By Jeffrey Cummings, MD, ScD, and James Leverenz, MD
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Currently, 105 therapeutic agents are in clinical trials for Alzheimer’s disease (AD). As research progresses, a better understanding of the biology of the disease and its development is allowing for even more targeted drug development. Researchers at Cleveland Clinic’s Lou Ruvo Center for Brain Health are active contributors in moving forward the science and the search for treatments.
Shifting the paradigm is an appreciation of AD’s three distinct stages — an extended preclinical phase, potentially up to 15 years, before symptoms occur; the prodromal stage, or mild cognitive impairment (MCI); and AD dementia, the most severe, debilitating end stage. Researchers now believe AD is more like prostate cancer, where changes are underway well before symptoms appear. Thus, the earlier silent phase may be the best time to treat, or ideally prevent, the disease.
AD’s hallmark cognitive and behavioral symptoms result from the build-up of amyloid plaques and tangles of tau protein in the brain; these aggregates destroy synapses that mediate memory and cognition. Research shows that for amyloid to exert its toxic effects, tau must be present and they work together to induce a diseased state. While amyloid is upstream of tau in AD pathogenesis and serves as a trigger for tau conversion to a toxic state, evidence shows that once toxic, tau intensifies amyloid toxicity. Nearly 70 percent of all drugs in clinical trials are disease-modifying therapies (DMTs) targeting various molecular pathways to disrupt or protect against these rogue interactions.
Variety of mechanisms and targets being studied
Hopes are high for the BACE (beta-site amyloid precursor protein cleaving enzyme) inhibitors as the Mission AD trials of elenbecestat begin recruitment. These 24-month studies will evaluate the efficacy and safety of the drug in patients with early stage MCI. Results from earlier trials showed that elenbecestat reduced the level of amyloid-beta protein in cerebrospinal fluid (CSF) by a median 70 percent (range 45 percent-90 percent), the most robust response seen to date. In mouse models, BACE inhibitors appeared to repair the neural damage caused by the accumulation of amyloid plaques and allowed these cells to return to normal function.
Positive results for aducanumab in AD have also been reported. In initial trials of patients with early AD, PET scan assessments revealed that aducanumab reduced amyloid in the brain in a dose- and time-dependent manner. In patients who received treatment for 36 months, some patients’ amyloid levels dropped below the cut-off for an Alzheimer’s diagnosis. This multicenter trial is now in phase 3 and actively recruiting in Cleveland and Las Vegas.
Understanding the role of inflammation in AD development continues to drive a wide range of research. The 10 anti-inflammatory agents currently in clinical trial have a variety of mechanisms, including anti-amyloid/anti-inflammatory, anti-amyloid RAGE antagonist, Beta-2 adrenergic receptor agonist, glutaminyl-peptide cyclotransferase inhibitor, anti-hyperlipidemic, and angiotensin II receptor blocker/PPAR-gamma agonist. Trial results are expected as early as next year on the latter.
Repurposing, genetics, and lifestyle
Another avenue of research is looking to repurpose already-approved drugs. A new trial is examining the neuroprotective properties of rasagiline in patients with mild to moderate AD. Previously approved for use in patients with Parkinson’s disease where it offers a benefit in motor skills, AD researchers noticed improvements in memory in previous trial results and sought funding for the current 6-month trial; recruitment, which is ongoing in Las Vegas and Cleveland, is expected to end in June 2018.
A recent trial of bexarotene assessed the impact of the repurposed cancer drug on brain amyloid in patients with AD. The drug reduced amyloid burden and increased serum amyloid-beta in ApoE4 noncarriers, findings that Dr. Cummings, who served as principle investigator, and colleagues believe warrant further study.
The interplay of lifestyle and genetics in AD development is also being examined. Two researchers at Cleveland Clinic Lou Ruvo Center for Brain Health have been awarded grants to explore the interaction between ApoE4, a key risk factor for AD, and the role of exercise on disease development. Preliminary data on ApoE4 carriers shows that those who are more physically active convert to cognitive impairment/develop symptoms at a slower rate than those who don’t exercise. Stephen Rao, PhD, is leading an observational study to try to hypothesize how exercise interacts with the immune system to create this effect. A second study, by Jagan Pillai, MD, PhD, will look at the interaction between the immune system and the conversion to cognitive impairment in cognitively normal ApoE4 carriers to determine how physical activity conditioning impacts AD brain changes over time. Stay tuned!
Expert evaluation services and patient interactions
With the recognition of a potential 15-year presymptomatic phase, community physicians can expect more patients to ask, “Could this be Alzheimer’s?” Our clinician-researchers are available to provide expert evaluation to help community physicians distinguish between normal aging and a very early AD diagnosis. Such evaluations can contribute to the success of medical research as they can help identify participants who may be candidates for clinical trials in this disease state. The need is great: recent reports indicate that to complete already-registered clinical trials for AD, more than 50,000 patients with preclinical AD, MCI and AD dementia will be needed.
Clinical trial participants tell us trials are a very satisfying experience for them. They find the trial services supportive, and often if they finish one trial they inevitably want to go into another. The clinical trial process allows patients, their families and physicians to participate in advancing the science that will eventually lead to meaningful treatments. These are complex problems. It will take everybody working together to find solutions.
Jeffrey Cummings, MD, ScD, Director of Cleveland Clinic Lou Ruvo Center for Brain Health
James Leverenz, MD, Director, Cleveland Site, Lou Ruvo Center for Brain Health
For more on brain health studies visit our Clinical Trials webpage.
Read more about the drug development pipeline for Alzheimer’s diseases in this ScienceDirect journal article co-written by Dr. Cummings.