Alzheimer’s disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.

Keywords: Alzheimer’s disease, dementia, neurofibrillary tangles, neurodegeneration cascade.

Contributions of Obesity and T2DM to Cognitive Impairment and Neurodegeneration

Epidemiologic studies demonstrated that individuals with glucose intolerance, deficits in insulin secretion, or T2DM have a significantly increased risk for developing mild cognitive impairment (MCI) or AD-type dementia. Longitudinal studies provided further evidence that T2DM [91, 92] and obesity/dyslipidemic disorders [93] were correlated with later development of MCI, dementia, or AD [91, 94–99]. However, one study showed that obesity itself, with or without superimposed T2DM, increased the risk for MCI, AD, or other forms of neurodegeneration [100], suggesting that systemic factors related to obesity, other than T2DM, can promote neurodegeneration. On the other hand, although a relatively high percentage of individuals with MCI or dementia have T2DM, peripheral insulin resistance, or obesity, the vast majority of patients with AD do not have these diseases. To gain a better understanding of the contributions of T2DM and obesity to neurodegeneration, attention must be given to postmortem human and experimental animal studies.

In general, the arguments made in favor of the concept that T2DM or obesity causes AD are not founded; however, the concept that peripheral insulin resistance disease states contribute to cognitive impairment and AD pathogenesis or progression does have a sound basis. Against a causal role are the findings that, postmortem human brain studies demonstrated no significant increase in AD diagnosis among diabetics [101], and similarly abundant densities of senile plaques and rates of neurofibrillary tangle pathology were observed in subjects with T2DM compared with normal aged controls, although peripheral insulin resistance was more common in AD than with normal aging [102]. Since neurofibrillary tangles and dystrophic neurites are hallmarks of AD and correlate with severity of dementia, the abovementioned findings in human postmortem studies indicate that T2DM alone is not sufficient to cause AD. On the other hand, in experimental mouse and rat models, chronic high fat diet (HFD) feeding and diet induced obesity (DIO) with associated T2DM, do cause cognitive impairment with deficits in spatial learning and memory [103, 104]. Moreover, experimental obesity with T2DM causes mild brain atrophy with brain insulin resistance, neuro-inflammation, oxidative stress, and deficits in cholinergic function [105, 106]. An important qualifier about these studies is that the associated brain abnormalities were typically modest in severity, and they were devoid of the most important structural lesions that characterize AD, i.e. neurofibrillary tangles. Therefore, observations both in humans and experimental models suggest that while obesity or T2DM can be associated with cognitive impairment, mild brain atrophy, and a number of AD-type biochemical and molecular abnormalities in brain, including insulin resistance and oxidative stress, they do not cause significant AD pathology. Instead, the findings suggest that T2DM, obesity, and probably other peripheral/systemic insulin resistance states serve as co-factors contributing to the pathogenesis or progression of neurodegeneration. The significance of these results is that therapeutic strategies designed to treat T2DM, obesity, and systemic insulin resistance could help slow the progress or reduce the severity of AD, but they will not likely prevent it altogether. Correspondingly, a number of studies have already demonstrated that treatment with hypoglycemic or insulin sensitizer agents can be protective in reducing the incidence and severity of AD brain pathology [107].

Factors Mediating Cognitive Impairment and Neurodegeneration in Disease States with Systemic Insulin Resistance

Alzheimer’s is a Brain Diabetes Mellitus [Type 3 Diabetes]

A convincing argument could be made that AD, in its pure form, represents a brain form of diabetes mellitus [7, 8] since, AD is associated with progressive brain insulin resistance in the absence of T2DM, obesity, or peripheral insulin resistance [7, 8, 89, 90]. Moreover, postmortem studies demonstrated that the molecular, biochemical, and signal transduction abnormalities in AD are virtually identical to those that occur in T1DM and T2DM [7, 8, 91, 152–156]. The strongest evidence lending support to this concept comes from experimental animal studies in which rats were administered intracerebroventricular injections of streptozotocin, a pro-diabetes drug. The treated rats developed cognitive impairment with deficits in spatial learning and memory, brain insulin resistance and insulin deficiency, and AD-type neurodegeneration, but not diabetes mellitus [22, 157–160]. In contrast, i.p. or i.v. administration of streptozotocin causes diabetes mellitus with relatively mild degrees of hepatic steatosis and neurodegeneration [157, 161–163]. These findings indicate that exposure to a single pro-diabetes drug can cause organ/tissue degeneration characterized by impairments in insulin signaling and energy metabolism, with attendant increased oxidative stress, mitochondrial dysfunction, and cell death. However, disease spectrum and target organ involvement are governed by dose and route of drug administration.

