It has been estimated that globally, more than 35 million people suffer from Alzheimer’s disease or other type of dementia, and without some medical breakthrough, this number will double every twenty years reaching a staggering 115.4 million people by 2050. The annual worldwide economic cost of Alzheimer’s disease and other forms of dementia is estimated at US$315 billion, while no parameters exist for quantifying the emotional expense borne by family members and caregivers associated with those afflicted.
With hope of identifying a specific biochemical deficiency supportive of a repletion therapeutic regimen analogous to levodopa treatment in Parkinson’s disease, research in the late 1960s and early 1970s identified a substantial deficits in choline acetyltransferase (ChAT) the enzyme responsible for the synthesis of acetylcholine (Ach), in the neocortex of Alzheimer’s patients with subsequent discovery of more widespread deficiency of Ach release and activity. These findings supported the “cholinergic hypothesis” of Alzheimer’s disease and provided the groundwork for the subsequent development of pharmaceutical interventions designed to enhance the provision of Ach to the deficient brain with the hope of re-establishing compromised cognitive function typifying the disease.
Subsequently, medications designed to inhibit acetylcholinesterase and thus enhance Ach availability, were introduced into the healthcare marketplace and rapidly gained worldwide utilization. Indeed, cholinesterase inhibitors are by far the most widely prescribed “treatments” for Alzheimer’s disease despite meaningful evidence of their efficacy.
In a recent report in the British Medical Journal on Neurology, Dr. Hanna Kaduszkiewicz and colleagues reviewed “All published, double-blind, randomized controlled trials examining the efficacy on the basis of clinical outcomes…” of the three most commonly prescribed cholinesterase medications “compared with placebo in patients with Alzheimer’s disease.” Twenty-two trials met their inclusion criteria and their published conclusions stated, “Because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer’s disease is questionable.” And further, “Recommendations for the use of cholinesterase inhibitors do not seem to be evidence based.”
Integrative or complementary healthcare practices focus on diet and other modifiable lifestyle factors and their role in the genesis and progression of disease processes. Perhaps because of the virtual absence of any meaningful pharmaceutical approach to the treatment of Alzheimer’s disease, the tenants of these “alternative approaches” are gaining more attention, and with good reason. Being held to the standard of “evidence- based medicine” several modifiable lifestyle factors demonstrate unequivocal evidence of efficacy in enhancing several domains of cognitive function associated with early Alzheimer’s disease or “mild cognitive impairment,” the latter a syndrome now recognized as a harbinger of the former.
Caloric Restriction (CR)
Animal studies suggest that calorie restricted diets are beneficial for cognitive function. CR has been demonstrated in various animals to enhance the availability of brain-derived neurotrophic factor (BDNF), a neurotrophin functioning to support neuronal survival, synapse and dendrite formation as well as growth and differentiation of new neurons (neurogenesis) in the hippocampus, a flash point of degeneration in the animal model of Alzheimer’s disease as in humans. Indeed, it is likely that BDNF is a requirement for neurogenesis in the hippocampus. Caloric restriction in humans has similarly produced significant increase in BDNF. Chilean researchers have demonstrated increase of serum BDNF levels by approximately 30% in overweight and obese humans subjected to a 25% calorie reduction for three months.
In a similarly designed dietary interventional study, memory function, a hallmark of Alzheimer’s disease, was assessed at onset and after 3 months in 50 healthy to overweight subjects, mean age 60.5 years placed on a 30% reduced calorie diet, compared to a matched nonintervention group. A significant increase in verbal memory scores was observed in the calorie restricted subjects compared to those with unrestricted access to calories. The authors concluded that their study demonstrated “experimental evidence in humans that calorie restriction improves memory,” and reasoned that this effect was likely mediated by the action of CR on enhancement of neurotrophic factors.
Caloric restriction is a powerful epigenetic modulator. Beyond enhancement of BDNF production, animal research demonstrates CR induced gene activation is associated with mitochondrial biogenesis, enhanced ATP production, reduction of inflammatory cytokines, enhancement of detoxification, reduction of neuronal apoptosis, and enhanced antioxidant protection, all of which would seemingly provide protection for neurons and likely prove beneficial for the at risk brain manifesting early cognitive dysfunction.
While recommending a 25-30% dietary calorie reduction to patients may at first seem draconian, this recommendation is tempered by the recognition that in the United States, and likely in many developed countries, average adult caloric consumption is approximately 20% greater than is required to maintain ideal body mass.
The important role of physical exercise in treatment protocols for various diseases including coronary artery disease, diabetes, depression, and obesity is well established. Research clearly indicates that exercise reduces not only the risk for development of these and other conditions, but limits their progression and serves to enhance clinical improvement as well. Each of these conditions shares several important features with Alzheimer’s disease. All are characterized by higher levels of inflammatory markers including C-reactive protein, as well as increased markers for oxidative stress. And all are more common in individuals with higher caloric intake as well as those maintaining a sedentary lifestyle. Both inflammation and oxidative stress are key players in the pathophysiology of these conditions and both of these processes are ameliorated by physical exercise.
Like calorie restriction, physical exercise enhances neurogenesis, leading to the proliferation of neural stem cells in laboratory animals. And again, current research seems to spotlight the role of BDNF in this process.
