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The Future of Alzheimer’s is MultiModal: But Which Ones?

By Craig P. Tanio, MD, FACP, IFMCP at Rezilir Health

In the last month, two major events happened in Alzheimer’s research, which represent some different choices around how care for prevention and treatment is likely to unfold.

Proof of Concept Study of ReCode

Dr. Bredesen and colleagues published their proof of concept study in pre-publication format, which is subject to edits before it is published in a peer-reviewed journal. The study’s purpose was to see if a precision medicine approach to mild cognitive impairment and Alzheimer’s disease would be effective enough to warrant a larger, randomized controlled clinical trial. The study enrolled 25 consecutive patients in Northern California and looked at outcomes at 0,3,6 and 9 months.

The treatment team included a physician, health coach, nutritionist and a physical trainer. They were treated with a personalized precision medicine protocol that identified and attempted to address potentially contributory factors including

  • Restoring insulin sensitivity

  • Improving hyperlipidemia

  • Resolving inflammation and removing the cause if possible

  • Treating pathogens

  • Optimize energetic support including oxygenation, cerebral blood flow, ketone availability and mitochondrial function

  • Optimize trophic support including hormones, nutrients and trophic factors

  • Treat autoimmunity if identified

  • Remove toxins if identified

Two pictures summarize the substantial, sustained and statistically significant improvement in cognitive scores in the vast majority of patients.

This type of improvement has not been reported in the clinical literature before! It certainly meets the test for a randomized clinical trial which in my opinion should be done as soon as possible and it does look like there will be private foundation funding for a randomized clinical trial of this approach.

A reasonable estimate for patients that aren’t in a clinical trial is that it may cost $30k for a patient to do this type of intervention, with the majority of it (at this point in time) uncovered by insurance. There were no major side effects from the treatments which addressed the multifactorial causes of increased amyloid that Dr. Bredesen has postulated.

FDA Approves Aducanab for its effect on biomarkers but not clinical outcomes

On June 7th, the FDA ultimately approved Aducanumab, a monoclonal antibody against amyloid, manufactured by Biogen despite its advisory committee ruling against it. In its ruling, there were three facts that were clearly apparent.

  • Aducanumab did not improve clinical outcomes; cognitive scores of patients did not change unlike the Bredesen study

  • There was substantial reduction in amyloid as measured by PET scans.

  • There were significant side effects that need to be monitored. They are known as ARIA – Amyloid Related Imaging Abnormalities. There is ARIA-H and ARIA-E which stand for hemorrhage (bleeding) and edema (swelling) respectively and this happens in about 30-40% of patients. 25% of patients with ARIA-E will have symptoms and about 1% will have substantial symptoms.

In a statement, the FDA said that the data from EMERGE (NCT02484547) and ENGAGE (NCT02477800) suggested aducanumab “consistently and very convincingly” reduced amyloid plaques in both a dose- and time-dependent fashion and that it anticipates that this reduction will result in a corresponding reduction in clinical decline.2 As such, the agency’s approval is “contingent upon verification” of this potential clinical benefit in a phase 4 confirmatory trial.3

This was a major change in policy for the FDA which had signaled in 2018 that they would support changes in biomarkers rather than a clinical endpoint for Alzheimer’s treatments.

A number of prominent members of the FDA’s own advisory committee resigned signaling their disagreement with the FDA moving away from a clinical endpoint to a biomarker. Most notably, Dr. Aaron Kesselman from Harvard wrote in a scathing resignation letter that “it is clear to me that FDA is not capable of adequately integrating the Committee’s scientific recommendations into its approval decisions.”

A reasonable estimate is that it may cost $75-$85k ($53k for the drug, $20k plus for imaging and other items) of which insurance is likely to cover a majority of this since this is FDA approved.

Interestingly, leaders in the neurology community were postulating a future in which there was multi-drug therapy for Alzheimer’s similar to HIV or cancer, although it is clear that at this point in time, none of the individual drugs work that well individually.

“I just think this has become a sort of mantra that people can use that, of course, we need to do combination drugs. It’s very easy to say that, isn’t it? No one’s got any evidence that it is going to work, so it’s a way of sort of comforting ourselves when none of the drugs that we have, at the moment and in development, appear to be working. We think, “Well, maybe if we were to put them all together, it would somehow be better and work.” But until we do the trials, and we actually demonstrate a significant sort of effectiveness or efficacy, we just don’t know.”


Science and medicine will only progress forward if we test hypotheses.

The ReCode data is tremendous – significant clinical improvement, no dangerous side effects. The only practical downside of the approach is that it isn’t a patented drug / or device so there will be less research money available as it will have to come from the NIH or Private Foundations rather than Big Pharma. The clinical trial is expected to start early next year.

In terms of the amyloid hypothesis, expect a large slew of pharmaceutical studies coming down the pike on reducing amyloid now that the first drug has been approved and the standards are clear – if a biomarker is reduced it will be approved regardless of whether it changes clinical outcomes.

Both of these paths need to be tested. A reasonable approach would start to include lifestyle arms into most / all of pharmaceutical clinical trials to see if there is an additive benefit of lifestyle interventions given the considerable magnitude of change found by the ReCode approach.


  1. Toups et al. Precision Medicine Approach to Alzheimer’s Disease: Successful Proof-of-Concept Trial Accessed June 7, 2021

  2. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. FDA. June 7, 20121. Accessed June 7, 2021.


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