The Evanthea Clinical Trial

There has been ongoing interest in a functional medicine approach to cognitive decline and dementia.  Most of the papers published by Dr Bredesen and his team in the last ten years have been case reports and evidence has been largely preliminary and anecdotal.  It has also been hard to replicate as the treatment approach is multi-modal and not a single treatment which can easily be replicated in a study.  The approach, as in all of functional medicine, is PERSONALIZED and PRECISION based.  In other words, no two dementia patients have the same specific underlying combination of mechanisms and thus require an individualized approach.  For the first time, to my knowledge, we now have a randomized controlled trial that puts the functional medicine approach to the test against the standard of care treatment of early cognitive decline and early dementia.  I had the opportunity to hear the lead investigator of the trial Dr Kat Toups speak and read a preview of the paper outlining the multicenter multi-investigator trial. 

In the Evanthea trial of 72 patients with mild / early cognitive impairment were randomized to receive a personalized precision based functional medicine protocol or standard of care treatment.  Two thirds of the patients received the protocol and one third received standard neurology care.  Patients were excluded from the trial if they scored below a moderate to severe on the Montreal Cognitive Assessment (MoCA).  Each patient was also required to have a study partner to assist in the lifestyle and tracking throughout the study.  CNS Vital Signs which is a battery of neurocognitive testing was used to assess patients throughout the 9 month intervention along with quantitative MRI.

The treatment arm was given a ketogenic diet, exercise, brain training and mindfulness protocols.  In addition they received hormone replacement therapy for the trophic effects on the brain where applicable as well as treatment of underlying infections and toxic exposures. 

Here are my take aways from the Evanthea trial:

“Dementia is preventable and treatable as long as we address things EARLY.”  This was the comment by the lead investigator in her presentation on the neurodegenerative disorders.

It has been my observation that in the large majority of patients I have seen with cognitive decline, I am seeing them as the “last resort” and well beyond the mild stages of dementia.  In this clinical trial, only patients with mild cognitive impairment were allowed to participate.  I agree sadly that often dementia is present well before it is bad enough and there is intervention.   We do not know if the results of this study would have been the same if they had included all stages of dementia.  I suspect not.  Do not wait, intervene early and aggressively is my understanding. 

The approach has to be personalized.  Most of the treatments currently available target amyloid.  Their current thinking is that amyloid accumulates outside of neurons to protect them from neural inflammation.  This is a downstream approach.  A personalized approach asks the question, why is the body making the amyloid plaque in the first place?  Targeting that and perhaps then in combination with anti-amyloid medications could be useful.  This is perhaps why the anti-amyloid pharmaceutical studies have been disappointing as the underlying cause is not being addressed.  Precision medicine takes into account the unique features of that one patient with the diagnosis of dementia. This makes it hard to reproduce but not impossible.  The fact that this study was done over multiple centers suggests that the system approach is reproducible but is more challenging than just prescribing a single pill or pharmaceutical intervention.

It takes a village.  Being under the care of a physician trained in functional medicine is not enough.  In this study each participant had a support team.  They all had a family member “study partner” to help execute the testing and protocol.  They all had a health coach, nutritionist and exercise coach.  The treatment protocol involved a ketogenic diet, daily exercise, sleep tracking, brain training and mindfulness practices.  These are hard things to do for everyone and particularly a person with dementia.  I have also noticed in clinical practice the patients that respond the best to this approach have a family member helping them with the testing and changes. 

Wide net battery testing upfront is best.  It is easy to get overwhelmed by testing and for a lot of conditions we can take a step by step piecemeal approach.  My take home however from this study is to test upfront.  We KNOW the natural progression of neurodegenerative conditions and time is basically neurons.  Figure out the key factors contributing to neuroinflammation early if possible.  This study included the following testing:

• Hearing and Vision Testing
• Sleep Apnea Screening
• Mammogram (for women as Hormone Replacement Therapy was part of the intervention)
• Dental Pathogen Testing
• Large Battery of Laboratory Testing
  • Brain Biomarkers
  • Nutrients
  • Omega 3 Fatty Acids
  • Metals
  • Cardiometabolic and Inflammatory Markers
  • Hormones
  • Immune Markers
  • Infections
  • Mycotoxins
  • Microbiome Testing
  • Genetics

In my opinion, addressing mycotoxins and chronic infections that contribute to cognitive decline  are the hardest but also the most important and is why the results of this study went beyond what other lifestyle trials have done. 

Adherence to lifestyle choices are a key foundation but not a standalone.

Treatment outcomes in comparison to lifestyle alone and in comparison with the trials on anti-amyloid pharmaceuticals is superior.  

The approach takes commitment.  

The patients in this study tracked their sleep, used continuous glucose monitoring, food tracking, brain training, monitored ketones, exercised and practiced mindfulness.   All participants even had testing of the home for mycotoxin.   I think that as humans we often dismiss our own vulnerabilities and susceptibilities and nobody would take this attention and care unless our lives depended on it.  The fact is our health and vitality as we age does depend on attention to details of lifestyle.  It is estimated in 2025 that 10% of adults aged 65 and older and an estimated 7 million people suffer from some degree of dementia and that will nearly double by 2050!  Acting early and prevention is the best thing you can do to ensure the health of your brain as you age but it does take commitment and consistency over time to healthy lifestyle choices. 

References:

https://clinicaltrials.gov/study/NCT05894954

Reversing Cognitive Decline: 2025 RCT Presentation at IMMH by Dr. Kat Toups