Despite overwhelmingly convincing data, relevance of this specific model to the human condition remains open to question because streptozotocin is generally not available to humans. On the other hand, this hypothesis is rendered more appealing by the realization that streptozotocin is a nitrosamine-related compound, and that over the past several decades, Western societies have been assaulted by continuous and increasing exposures to environmental and food-related nitrosamines. We conducted experiments to determine if low, sub-mutagenic doses of nitrosamine compounds that are found in food, e.g. N-nitrosodiethylamine (NDEA), could cause insulin resistance diseases. Alarmingly, those studies showed that low-dose and very limited exposures to NDEA cause T2DM, non-alcoholic steatohepatitis, visceral obesity, cognitive impairment, and AD-type neurodegeneration with peripheral, hepatic, and brain insulin resistance [123, 124], similar to the effects of streptozotocin. Moreover, the adverse effects of NDEA on neuro-cognitive deficits, peripheral, hepatic, and brain insulin resistance, steatohepatitis, and neurodegeneration were exacerbated by chronic high fat diet feeding [164, 165]. Therefore, depending on the structure of the compound, dose, and route of administration, exposures to nitrosamine-related chemicals can cause insulin resistance diseases in multiple different target organs, including brain. In addition to providing evidence that the relatively recent epidemics of sporadic AD, T2DM, and non-alcoholic steatohepatitis/metabolic syndrome could be mediated by environmental or dietary exposures [1], these studies demonstrate that insulin resistance diseases with essentially the same underlying cellular abnormalities, can develop in various organs and tissues. This phenomenon could account for the overlapping increases in prevalence rates of various insulin resistance diseases within the past several decades, as well as the very frequent but incomplete overlap between AD and obesity, T2DM, and NASH [102], which did not exist prior to 1980, and is not accounted for by aging of the population [1].

Strategies for Early Diagnosis and Evaluation of Treatment Responses -Neuroimaging

The combined use of clinical and postmortem assessments provides the most accurate means of diagnosing AD. However, further advancements in detection, monitoring and treatment, particularly in the early stages of disease, will not likely occur without additional objective and standardized tools [166]. Although magnetic resonance imaging [MRI] of the brain can be used to track progression of medial temporal lobe atrophy as mild cognitive impairment (MCI) advances toward AD, and AD worsens in stage and severity [167], the diagnostic specificity of such a single-pronged approach is limited [168]. On the other hand, emerging evidence suggests that assessments of brain function, including flow and metabolism, combined with structural abnormalities may substantially improve diagnostic accuracy and help monitor disease progression. For example, the progressive cortical hypo-perfusion and hypo-metabolism that accompany advancement of AD, can be readily detected by single photon emission computed tomography (SPECT]) [169, 170] and positron-emission tomography (PET) [12, 168, 171–174]. Furthermore, tracking deficits in flow and metabolism to specific brain regions that are targeted by AD could help improve diagnostic accuracy. In this regard, detecting metabolic and blood flow impairments in the posterior cingulate and parietal-temporal cortices would support an AD diagnosis [175]. On the other hand, it is unlikely that neuroimaging will ever stand alone as a diagnostic tool since this approach cannot replace sophisticated clinical assessments that detect subtle neurobehavioral abnormalities that help distinguish one form of neurodegeneration from another. In addition, the fact that several types neurodegenerative disease, including ischemic encephalopathy, can overlap with the structural targets in AD, supports the argument that, right now, we need better, non-invasive diagnostic measures that go beyond, but also compliment neuroimaging assessments of brain structure, flow and metabolism.

Functional MRI adds an important diagnostic dimension because it combines neuro-imaging with assessments of brain metabolic responses to stimuli, including insulin [171, 176]. In addition, the joint use of PET with diffusion tensor imaging to correlate severity of cortical hypo-metabolism with loss of white matter integrity [177] holds promise in terms of improving our ability to diagnose and monitor progression of AD, based on objective stage-dependent structural, functional, and metabolic criteria for neurodegeneration. Detection of leukoaraiosis and white matter high intensity lesions in diabetics could help predict individuals at risk for cognitive impairment and dementia [178]. The expectation is that ultimately, the use of sensitive functional neuroimaging, combined with structural imaging and multimodal biomarker panels, will improve diagnostic accuracy and facilitate evaluation of treatment effects in the early stages of AD [179–181].

Strategies for Early Diagnosis and Evaluation of Treatment Responses – Cerebrospinal Fluid and Peripheral Blood Biomarkers

Biomarkers for detecting and diagnosing severity of AD have largely been focused on measuring AβPP-Aβ, tau, and phospho-tau in cerebrospinal fluid (CSF) [182, 183]. Changes in CSF levels of Aβ-42, total tau, and phospho-tau [181] can help predict progression from MCI to dementia [184], or aid in establishing a diagnosis of AD [185]. At least in some studies, the sensitivity and specificity of these CSF biomarkers approach 85% for diagnosing AD and distinguishing AD from MCI [175, 179, 183, 186–188]. However, inter-laboratory variability and the lack of standardization measures to ensure quality assurance, have limited broad and independent use of these assays [189, 190]. Moreover, since at the core of the neurodegenerative process is protein misfolding and aggregation, biomarkers are needed to identify and quantify oligomeric neurotoxic aggregates of tau and Aβ-42 [191]. Beyond these issues lay concerns that by limiting our considerations to basically two biomarkers, we have failed to significantly advance the field. In fact, for various reasons, this rather circumscribed approach has not proven to be sufficiently sensitive to render an accurate diagnosis of AD or predict outcomes of MCI in a case-by-case basis [192].

