by Sara Gottfried, MD and Christopher Moulton, PhD
We’ve been told that cognitive function in healthy individuals naturally declines with age. Or does it? Recent case series have brought this central tenet of the aging brain into question and suggest the hypothesis that cognitive decline may be more mutable than once believed. Dale Bredesen, MD, of the David Geffen School of Medicine at UCLA, and collaborators have advanced a systems-based approach to address the factors that put the brain at risk of cognitive decline. Limited evidence suggest that his approach may work. This article explores Dr. Bredesen’s latest case series.
Certainly, most aspects of cognition, such as executive function and short-term memory, diminish from their peak in early adulthood, although accumulated knowledge continues to increase throughout the lifespan.1 The rate of age-related cognitive decline varies; however, this process occurs more rapidly in conditions such as mild cognitive impairment (MCI), and in numerous forms of dementia such as Alzheimer’s disease (AD) and frontotemporal dementia.2
While CDC data (based on death certificates) conservatively estimates Alzheimer’s disease to be the 6th leading cause of death in the US,3 other, targeted investigations suggest a greater mortality burden, with Alzheimer’s as the 3rd leading cause of death, with over 5 million Americans afflicted as of 2014.4
To date, there are no effective pharmacologic treatments to halt Alzheimer’s disease progression, and approved drugs such as acetylcholinesterase inhibitors mitigate symptoms but do not alter the course of dysfunction.5 Discouragingly, the pipeline for new drug monotherapies lacks promise or long-term efficacy.6 Dr. Bredesen provides a helpful analogy for why monotherapy doesn’t seem to work, and instead, a pleiotropic approach may be better. He writes in his book The End of Alzheimer’s that drug companies have been like roofers called to a home with 36 holes in the roof. The roofer fixes one hole, but does nothing about the other 35 holes, so the home continues to be flooded with rainwater. Such is the case with Alzheimer’s disease.
Therefore, a multi-component, lifestyle intervention might reduce the risk for accelerated cognitive decline and offer functional improvement,7,8 which may extend to potential therapeutic benefit in conditions of cognitive impairment such as AD.
Role for lifestyle medicine?
For decades, the most favored therapeutic strategies have aimed to reduce or eliminate the Alzheimer’s-associated pathologies amyloid beta and tau,9 but an alternate viewpoint has gained support in that amyloid beta and tau are mediators, but not the root cause of AD. For example, recent evidence has uncovered that amyloid beta has antimicrobial properties,10 and relatedly herpes simplex virus has recently been implicated some forms of AD,11 suggesting that some forms of AD may have an infectious component. Similarly, insulin resistance has been associated with neurotoxic aggregations of amyloid beta.12 Therefore, it may be advantageous to address the underlying root causes that precede the development of these pathologic mediators.
Dr. Bredesen’s systems-based approach targets these underlying factors.13 From this perspective, accelerated neurodegeneration is a consequence of an imbalance between the collective processes that support or create synaptic connections between neurons and the processes that diminish or destroy synapses. In this model, the goal is to optimize the conditions that favor synapse generation, thereby enabling neural plasticity and function.
Therefore, Bredesen and his team developed a comprehensive treatment approach that evaluates numerous physiologic and metabolic parameters of an individual patient and attempts to optimize these states through a variety of tailored interventions, including glycemic regulation through diet and exercise, stress reduction, sleep improvement, gut health support, brain trophic factor support, addressing latent infections, and consideration of toxic burden (e.g., heavy metals).14 Two successive case reports have described preliminary results of 19 patients who undertook this individualized treatment program,14,15 all of whom demonstrated subjective functional improvement and in some cases achieved notable improvement in objective measures (e.g., increase in hippocampal brain volume from 17th to 75th percentile.)
The latest case series
Dr. Bredesen’s recent case report has now expanded those findings to 100 patients who have participated in the treatment program, the results of which were reported from multiple clinicians at multiple study sites.16
- All participants had an initial diagnosis of subjective cognitive impairment (SCI),17 MCI, or AD.
- The majority of patients (72 of 100) had additional objective measures for diagnosis, such as positive amyloid or FDG-PET scan, brain volume as measured by MRI or CT, or neuropsychological assessment such as the Mini-Mental State Exam (MMSE) or Montreal Cognitive Assessment (MoCA).
