Alzheimer’s disease is the third leading cause of death in the United States (James 2014). Over 5 million Americans are currently diagnosed with Alzheimer’s disease (AD) and it is estimated that as many as 45 million Americans may eventually develop AD (Plassman 2011; Seshadri 1995). Almost 20 years ago the Centers for Disease Control estimated the annual cost of caring for Alzheimer’s disease patients at $100 billion (CDC 2000). The social and economic burdens of Alzheimer’s disease continue to increase as the population gradually ages. Available pharmacologic treatments of AD are sometimes effective for early mild symptoms of cognitive impairment but are ineffective against severe symptoms. These circumstances have led to enormous research efforts aimed at developing more effective treatments and preventive strategies.

Limitations of available pharmacologic treatments

In recent decades the research emphasis on pharmacologic treatments of Alzheimer’s disease has shifted from vasodilators to drugs that increase brain levels of the neurotransmitter acetylcholine. Currently available pharmacologic treatments of AD work by inhibiting the enzyme that breaks down acetylcholine, increasing available levels of the neurotransmitter that is critical for learning and memory. Commercially available cholinesterase inhibitors have significant adverse effects and are only effective against mild or early symptoms of Alzheimer’s disease but not other forms of dementia. Early promising results of studies on tacrine, the first commercially marketed acetylcholinesterase inhibitor, were offset by findings of significant hepatotoxicity (liver toxicity). Second-generation acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are no more effective than tacrine but require less frequent dosing and have fewer associated safety issues. These concerns led to discontinuation of tacrine in 2013.

Other pharmaceutical agents that have been investigated for possible cognitive-enhancing benefits in dementia include the monoamine oxidase inhibitors (MAOIs), estrogen replacement therapy (i.e., in cognitively impaired postmenopausal women), naloxone, and various neuropeptides, including vasopressin and somatostatin (Zandi et al., 2005). Promising novel Western biomedical treatments of Alzheimer’s disease currently being investigated in clinical trials include a vaccine that may immunize individuals against formation of amyloid-β, secretase inhibitors, anti-inflammatory agents, and statins (Herline 2018; Cao 2018). Results of studies on statins in dementia have been inconsistent. However, a 2017 meta-analysis of 31 studies that met inclusion criteria for size and rigor found that regular statin use is associated with significant reduction of risk of developing dementia (Zhang 2018).

The central role of diet in reducing Alzheimer’s risk

Pathological changes in the brain that lead to Alzheimer’s disease start many years before the onset of cognitive decline hence dietary changes play an important role in delaying or preventing Alzheimer's disease (Rodriguez-Vieitez 2016). A high calorie diet promotes formation of damaging free radicals that cause many neuropathological changes in the brain increasing the risk of Alzheimer’s disease. Adhering to a Mediterranean diet emphasizing fish, fresh vegetables and fruits (Feart 2009; Morris 2015; Barnard 2014; Grant 2016), moderating alcohol consumption (Letenneur 2004), and regular exercise, significantly reduce the risk of developing Alzheimer’s disease. A recent study found that the MIND diet (Mediterranean-DASH Intervention for Neurodegenerative Delay) may reduce the risk of Alzheimer’s by up to 50% (Morris 2015). An early meta-analysis of findings from 18 community-wide studies concluded that the risk of Alzheimer’s disease increased linearly at a rate of 0.3% with every 100-calorie increase in daily intake (Grant, 1997). The same meta-analysis showed that fish consumption was the only specific dietary factor associated with a measurable reduction in the risk of developing Alzheimer’s disease.

Regular intake of foods rich in omega-3 fatty acids may be inversely related to cognitive impairment and the rate of overall cognitive decline in nondemented elderly individuals. Regular consumption of foods rich in omega-3, especially fish, may reduce oxidative stress and associated atherosclerotic changes in the brain, indirectly lowering the risk of cognitive decline due to cerebrovascular disease. In contrast, high dietary intake of omega-6 polyunsaturated fatty acids, including linoleic acid, may contribute to increased oxidative stress in the brain, indirectly promoting atherosclerosis and increasing the risk of stroke. A large epidemiologic study found that fish consumption 2 to 3 times weekly significantly reduces the risk of cognitive decline in elderly populations (Kalmijn, Feskens, Launer, & Kromhout, 1997). Findings from a prospective cohort study (Morris et al., 2003) suggest that individuals who consume fish at least weekly have a 60% lower risk of developing Alzheimer’s disease compared with individuals who seldom eat fish. However, a similar study failed to show a correlation between fish consumption and the risk of developing Alzheimer’s disease (Englehart et al 2002). Another study found that enhanced cognitive performance in nonimpaired middle-aged individuals is correlated with high intake of fatty fish and other foods rich in omega-3 fatty acids (Kalmijn, van Boxtel, Ocke, Vershuren, Kromhout, & Launer, 2004).

