The idea that AD is recalcitrant to all interventions is grounded in a belief that has been largely disproven within the last decade - that the nervous system is static and categorically unchangeable. The large cost and consistency of failed drug trials over the last several decades leads us to 1 central conclusion: Alzheimer's disease is a multifactorial phenomenon which develops over several decades prior to the onset of symptoms and is, in large part, a result of lifestyle.
Fortunately, the concept of neuroplasticity is quickly becoming mainstream. A 2014 study by UCLA, though small (improvement in 9 out of 10 participants), for the first time showed a reversal of mild to moderate AD using a comprehensive approach of individualized diet and lifestyle recommendations.2 Of all of the systemic factors at play, perhaps none is more crucial to address than insulin resistance.
"DIABETES OF THE BRAIN"
A key finding in our evolving understanding of relevant pathology is the strong correlation between AD and insulin resistance, metabolic syndrome, and type 2 diabetes (T2DM). In fact, as much as 40% of AD pathology has been attributed to hyperinsulinemia.3,4 Higher HbA1c levels correlate with lower cognitive capacity and changes in hippocampal microstructure, and positive APOE e4 genetic status (the most well-studied genetic determinant of AD risk) is correlated with increased risk of T2DM, altered lipid profiles, and cardiovascular disease.5,6As long-standing impaired cerebral glucose metabolism is a central aspect of AD pathology, research suggests that intervention at midlife may be especially critical for outcome success.7Further, successfully addressing diabetes in later life reduces the conversion of mild cognitive impairment to AD and all-cause dementia.8
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.9,10 Impairments in brain insulin/IGF signaling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ aggregates.11 Some of the proposed mechanisms, all of which are at least partially amenable to naturopathic approaches, are listed in Figure 1.11
THREE DIETARY APPROACHES
A comprehensive approach to AD must be multifactorial (Table 2), but the foundation of any successful therapy for dementia must begin with diet. For AD, the foundation of a successful 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.12
MIND YOUR DIET
A hybrid Mediterranean and DASH diet (see Table 1), with several cognition-specific modifications, was studied in a population of 923 participants who were followed for 4.5 years. Aptly named the MIND diet, those who scored in the highest 1/3 of adherence (strict adherence) to the diet had a 53% risk reduction of developing AD.13 Just as impressive, those who were in the middle 1/3 (moderate adherence) had a 35% risk reduction.
For the majority of patients consulting a naturopathic physician, though, adherence to this diet will not seem especially strict; for example, a positive score was obtained by limiting red meat to a still-excessive 4 times per week. Also, the glycemic index of foods consumed was not a considered measurable, providing a further opportunity to optimize the diet. Even still, 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 symptoms set in.
Table 1. MIND Diet Used in Clinical Study13
Foods to Eat
· Green leafy vegetables (eg, spinach and salad greens): At least 6 servings/wk
· Other vegetables: At least 1 serving/day
· Nuts: 5 servings/wk
· Berries: 2 or more servings/wk
· Beans: At least 3 servings/wk
· Whole grains: 3 or more servings/day
· Fish: Once per week
· Poultry (eg, chicken or turkey): 2 times/wk
· Olive oil: Use it as your main cooking oil
· Wine: 1 glass/day
Foods to Avoid
· Red meat: Fewer than 4 servings/wk
· Butter & margarine: Less than 1 tbsp/day
· Cheese: Less than 1 serving/wk
· Pastries & sweets: Fewer than 5 servings/wk
· Fried or fast food: Less than 1 serving/wk
Therapeutic fasting has long been an approach of the hygienic physicians, and it was relied upon heavily in the origins of nature cure. In industrialized countries where (fast) food is readily available, the population is overeating at unprecedented rates. A higher intake of calories and fat in 980 elderly individuals studied over 4 years was associated with 2.3-fold higher AD risk, but only in those who were APOE4+.14 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.16 In most studies of intermittent or alternate-day fasting, visceral fat loss parallels overall weight loss, on the order of 4-7% over 6-24 weeks of treatment.16
While sufficient long-term outcome studies in humans are currently lacking (many animal studies have been conducted), several small trials exist. Caloric restriction (CR) 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).17
There are several potential cellular mechanisms involved with these diets (thought mostly to result from the hormetic effect of energy restriction), the best studied of which include reduced oxidative stress, improved cellular bioenergetics, enhanced neurotrophic factor signaling (BDNF and FGF2), and reduced inflammation (reduced TNFα, IL-1β and IL-6).18,19While many variations of caloric restriction and intermittent fasting exist, higher compliance and safety profiles are expected with daily overnight fasts (ranging from a minimum of 12 hours to 16 or 18 hours) compared to longer fasts. Of course, every patient should be assessed on an individual basis and carefully monitored throughout treatment.
Another key benefit of intermittent fasting or caloric restriction is the induction of ketosis after 12-16 hours of fasting. Glucose hypometabolism (leading to chronic brain energy deprivation) in AD patients is roughly 20-25% lower than in age-matched, cognitively-normal individuals.20 In those prone to diabetes, these changes are often most pronounced in the frontal cortex, and in some can be discovered at ages as young as 24 years old.21Importantly, 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).22,23 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. For this reason, an alternate fuel source is required and fortunately 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 restrictive of carbohydrates. A common macronutrient profile would include a maximum 30 g carbohydrate, 1 g protein/kg body weight, and the rest of 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 increase ketone body levels regardless of macronutrient intake; MCT oils provide a linear dose-response relationship to increased plasma ketones. A therapeutic dose is 2 tbsp of organic virgin coconut oil per day, which provides on average 20 g of MCTs.24 This dose should be titrated gradually to avoid digestive disturbance. Otherwise, MCT oils have been shown to be safe, with a 30-day treatment of 30 g/day of MCTs not adversely affecting body weight, body fat content, body mass index, serum glucose, insulin, triglycerides, cholesterol, or free fatty acids.25
Comment: See also:
True familial Alzheimer's disease is exceedingly rare, and while there is a genetic component (positive APOE4 status), this effect can be mitigated with a naturopathic approach. AD is, of course, a disease manifesting in end-organ brain pathology. Viewed in this reductionist way, it is likely to continue to be a burden plaguing the industrialized world in increasing numbers. However, if approached as a systemic disease with brain-specific susceptibility, perhaps the naturopathic profession can be at the forefront of preserving all which is at stake.