Research

A proof-of-concept trial with 25 participants aged 50 to 76, all with MCI (pre-Alzheimer’s) or early-stage dementia was published in medRxiv in May 2021. Over nine months, researchers, including Bredesen found that 21 improved (84%), one showed no change (4%), and three declined (12%).

Cognitive assessments included MoCA (Montreal Cognitive Assessment), CNS Vital Signs (an online, quantitative, multi-domain neuropsychological battery), BrainHQ (computerized brain training and assessment), AQ-21 (Alzheimer’s Caregiver Assessment Questionnaire), and AQ-20, a caregiver measurement-of-change rating scale. MRI brain imaging complemented the cognitive testing and showed that the brain shrinkage that typically occurs with MCI and dementia was prevented.

The report concluded that a larger, randomized controlled trial is warranted, and this follow-up study is already in the works.

In September 2021 researchers, including Bredesen, used the same novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline) that was successful in the small, proof-of-concept trial. They set out to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage Alzheimer’s disease (AD).

The 255 individuals participants submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions.

Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program.

By comparing baseline to follow-up testing, researchers observed that MoCA scores either significantly improved or stabilized in the entire participant pool—results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies—and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool.

Findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function.

Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians.

The current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline.

A study that included Dr. Bredesen in 2016 was the first to find promising anecdotal evidence of reversal of cognitive decline in patients with early Alzheimer's disease or its precursors. Researchers used a novel programmatic approach involving metabolic enhancement, with promising anecdotal results.

Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements.

In the study Feasibility of an MI-CBT ketogenic adherence program for older adults with mild cognitive impairment, researchers used the National Institutes of Health Obesity-Related Behavioral Intervention Trials model for intervention development to establish the feasibility and proof of concept of a motivational ketogenic nutrition adherence program for older adults with mild cognitive impairment.

This was a single-arm, single-center feasibility trial that included nine participants (aged 64–75) with possible amnestic mild cognitive impairment. Participants completed pre- and post-intervention neuropsychological assessments and tracked their macronutrient consumption using food diaries and ketone levels using urinalysis test strips daily.

All participants who began the trial completed the 6-week ketogenic nutrition adherence program, including completion of the pre- and post-assessments. Eight participants achieved measurable levels of ketones during the program. A Wilcoxon Signed-Rank test demonstrated significant improvement in cognitive performance from baseline (median = 88) to follow up (median = 96, Z = − 2.26, p = .024). The average difference in cognitive performance from baseline to follow-up was − 7.33 (95% CI − 12.85, − 1.82).

Results published in July 2021 supported the feasibility for moving to the next phase and demonstrated proof of concept for the intervention. The next step is a randomized pilot trial to test clinical signals of effect compared to a control condition.

This research found that among patients with dementia or mild cognitive impairment, randomized controlled trials (RCTs) documented better cognitive scores after 6 to 12 months of exercise compared with sedentary controls.

One year of aerobic exercise in a large RCT of seniors was associated with significantly larger hippocampal volumes and better spatial memory; other RCTs in seniors documented attenuation of age-related gray matter volume loss with aerobic exercise. Cross-sectional studies similarly reported significantly larger hippocampal or gray matter volumes among physically fit seniors compared with unfit seniors. Brain cognitive networks studied with functional magnetic resonance imaging display improved connectivity after 6 to 12 months of exercise.

Researchers found that besides a brain neuroprotective effect, physical exercise may also attenuate cognitive decline via mitigation of cerebrovascular risk, including the contribution of small vessel disease to dementia. Exercise should not be overlooked as an important therapeutic strategy.