- Apolipoprotein E (ApoE) status was reported in 80 of 100 patients, as a single ApoE 4 allele is associated with a 3-4x increased risk of AD development.18
- Improvement in various objective measures was reported in >90% of participants; for example 64 of 65 patients assessed by MoCA19 demonstrated improvement at follow-up (average increase 4.65 +/- 2.96 points, total possible score 0 – 30).
- Other measured improvements include increases in quantitative EEG beta power, elevated MMSE scores, and improved performance on the California Verbal Learning Test.
The favorable effects from this case report of 100 patients provide accumulating evidence that such an individualized, systems-based approach can potentially address neurodegenerative cognitive decline at greater scale. In fact, Dr. Dale Bredesen explains that, “As noted in the paper, it is possible that the drug candidates may actually be more efficacious in the presence of a personalized, precision medicine program.”
To build the evidence base, we need prospective, randomized controlled trials to validate these findings more broadly. However, there are methodological challenges evaluating personalized, n=1 interventions in the context of randomized control trials, which typically evaluate treatments that are uniform among participants.20 Furthermore, there is a systematic problem translating hypotheses into evidence in trials. Dr. Bredesen shares that, “IRBs have now turned down a trial on this approach 3 times, so it is being amended and resubmitted. In the long run, we need to be able to carry out multi-variable clinical trials that address the interactive, network nature of complex chronic illnesses.” Nonetheless, considering the lack of effective alternatives, clinicians may wish to consider carefully such a personalized lifestyle medicine approach when counselling and treating patients with cognitive decline.
- Bendayan R et al. Decline in memory, visuospatial ability, and crystalized cognitive abilities in older adults: normative aging or terminal decline? J Aging Res. 2017;2017:6210105.
- Li G et al. Cognitive trajectory changes over 20 years before dementia diagnosis: a large cohort study. J Am Geriatr Soc. 2017;65(12):2627-2633.
- CDC. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm. Accessed February 25, 2019.
- James BD et al. Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014;82(12):1045-1050.
- Kobayashi H et al. The comparative efficacy and safety of cholinesterase inhibitors in patients with mild-to-moderate Alzheimer’s disease: a Bayesian network meta-analysis. Int J Geriatr Psychiatry. 2016;31(8):892-904.
- Cummings J et al. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement Transl Res Clin Interv. 2018;4:195-214.
- Ngandu T et al. 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 randomised controlled trial. Lancet. 2015;385(9984):2255-2263.
- Andrieu S et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16(5):377-389.
- Godyń J et al. Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep PR. 2016;68(1):127-138.
- Soscia SJ et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PloS One. 2010;5(3):e9505.
- Harris SA et al. Molecular mechanisms for herpes simplex virus type 1 pathogenesis in Alzheimer’s disease. Front Aging Neurosci. 2018;10:48.
- Matioli MNPS et al. Mechanisms linking brain insulin resistance to Alzheimer’s disease. Dement Neuropsychol. 2015;9(2):96-102.
- Bredesen DE et al. Next generation therapeutics for Alzheimer’s disease. EMBO Mol Med. 2013;5(6):795-798.
- Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014;6(9):707-717.
- Bredesen DE et al. Reversal of cognitive decline in Alzheimer’s disease. Aging (Albany NY). 2016;8(6):1250-1258.
- Bredesen DE et al. Reversal of cognitive decline: 100 patients. J Alzheimers Dis Parkinsonism. 2018;8(5):6.
- Zuniga KE et al. Subjective memory impairment and well-being in community-dwelling older adults. Psychogeriatrics. 2016;16(1):20-26.
- Löwe LC et al. The effect of the APOE genotype on individual BrainAGE in normal aging, mild cognitive impairment, and Alzheimer’s disease. PLoS One. 2016;11(7):e0157514.
- Nasreddine ZS et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.
- Xie T et al. N-of-1 design and its applications to personalized treatment studies. Stat Biosci. 2017;9(2):662-675.
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.
Christopher Moulton, PhD is the Therapeutic Platform Lead for Cognition & Special Projects at Metagenics. Dr. Moulton endeavors to develop innovative, science-based solutions for practitioners to improve and enhance the well-being of their patients. Relatedly, he engages with the scientific & medical communities to better understand the potential of personalized nutrition to advance health care. Dr. Moulton completed a PhD in Nutritional Sciences at the University of Illinois in Urbana-Champaign. He also holds a Master’s degree in Exercise Physiology and a Bachelor’s degree in Biochemistry. Prior to joining Metagenics, Dr. Moulton managed the Center for Nutrition, Learning, & Memory, a public-private partnership focused at the intersection of nutrition & neuroscience.