Multiple animal studies have validated the role of physical exercise in reducing memory deficits. Human studies are now confirming the same relationship. In a recent randomized trial published in the Journal of the American Medical Association, 138 study participants having established subjective and objective mild cognitive impairment aged 50 years or older were randomized to either participate in a 24-week home-based exercise program or not. The exercise program added approximately 142 minutes of physical activity per week or about 20 minutes each day. At 18 months, participants in the intervention demonstrated improvements in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) of 0.69 points, a score 340% higher than that found for the cholinesterase inhibitor donepezil (Aricept®) for the same length of time, the latter score felt not to have clinical significance. The authors concluded, “Unlike medication, which was found to have no significant effect on mild cognitive impairment at 36 months, physical activity has the advantage of health benefits that are not confined to cognitive function alone, as suggested by findings on depression, quality of life, falls, cardiovascular function, and disability.”
Integrative medicine is often criticized by mainstream practitioners as lacking evidence- based underpinning for its seemingly unorthodox practices. Indeed, a level playing field should hold all participants in the game of healthcare to the same standards. Requiring scientifically validated evidence to support specific recommendations for patient care represents the current standard and assures patients the highest quality of care in terms of efficacy and safety. At present, the recommendations for caloric intake reduction and physical exercise are the only meaningful evidence-based therapies available for individuals with early dementia. Adhering to evidence-based practice as it relates to early dementia will represent a massive cost savings for healthcare systems and eliminate the potential risks of medication induced negative consequences.
Over the past two decades, a far more comprehensive etiologic hypothesis has evolved, one that relates Alzheimer’s disease to oxidative stress. This understanding holds that a more antecedent process underlies the ultimate deficiency of acetylcholine. Further, the action of reactive oxygen species underlying the process of oxidative stress is far more comprehensive in that it offers an understanding of the now well described events of oxidative damage to nuclear DNA, mitochondrial dysfunction as a consequence of mitochondrial DNA damage, oxidative damage to fat and protein, and the ultimate event of neuronal apoptosis. Indeed, laboratory analysis measuring increased levels of 8-Hydroxydeoxyguanosine, lipid peroxides, and protein carbonyls, measurements of oxidative damage to DNA, lipids, and proteins respectively, are clearly related to Alzheimer’s disease severity and risk.
The fundamental role of reactive oxidative species in Alzheimer’s has thus prompted investigations evaluating antioxidant intake and risk for the disease.
Dr. Martha Claire Morris determined that increased dietary consumption of vitamin E was strongly associated with reduced risk for Alzheimer’s disease. Others have demonstrated a strong correlation not only of vitamin E, but vitamins C and A as well. Beyond blood levels or retrospective analysis of dietary consumption of antioxidants, the use of nutritional supplements has been demonstrated to be associated with a remarkable risk reduction for the disease.
Oxidative stress has been implicated in the risk, progression, and severity of Alzheimer’s disease. In a review of the pertinent literature in a report entitled, Damage to Lipids, Proteins, DNA, and RNA in Mild Cognitive Impairment, Dr. William Markesbery stated, “These studies establish oxidative damage as an early event in the pathogenesis of Alzheimer disease that can serve as a therapeutic target to slow the progression or perhaps the onset of the disease.”
These reports provide substantial support for aggressive antioxidant supplementation in the treatment of Alzheimer’s disease. At the Perlmutter Health Center, our evaluation of Alzheimer’s patients, patients experiencing mild cognitive dysfunction, and those individuals “at risk” by virtue of family history, elevated homocysteine level, or genetic predisposition (carriers of the APOE-4 allele) begins with an assessment of oxidative stress. We employ a measurement of serum lipid peroxides, an indicator of oxidative damage to lipids. Following institution of a comprehensive antioxidant program, the lipid peroxide study is repeated at 4-month intervals until normalized.
Core daily components of our antioxidant regimen include vitamin E (d-alpha tocopherol) – 400 IU, Vitamin C – 400mg, alpha lipoic acid – 200mg, N acetyl-cysteine – 800mg, coenzyme Q10 – 200mg, and vitamin D3 – 6,000 IU. Based upon the lipid peroxide study, we typically need to increase daily antioxidant coverage by increasing vitamin E to 800 IU, vitamin C to 2000mg, and alpha lipoic acid to 800-1000mg daily.
In addition, in more advanced cases or in patients whose lipid peroxide function fails to normalize, our clinic utilizes glutathione, a comprehensive brain antioxidant, given intravenously, typically at a dosage of 2400mg twice weekly. Indeed, we frequently observe profound clinical improvement in Alzheimer’s patients receiving this intravenous antioxidant.
Other important components of our protocol include B vitamin supplementation in patients demonstrated to have elevated homocysteine ( > 8 µmol/l) as well as generous supplementation of docosahexaenoic acid (DHA) an omega-3 fatty acid that, like caloric restriction and physical exercise, is associated with increasing BDNF.
There is no currently available pharmaceutical intervention for Alzheimer’s disease supported by meaningful scientific evidence. The integrative interventions described above not only are supported by well respected research, but are cost effective and fulfill the dictum, “above all, do no harm.”
Integrative Medicine Approaches for Early Alzheimer’s Disease
Published in the Swedish Medical Journal
David Perlmutter, MD, FACN, ABIHM