Like insulin, GLP-1 stimulates neuritic growth in CNS neurons and exerts neuroprotecive actions against glutamate-mediated excitotoxity, oxidative stress, trophic factor withdrawal, and cell death [311
]. In addition, inhibition of dipeptidyl peptidase-4, which degrades GLP-1, reduced oxidative and nitrosative stress, inflammation, memory impairment, and AβPP-Aβ deposits in an AD transgenic mouse model [314
]. At the very least, these observations support the hypothesis that insulin resistance and deficiency play critical roles in the pathogenesis of AD. Importantly, GLP-1 can cross the blood-brain barrier, and may effectively reduce brain AβPP-Aβ burden in AD [309
]. With the realization that GLP-1 has a short half-life and therefore limited practical use for long-term therapy, synthetic long-lasting analogues of GLP-1 have been generated and proven to be effective in preserving cholinergic neuron function [316
]. The development of GLP-1 receptor agonists, such as Geniposide or Exendin-4, which harbor the same neuro-protective and neuro-stimulatory properties as GLP-1 [317
], but have longer half-lives [311
], may provide effective and standardized long-term options for treating brain insulin resistance diseases such as AD. Finally, a future approach could be to utilize a form of gene therapy in which genetically modified mesenchymal or stem cells are implanted into the lateral ventricles for sustained delivery of neuro-stimulatory and neuro-protective agonists [320
], including GLP-1 [323
Peroxisome proliferator-activated receptors [PPAR] are steroid hormone super family ligand-inducible transcription factors that enhance insulin sensitivity, modulate glucose and lipid metabolism, stimulate mitochondrial function, and reduce inflammatory responses [326
]. Three classes of PPARs are recognized, PPAR-α, PPAR-δ, and PPAR-γ. All 3 are expressed in the adult brain, although PPAR-δ is most abundant, followed by PPAR-γ [8
]. PPAR agonist treatments improve cognitive performance in experimental animal models [83
] and in humans with AD or MCI [148
]. The PPAR-γ agonist, rosiglitazone, has been most widely studied in human clinical trials. In addition to its insulin sensitizing and anti-inflammatory properties, rosiglitazone, like metformin, increases expression of the GLUT4 glucose transporter and glucose metabolism. Moreover, simultaneous treatment with PPAR agonists such as, rosiglitazone, enhances the therapeutic effects of metformin+insulin.
In a small double-blind, placebo-controlled trial, investigators showed that rosiglitazone treatment significantly preserved performance on delayed recall and attention tasks relative to the placebo-treated group, which continued to decline [332
]. However, a later study found that rosiglitazone therapy was mainly effective in preserving cognition in patients who were ApoE ϵ4-negative, while the ApoE ϵ4+ subjects showed no improvement or continued to decline [333
]. Despite promising experimental results, initially positive clinical studies, and supportive evidence that impaired glucose metabolism and insulin resistance are key components in the pathogenesis of AD, the most recent outcome of a rosiglitazone monotherapy, randomized double-blind placebo controlled phase III study was negative with respect to improvements in objective cognitive assessments, but highly statistically significant based on clinical and caregiver impression [334
]. Potential explanations for these disappointing results include the following: 1) effective treatment of neurodegenerative diseases may require a different isoform of PPAR agonist, i.e. PPAR-δ, since PPAR-δ is abundantly expressed in the brain, and previous studies showed that PPAR-δ agonist treatment more effectively prevented AD-type neurodegeneration and neurocognitive deficits compared with PPAR-α and PPAR-γ agonists [83
]; 2) the biodistribution of the PPAR agonists may not have been optimized based on the structure of the compounds; and 3) mono-therapy may not be sufficient, and instead the combined administration of a PPAR agonist with insulin or GLP-1 and metformin may be required to effectively treat AD-associated brain insulin resistance and metabolic dysfunction.
