect younger generations from developing Alzheimer’s.