Value in identifying pre-clinical Alzheimer’s disease

By Ken Sharlin

Integrative practitioners have long embraced the idea that effective treatment of illness should be at the root cause level. Therefore, we often begin with the gut, even when addressing the brain. The advantage here, too, of this upstream approach is that it improves simultaneously the expression of many chronic conditions affecting our patients or prevents future problems for others. We understand that what underlies these conditions is inflammation, excessive oxidative stress, and abnormal patterns of aging as a result of lifestyle, environment, and genomic variations that confer susceptibility upon each of us.

A recent editorial in the journal Age and Aging led by Jenny McCleery, PhD, of the Oxford Health NHS Foundation Trust, asks us to read on as providers constrained by the notion that those with the underlying pathology who do not yet manifest the illness clinically may never do so. Or, that the identification of biomarkers is reductionist because it ignores the multiple pathologies contributing to the biomarkers thereby homogenizing the disease cause, and therefore the avenues for treatment.

There has been a 100 percent failure rate in drug development for Alzheimer’s disease where the focus is disease-modifying therapy, most recently with the anti-amyloid drugs aducanumab and solanezumab. Equally disturbing is the meta-analysis published in JAMA Neurology suggesting that subjects enrolled in clinical trials for these Alzheimer’s treatments who were concomitantly on memantine or a cholinesterase inhibitor appear to have experienced greater cognitive decline, possibly confounding the results of the trials.

This frustrates those of us who see value in a pre-clinical diagnosis. These early clues allow us to engage our patients in a story about their health, here the health of their brains, and what they can do either on their own or with a skilled integrative practitioner to alter their disease trajectory.

In my office I always say, “why wait until the house is already burned to the ground to call the fire department?”

Dale Bredesen, MD, is famous for his reference to the “36 holes in the roof” when it comes to unique identifiable causes of Alzheimer’s disease. The recently published Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) Study showed that conventional practitioners, in fact, do change their diagnosis and management of patients based on this biomarker technology. In the paper, the proportion of Alzheimer’s diagnosis increased from 80.3 percent pre- positron emission tomography (PET) to 95.5 percent post-PET in patients with a positive scan, while in patients with negative scan results the rate of Alzheimer’s disease diagnosis decreased from 71.5 percent pre-PET to 10.2 percent post-PET. The most dramatic change was in those whose doctors thought their patients had Alzheimer’s until the scan was completed, only to discover they did not have the pathology.

The researchers in the IDEAS Study categorized the changes in management as Alzheimer’s disease drugs, Non-Alzheimer’s disease drugs, and counseling. But there is so much more to do. In the poignant narrative by Daniel Gibbs, MD, in the Journal of the American Medical Association, he describes his own diagnosis of Alzheimer’s, now 13 years since his first symptom appeared. He says, “I strongly believe that the first effective disease-modifying therapies for Alzheimer’s disease will be those targeted at the earliest stages of the disease, perhaps even before cognitive changes are apparent.”

Among the strategies used, Gibbs reads, “an average of two books per week…makes lists to stay track, uses mnemonics to remember important names, exercises daily…follows a Mediterranean-style diet, and remains socially engaged.”

Anecdotal data that cognitive decline can be reversed goes back to at least 2014 when Bredesen published his first paper, then followed it in 2016 when he clarified that the reversal of cognitive decline he saw were in individuals who either had the diagnosis of Alzheimer’s disease, four cases, or in those with Mild Cognitive Impairment (MCI), six cases. He said he could demonstrate objective measures of improvement using quantitative MRI and neuropsychological testing. Nine of the 10 cases he presented had one or two copies of the high-risk gene ApoE4 that confers a three- to 12-fold risk of the development of Late Onset Alzheimer’s disease. About the same time the results from a two-year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER) demonstrated a significant beneficial effect, 25 percent higher in the interventional group compared to the control group, using a neuropsychological test battery.

Other researchers have followed. Majid Fotuhi, MD, PhD, demonstrated that 84 percent of patients participating in a personalized 12-week “Brain Fitness Program” for improving cognitive function and increasing hippocampal volume in elderly with MCI could benefit. They used strategies that involved cognitive stimulation, diet, omega-3 supplementation, fitness, and mindfulness meditation. Dorothy Keine, MS, showed that novel software could design a precision medicine-based approach to provide personalized treatment recommendations to slow or reverse biological drivers of Alzheimer’s disease. The personalized care plan delivered to physicians and supported by health coaches resulted in improved memory function in 80 percent of participants. Participant interventions included prescription medications, nutraceuticals, the MIND diet, exercise, sleep optimization, stress reduction, and brain stimulation.