Alpha Lipoic Acid (ALA)
ALA is a natural compound that supports mitochondrial function, serving as a cofactor for pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Importantly, ALA enhances production of acetylcholine by activating choline acetyltransferase and increasing glucose uptake [335
]. Therefore, the potential benefits of ALA are mediated by the supportive actions of ALA on insulin and GLP-1. However, beyond those effects, ALA has anti-oxidant effects, since it serves as an inhibitor of hydroxyl radical formation and can scavenge reactive oxygen species and lipid peroxidation products such as 4-hydroxy-2-nonenal [335
], which are increased in AD brains [336
]. In addition, ALA inhibits expression of pro-inflammatory cytokines and inflammation-associated nitric oxide synthase, which have important roles in mediating neuro-inflammation in the early stages of AD [338
]. Although there are few clinical trials examining the efficacy of ALA therapy for AD, there is some evidence that ALA may slow the progression of cognitive impairment in patients with moderately severe AD [335
Chromium is an often overlooked essential metal that has an important role in regulating the actions of insulin, including carbohydrate, protein, and lipid metabolism [342
]. Chromium enhances insulin sensitivity by increasing insulin receptor binding, insulin receptor number, and insulin internalization. In addition, chromium lowers blood glucose, triglycerides, and low density lipoprotein (LDL) cholesterol, increases high density lipoproteins (HDL), and reduces risk for cardiovascular disease [345
]. Moreover, chromium supplementation improves cognitive performance, including memory, promotes weight loss, and helps control diabetes. Chromium picolinate mediates its effects on body weight by reducing food craving and increasing satiety [347
]. Although food sources of chromium are fairly abundant and include, whole grains, lean meats, cheeses, corn oil, black pepper, thyme, and brewer’s yeast, most foods contain relatively low levels of chromium per serving (1-2 mcg), and most dietary forms of chromium are poorly absorbed. On the other hand, chromium picolineate, which is highly stable and consists of Cr[III] chelated with three molecules of picolinic acid, was formulated to increase the bioavailability of ingested chromium [346
]. In vivo
studies have demonstrated considerable safety associated with chromium picolinate use, including long-term exposures [348
Although clinical studies investigating the therapeutic effects of chromium picolinate supplementation have yielded conflicting results, in the vast majority of clinical trials (utilizing 150-1000 mcg/day), chromium picolinate was found to significantly improve glycemic control and reduce blood cholesterol and triglyceride levels in diabetics [350
]. With increasing age, plasma chromium levels decline. This phenomenon could partly account for aging-associated insulin resistance and cognitive decline since reduced levels of chromium are correlated with cognitive impairment and AD [351
]. In a recent double-blind placebo controlled clinical study, a 12-week period of chromium picolinate supplements administered to elderly subjects significantly reduced semantic interference on learning, recall, and recognition memory tasks [352
]. In addition, functional magnetic resonance imaging demonstrated increased activity in the thalamus, and frontal, parietal and temporal lobes of treated subjects, indicating that chromium picolinate can enhance cognitive function in elderly people [352
]. Due to its positive effect on insulin signaling mechanisms and relative safety, it appears that chromium supplementation has a role in long-term support of metabolic pathways, both systemically and within the CNS. Given the demonstrated roles of T2DM, obesity, and peripheral insulin resistance as mediators of cognitive impairment and neurodegeneration, and supportive evidence that improvements in insulin responsiveness enhance cognitive function and reduce neurodegeneration, the inclusion of chromium picolinate as a dietary supplement, or development of like compounds that achieve the same, or better and more reproducible effects could help target fundamental metabolic dysfunctions that occur early in the course of AD.
Diet, Supplements, and Lifestyle
There is little doubt that the explosion in insulin resistance diseases, including diabetes, obesity, non-alcoholic fatty liver disease, polycystic ovarian disease, and dementia, followed revolutionary changes in the Western diet that resulted in an exponential rise in the consumption of highly processed foods that either lack the appropriate nutrients for long-term support of CNS and systemic metabolic functions, or contain added ingredients that impair protective actions of natural food substances [455
]. Until recently, long-term pro-active nutritional support has taken a back seat with respect to disease prevention, particularly among allopathic physicians. In retrospect, the concept is illogical given the clear evidence that: 1) certain amino acids help elaborate neurotransmitters and trophic factors for brain function; 2) omega-3, other essential fatty acids, and Vitamin E (alpha tocopherol) [456
] support membrane maintenance and renewal needed for neuronal plasticity; 3) Vitamins A, C, E, and beta carotene have anti-oxidant properties; and 4) many B vitamins, including Vitamins B1 (thiamine), B2 (riboflavin), B3 (niacin), B6 (pyridoxine), B9 (folate), and B12 (cobalamin) are required for a broad range of neurological functions, including cognition [457
Omega-3-fatty acids function as ROS scavengers, and they are essential for brain growth and function throughout life. For example omega-3 fatty acids modulate various neuronal functions, protect against neuronal oxidative stress, and inhibit signaling pathways that promote tau phosphorylation and assembly into paired helical filaments [458