Multi-modal interventions aimed at optimizing life-style factors

Positive findings of studies on diet in dementia are confounded by the fact that individuals who follow healthy dietary preferences also engage in other health-promoting behaviors that reduce risk of dementia, for example regular exercise and moderate alcohol consumption (Barberger-Gateau, Letenneur, Deschamps, Peres, Dartigues, & Renaud, 2002). These findings have led to recent studies on so-called ‘multi-modal’ interventions aimed at identifying specific combinations of lifestyle factors that play the most significant roles in preventing or delaying onset of Alzheimer’s disease.

It is estimated that one third of Alzheimer’s disease cases are caused by one or more lifestyle factors that can be modified suggesting that multi-modal interventions addressing many of these factors may have significant preventive benefits. Important modifiable lifestyle factors are low education, hypertension, diabetes, obesity, smoking, sedentary lifestyle and depressed mood. So far only one large multi-center study has investigated multi-modal interventions aimed at preventing Alzheimer’s disease in elderly at-risk individuals (Ngandu 2015). That study found significant improvement in overall cognition, improved processing speed and executive functioning in the treatment group that were significantly greater than in the control group. Other multi-modal studies are ongoing at the time of writing.

Along similar lines, case reports have been published of dramatic improvement in individuals diagnosed with early Alzheimer’s disease who adhere to multi-modal life style changes (Bredesen 2014) aimed at enhancing cognitive performance and reducing metabolic risk factors. These findings show that, in at least some cases, symptoms of early Alzheimer’s disease can be reversed within 6 months after initiating a comprehensive lifestyle regimen (Bredesen 2014). The goal of this approach is to normalize multiple metabolic parameters related to inflammation in the body, thus interrupting the pathological processes that eventually lead to Alzheimer’s disease. Beneficial effects achieved through dietary modification, regular exercise, stress management or a mindfulness practice, and supplementation with natural supplements probably involve different mechanisms at multiple levels in the body and brain including enhanced immune function; reduced insulin resistance; reduced inflammation; reduced brain atrophy and stimulation of new synapse formation.

The protocol, called metabolic enhancement for neurodegeneration (MEND), entails comprehensive laboratory screening that may include serologic studies of inflammatory markers, functional brain scans, genetic analysis of risk, and cognitive testing. Personalized lifestyle changes and nutritional strategies are subsequently recommended to correct underlying causal factors of cognitive decline identified in screening. The MEND protocol includes the following specific recommendations:

• Strict adherence to a low-glycemic diet
• 12-hour fast each night (including 3 hours before bedtime)
• Consumption of probiotic-rich foods like plain Greek yogurt, kombucha, kefir, and fermented foods like miso and sauerkraut, and antioxidant-rich foods like blueberries and blackberries
• 8 hours sleep every night, treating sleep apnea when it is present and use of melatonin if needed
• A regular mind-body or mindfulness practice
• Regular exercise 30 to 60 minutes 4 to six times a week
• Vitamin B-12 (goal is serum vitamin B-12 levels higher than 500)
• Curcurmin 400 to 500mg 3 to 4 times daily (taken with meals for better absorption)
• Citicoline 1000 to 2000mg and the omega-3 fatty acid (DHA)
• Daily supplementation with vitamin D3 in individuals with vitamin D deficiency vitamin E 400 mg (mixed tocopherols and tocotrienols); vitamin C 500-1,000 mg
• Alpha lipoic acid 200 mg

Many individuals with early Alzheimer’s disease (including some individuals with the ApoE4 gene who are at very high risk of developing an early severe form of Alzheimer’s disease) who adhere to the MEND protocol report sustained improvement in cognitive performance for several years and no longer meet criteria for a diagnosis of Alzheimer’s disease. Large prospective controlled trials are needed to confirm findings of case reports and elucidate the roles of specific lifestyle changes, metabolic factors and natural supplements in reversing or slowing rate of progression of Alzheimer’s disease.