Last year, Richard Isaacson, MD, proposed with co-authors another precision medicine algorithm, here for the prevention of Alzheimer’s disease. They considered factors defined by Anthropometrics, Blood biomarkers, and Cognition, the “ABCs” of Alzheimer’s prevention, and had general intervention categories based on these to include cardiovascular risk factor management, physical exercise, nutrition,, sleep, cognitive enhancement, social interaction, sense of purpose, stress management, and oral hygiene. Similar strategies were used in the most recent paper that included several authors led by Bredesen, with the largest contribution of patients from my clinic, which showed reversal of cognitive decline in 100 patients.

The paradigm is shifting. More practitioners have become aware of scientific data emerging from laboratories and research centers around the world that can be readily translated into clinical practice without waiting for a drug. The annually updated report from the Alzheimer’s Association now estimates 5.8 million Americans are affected by the disease reflecting a rate of rise of about 100,000 persons per year. With the Centers for Medicare and Medicaid Services reporting that U.S. healthcare spending reached $3.5 trillion in 2017 or about 17.9 percent of gross domestic product, integrative practitioners have a unique role to play in curbing the impact Alzheimer’s disease on individuals and on society.

While reversal of cognitive decline holds promise, too, the benefit of awareness of disease by biomarker status, before clinical symptoms appear, arms us with more powerful information and action plans than McCleery gives credit to, and we now know are possible. As for me, I’m seeing smoke and I’m calling the fire department now.

References

Bredesen, D., Amos, E., and Canick, J. (2016). Reversal of Cognitive Decline in Alzheimer’s Disease. Aging. Retrieved from: https://www.aging-us.com/article/100981/text

Bredesen, D. (2014) Reversal of Cognitive Decline: A Novel Therapeutic Program. Aging. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/fulltext

Bredesen, D., Sharlin, K., and Jenkins, D. (2018). Reversal of Cognitive Decline: 100 Patients. Journal of Alzheimer’s Disease & Parkinsonism. Retrieved from: https://www.omicsonline.org/open-access/reversal-of-cognitive-decline-100-patients-2161-0460-1000450-105387.html

Fotuhi, M., Lubinski, B., and Hausterman, N. (2016). A Personalized 12-Week “Brain Fitness Program” for Improving Cognitive Function and Increasing the Volume of Hippocampus in Elderly with Mild Cognitive Impairment. The Journal of Prevention of Alzheimer’s Disease. Retrieved from: http://www.jpreventionalzheimer.com/all-issues.html?article=183 

Gibbs, D. (2019). Early Awareness of Alzheimer’s Disease – A Neurologist’s Personal Perspective. JAMA Neurology. Retrieved from: https://jamanetwork.com/journals/jamaneurology/fullarticle/2724326

Isaacson, R., Ganzer, C., and Hristov, H. (2018). The Clinical Practice of Risk Reduction for Alzheimer’s Disease: A Precision Medicine Approach. Journal of Alzheimer’s & Dementia. Retrieved from: https://www.alzheimersanddementia.com/article/S1552-5260(18)33513-1/fulltext

Keine, D., Walker, J., and Kennedy, B. (2018). Development, Application, and Results from a Precision-Medicine Platform that Personalizes Multi-modal Treatment Plans for Mild Alzheimer’s Disease and At-risk Individuals. Current Aging Science. Retrieved from: http://www.eurekaselect.com/166449/article

Kennedy, R., Cutter, G., and Fowler, M.. (2018). Association of Concomitant Use of Cholinesterase Inhibitors or Memantine with Cognitive Decline in Alzheimer Clinical Trials – A Meta-analysis. JAMA Network Open. Retrieved from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2712175

McCleery, J., Flicker, L., and Richard, E. (2019). When is Alzheimer’s not dementia – Commentary on The National Institute on Ageing and Alzheimer’s Association Research Framework for Alzheimer’s disease. Age and Aging. Retrieved from: https://academic.oup.com/ageing/article/48/2/174/5133577

Ngandu, T., Lehtisalo, J., and Solomon, A. (2015). A 2 Year Multidomain Intervention of Diet, Exercise, Cognitive Training, and Vascular Risk Monitoring Versus Control to Prevent Cognitive Decline in At-Risk Elderly People (FINGER): A Randomized Controlled Trial. The Lancet. Retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/fulltext

Rabinovici, G., Gatsonis, C., and Apgar, C. (2019). Association of amyloid positron emission tomography with subsequent change in clinical management among Medicare beneficiaries with mild cognitive impairment. JAMA. Retrieved from: https://jamanetwork.com/journals/jama/fullarticle/2729371