]. Aging-associated cognitive impairments have been linked to omega-3-fatty acid deficiencies, while dietary supplementation with docosahexaenoic acid (DHA), which is the major form of omega-3 fatty acid found in neurons and available in the diet from oily fish [459
], was shown to be neuroprotective in lowering the risks of cognitive impairment and AD [458
]. Observational studies provide positive evidence that chronic omega-3 ingestion is beneficial to cognitive function [458
], while low fish consumption increases risk for AD [462
]. Experimentally, eicosapentaenoic acid (EPA) and DHA reduce AβPP-Aβ fragment formation, and DHA enhances synapse formation [463
]. Although observational and epidemiological studies positively support the concept that omega-3 and other essential fatty acids should be regularly incorporated into the diet, specific guidelines regarding dosages and frequency are difficult to establish because firm conclusions can seldom be drawn based on short-term clinical trials [460
With regard to the B vitamins, thiamine (B1) is needed for glucose metabolism and energy production, and thiamine deficiency syndromes include psychosis, dementia, peripheral neuropathy, and heart failure. Folate (B9) preserves memory during aging, and when combined with vitamin B12, delays the onset of dementia. Deficiencies in pyradoxine [B6] and cobalamin [B12] are correlated with cognitive impairment. In addition, B12 negatively regulates plasma homocysteine, and high levels of homocysteine increase risk for cardiovascular disease, cerebrovascular disease, and cognitive impairment. In short, deficiencies in B vitamins lead to chronic disablement of insulin signal transduction pathways, neurotransmitter functions, and cognition. Although many studies designed to objectively examine the therapeutic effectiveness of vitamin and nutritional supplements for preventing neurodegeneration have failed, conclusions drawn from their negative results should be cautious because for the most part, the study designs tend to be either underpowered or too limited in duration to achieve statistically significant results [464
]. Conceivably, population based epidemiologic studies, combined with experimentation, may provide the best guidance for the long-term use of dietary supplements for brain health.
Based on data culled from a broad range of studies on the effectiveness of lifestyle and dietary measures for supporting brain health and providing some degree of neuroprotection, the following conclusions could be drawn: 1) aerobic exercise and caloric restriction significantly improve cognitive performance and slow progression toward neurodegeneration. These effects are mediated by enhancement of insulin and IGF responsiveness and slowing of the aging process, in part due to SIRT1 activation. Aging is by far the most significant risk factor for AD [434
] and AD is mediated in large measure by brain insulin resistance and impaired energy metabolism [7
]. Therefore, measures that support or bolster insulin sensitivity, including exercise, caloric restriction, and loss of excess weight retard both aging and lower the risk of AD; 2) dietary supplements such as omega-3 fatty acids and compounds such as chromium picolinate, curcumin, alpha lipoic acid, cinnamon, and red bean lectin (stimulates GLP-1), that have insulin sensitizing properties [471
], could help support neuronal plasticity and signaling mechanisms that regulate neuronal metabolism and reduce fibrillarization of AβPP-Aβ and tau [394
]; 3) agents that reduce oxidative stress, including fat soluble vitamins, natural statins such as those supplied in red yeast rice, and polyphenols, including those present in red wine, green tea, curcumin, and soy isolate protein [472
], reduce the generation of reactive oxygen and reactive nitrogen species, DNA damage, and activation of pro-inflammatory, pro-injury, and pro-death signaling; 4) ample supplementation with multiple B vitamins that support nervous system and cardiovascular function, and reduce homocysteine levels [473
] are neuroprotective.
In summary, a vast volume of literature has been summarized and discussed in an attempt to demonstrate how seemingly disparate concepts and opinions about the mechanisms of neurodegeneration actually converge toward a relatively recently appreciated theme that impairments in brain insulin and IGF signaling and responsiveness are at the core of AD. Insulin and IGF resistance can account for the deficits in brain glucose utilization and energy metabolism that are detectable early in the course of AD. The attendant inhibition of insulin/IGF signaling leads to aberrant activation of kinases that lead to tau hyper-phosphorylation. Impairments in energy metabolism and glucose utilization have broad consequences due to increased oxidative stress, activation of pro-inflammatory cascades, and ROS generation, all of which promote aberrant AβPP expression and cleavage, AβPP-Aβ42 accumulation, and fibrillarization and misfolding of tau and AβPP-Aβ. Increased ROS production causes electrophilic attacks on proteins, lipids, and nucleic acids, resulting in the formation of adducts that promote further structural and functional damage, oxidative stress, ubiquitination of proteins, targeting them for degradation. Insulin/IGF resistance impairs lipid metabolism, leading to disruption of myelin homeostasis. AD is associated with white matter atrophy, myelin loss, and increased myelin breakdown with production of potentially toxic sphingolipids, including ceramides. Neurotoxic ceramides promote insulin resistance, neuroinflammation, and oxidative stress. Finally, brain insulin/IGF resistance can also explain the frequent co-existence of cerebral microvascular disease, which substantially contributes to the neuropathology of AD.
