Alzheimer’s disease (AD) is the only common chronic disease that has no known cure or way to prevent its development. This is a critical problem because the rates of AD are expected to increase over the next several decades. In the United States, approximately 5.3 million people have AD, which comprises up to 80% of all dementia cases. That number is expected to increase to 13.8 million people by 2050.
The belief that AD does not respond to any intervention has largely disproven over the last 10 years. This belief was grounded in the idea that the nervous system is static and unchanging. Numerous drug trials were conducted over the last several decades, which has led to a significant conclusion: AD has multiple factors that develop over decades before the onset of symptoms and is a result of lifestyle.
The concept of neuroplasticity is gaining acceptance rapidly. A 2014 study by UCLA showed a reversal of mild to moderate AD using a comprehensive approach of individualized diet and lifestyle recommendations (improvement in 9 out of 10 participants). Of all of the systemic factors, one of the most important to address is insulin resistance.
Insulin resistance and the brain
An important finding of the pathology of AD is the strong correlation between AD and insulin resistance, metabolic syndrome, and type 2 diabetes. As much as 40% of AD pathology can be related to hyperinsulinemia. Higher HbA1c levels correlate with lower cognitive capacity and changes in hippocampal microstructure, and positive APOE e4 genetic status (a genetic determinant of AD risk) is correlated with increased risk of type 2 diabetes, altered lipid profiles, and cardiovascular disease. Research suggests that early intervention to address impaired cerebral glucose metabolism may be critical for the outcome success in treating AD. In addition, treating diabetes in later life reduces the conversion of mild cognitive impairment to AD and all-cause dementia.
Pathophysiology
It is also well known that the brain regions (especially the hippocampus) that rely most heavily on insulin and insulin-like growth factor (IGF) signaling are the most vulnerable to AD pathology. Impairments in brain insulin/IGF signaling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ aggregates.
Using a dietary approach
A comprehensive approach to AD must address multiple factors. However, the basis for successful therapy of dementia begins with diet. For AD, a diet must account for blood sugar abnormalities. Strict sugar control is even more crucial in the elderly population, as taste preferences increase for calorie- and carbohydrate-rich, micronutrient-poor, sweet foods.
Mediterranean and dash diets
A modified Mediterranean and DASH (dietary approach to stop hypertension) diet were studied in a population of 923 participants who were followed for 4.5 years. Named the MIND diet, those who had the greatest adherence (the top thirty-three percent) to the diet had a 53% reduction is the risk of developing AD. Those in the middle third in adherence had a 35% risk reduction. The MIND diet was associated with a slower rate of cognitive decline equivalent to 7.5 years of mental age. While the study outcome relates more to prevention than treatment, the same principles can be applied to individuals with an early diagnosis, as pathological changes typically occur long before the onset of symptoms.
Therapeutic fasting
Therapeutic fasting has long been relied upon heavily as a natural cure. In industrialized nations with an abundance of fast food outlets, obesity has skyrocketed. A higher intake of calories and fat in 980 elderly individuals studied over 4 years was associated with a 2.3-fold higher AD risk, but only in those who were APOE4+. In an 18-year study, those who habitually consumed fewer calories had lower AD rates, and for every 1.0 increase in BMI at age 70, AD risk increased by 36%.15 In a review of the metabolic effects of calorie-restricted or intermittent-fasting diets, insulin sensitivity measured via HOMA-IR correlated well with weight loss in most studies; 1 typical study correlated an 8% weight loss to a 33% improvement in insulin sensitivity. Similarly, reductions in fasting insulin of 20-31% were noted after 8-12 weeks of treatment. In most studies of intermittent or alternate-day fasting, visceral fat loss parallels overall weight loss, around 4-7% over 6-24 weeks of treatment.
While long-term outcome studies in humans need to be conducted, several small trials have produced interesting results. Caloric restriction of 3-4 months improved cognitive function in the elderly, as measured by verbal memory scores, in parallel with reduced fasting insulin and C-reactive protein (CRP).
There are several potential cellular mechanisms involved with these diets, including reduced oxidative stress, improved cellular bioenergetics, enhanced neurotrophic factor signaling (BDNF and FGF2), and reduced inflammation (reduced TNFα, IL-1β, and IL-6). While many variations of caloric restriction and intermittent fasting exist, daily overnight fasting (12-18 hours) generally produces better compliance and safety profiles. Every patient should be assessed on an individual basis and carefully monitored throughout treatment.
Ketogenic diets
Another key benefit of intermittent fasting or caloric restriction is the induction of ketosis after 12-16 hours of fasting. Glucose hypometabolism, which produces chronic brain energy deprivation in AD patients is roughly 20-25% lower than in age-matched, cognitively-normal individuals. For those with type 2 diabetes, these changes are often most pronounced in the frontal cortex and can occur in ages as young as 24 years old. The ability to produce and utilize ketone bodies as an alternate substrate may actually increase with age and with insulin resistance (which causes an increase in monocarboxylate transporters). While we only have 33 g/day of glucose from glycogen stores, the average human brain metabolizes 110-145 g/day of glucose for ATP production. This is why an alternate fuel source is necessary and provided by nature: ketone bodies (specifically beta-hydroxybutyrate and acetoacetate, which are beta-oxidized in the liver from long-chain fatty acids).
Ketogenic diets tend to be high in fat and very low in carbohydrates. A common macronutrient profile would include a maximum of 30 g carbohydrate, 1 g protein/kg body weight, and the rest of the calories from fat (20% saturated / 80% polyunsaturated and monounsaturated). An alternative that is likely to meet with higher compliance is the direct consumption of medium-chain triglycerides (MCTs), most readily available in coconut oil, which increases ketone body levels regardless of macronutrient intake; MCT oils provide a linear dose-response relationship to increased plasma ketones.
Final thoughts
Alzheimer’s disease resulting from heredity is very rare. There is a genetic component that can be mitigated with naturopathic approaches. AD is a disease that manifests in end-organ brain pathology. Without a change in lifestyle, AD will likely burden the industrialized world in increasing cases. However, if we approach the disease as a systemic disease, early interventions could include significant lifestyle and diet changes.