Genetic or familial forms of AD represent the minority of the overall population at risk for developing AD. Although valuable lessons have been and will continue to be learned by studying genetic forms of this disease, future efforts should be focused on understanding factors that contribute to the pathogenesis and progression of sporadic AD. Certainly the extremely rapid rise in AD prevalence rates, manifested by up to several hundred-fold higher age-adjusted rates in 2005 compared with 1980 cannot be explained by genetic factors, and instead parallels trends that characterize exposure models of disease [1
]. In fact, the age-adjusted trends in AD prevalence rates are similar to those observed for diabetes mellitus [1
]. Although we do not know the cause[s] of AD, epidemiological, observational, and experimental evidence together support the hypothesis that AD is a metabolic disease with virtually all of the features of diabetes mellitus, but largely confined to the brain. One very important conclusion that could be drawn from this review is that the concept of using mono-therapy to treat AD is wrong, and instead, multiple targets must be attacked simultaneously and over a prolonged period of time [260
], similar to current approaches used to treat malignancies. Future multi-modal therapies for AD should be directed at multiple levels of demonstrated weakness within the insulin/IGF signaling cascade, beginning with receptor sensitizers, agents to promote insulin production and release, e.g. GLP-1, inhibitors of oxidative stress, radical formation, and metal ion accumulation, tau phosphorylating kinase modulators, and co-factors that support glucose utilization, mitochondrial function, and energy metabolism. If effective, these combined treatments will likely enhance neurotransmitter activity and availability, neuronal plasticity, and neuronal survival, which are needed to preserve cognitive function.
Complementary and alternative medicine approaches have been used extensively and for centuries throughout the world. The institution of modern medicine has concerns and reservations about embracing the philosophies of naturopathic, homeopathic, and complementary and alternative medicine because allopathic medicine is evidence-based, i.e. based on objective scientific and clinical experimentation. As modern medicine advances scientifically, personalized diagnostics and therapeutics will continue to grow more mechanized, molecular, biochemical, and genetic test-driven, and algorithm-based. However, the unintended consequences include, rank dismissal or abandonment of common-sense preventive and counseling approaches. Unfortunately, we are still without effective means to accurately detect and characterize AD in its early stages, when it would be most responsive to treatment, and we lack effective and universally accepted long-term approaches to treatment and prevention of AD, despite enormous effort and funds spent over the past several decades. Inconsistencies among studies designed to evaluate the effectiveness of natural compounds for treating or preventing neurodegeneration stem from observational versus double-blind placebo controlled clinical trials, with generally more favorable data obtained from the former [475
Frustration over the lack of answers and sustained positive outcomes from state-of-the-art therapy, has probably helped to fuel the growing utilization of complementary and alternative medicine to treat AD. Instead of focusing on the use of pharmaceutical grade, FDA-approved drugs, emphasis is placed on lifestyle modifications, diet, macronutrient and micronutrient supplements, and consumption of natural compounds to prevent, retard, or cure chronic diseases [476
]. These approaches are generally dismissed outright, or met with heavy skepticism due to the lack of clear and systematic guidelines for evaluating effectiveness of complementary and alternative therapies for improving cognitive performance [477
]. Moreover, although specific nutritional deficiencies have been correlated with particular disease states, growth in our knowledge of how micro- and macronutrients contribute to brain and bodily health, and how they may prevent, delay, or modify the course of chronic disease, has been slow. Finally, many studies designed to objectively examine the effectiveness of these alternative approaches have been either underpowered or too limited in duration to achieve statistically significant results, leading some to conclude that such measures would be fruitless [464
]. Conceivably, population based epidemiologic studies, combined with experimentation, may provide the best guidance in the long-term use of dietary supplements.