Given the spectrum of other significant abnormalities that precede or accompany AD, it would seem more prudent to incorporate a broader spectrum of biomarkers into a multimodal panel to better characterize AD stage and progression [193]. For example, indices of oxidative stress, neuro-inflammation, mitochondrial dysfunction, metabolic derangements, and impaired insulin/IGF signaling should be integrated into the overall equation to improve the sensitivity and specificity of diagnosing AD [3, 193, 194]. The use of multi-analyte profiling would enable efficient capture of data and tracking of abnormalities as the biomarker indices shift with disease progression [195]. For example, CSF pro-inflammatory cytokine levels are elevated in the early stages of AD, as well as in MCI [196]. Similarly, MCI and early-stage AD are marked by increased oxidative stress with raised levels of redox-active iron in CSF [197]. These findings suggest that neuro-inflammatory and oxidative stress responses should be evaluated to help gauge the presence, severity, and progression of neurodegeneration in the early stages of disease. At the same time, it could be argued that these factors may be initially responsible for propagating the neurodegeneration cascade, and therefore should be considered as potential therapeutic targets. Although, in later stages of disease, oxidative stress and pro-inflammatory biomarkers, whether in plasma or CSF, seem to lack diagnostic utility [198], the persistently elevated CSF levels of oxidized coenzyme Q-10 and 8-hydroxy-2′-deoxyguaniosine suggest that mitochondrial and DNA oxidative damage mediate AD progression [199, 200], and therefore could be targeted therapeutically to slow the advancement of AD.

Peripheral blood biomarkers in lymphocytes and plasma hold some promise as non-invasive surrogate screening tools, and may provide a means to study populations at increased risk for developing AD [201]. For example, abnormalities in AβPP-Aβ cleavage are detectable in peripheral blood lymphocytes in AD. In addition, protein kinase C (PKC), which has an important role in stimulating AβPP-Aβ peptide formation and tau hyperphosphorylation, could serve as a peripheral blood biomarker, since conformational changes in the PKC enzyme that promote AD pathology are detectable in erythrocytes [202]. Similarly, from the perspective that neuro-inflammation promotes neurodegeneration, it may be possible to use elevated serum levels of acute phase proteins and pro-inflammatory cytokines to help gauge the likelihood of progressing from MCI to dementia, particularly in the early stages of disease when neuro-inflammation is likely to be a relevant biomarker [203]. However, the utility of peripheral blood cytokine and trophic factor levels as diagnostic aids for distinguishing AD from MCI has proven unacceptable due to disease heterogeneity and the multiple co-factors contributing to neurodegeneration [204]. The combined use of serum and CSF to measure AβPP-Aβ peptides, total tau, and phosphorylated tau has been proposed for diagnosis and monitoring responses to treatment [205]. But, this approach could be flawed because drug treatments may not produce detectable shifts in serum levels of AβPP-Aβ or tau [206]. Again, these limitations highlight the importance of establishing multi-pronged diagnostic approaches that will include CSF and serum bio-assays, together with functional and structural neuro-imaging studies to diagnose AD and predict progression from MCI to AD [183].

In designing comprehensive CNS neurodegenerative disease biomarker panels, it should also be possible to capitalize on the concept that AD is a metabolic disease that closely resembles a brain form of diabetes mellitus. CSF assays could be used to detect brain insulin resistance and insulin deficiency, while peripheral blood studies could be used to simultaneously assess peripheral insulin resistance status marked by reduced glucose tolerance, hyperglycemia, hyperinsulinemia, accumulation of advanced glycation endproducts, and reactive oxygen species [178]. For example, AD is associated with significantly reduced CSF insulin levels, but in some cases, hyper-insulinemia as well [178, 207]. The finding that plasma and CSF insulin levels may be significantly elevated in AD relative to normal aged controls after an oral glucose load, but not at basal or post-fasting time points [11] suggests that insulin resistance in AD should be assessed with dynamic functional rather than static assays. This concept is reinforced by the fact that the extent of these abnormalities correlates with severity of dementia, particularly among individuals who lack the ApoE-ϵ4 allele [208]. On the other hand, not all studies have been able to confirm reduced CSF insulin levels in AD [209]. Finally, in AD, CSF levels of IGF binding proteins [IGFBP] 2 and 6 [210], and both CSF and serum levels of IGF-1 [211] are elevated relative to control [210]. This suggests that, in addition to insulin resistance, AD is associated with IGF-1 resistance in the brain, and therefore attending to just one or the other signaling pathway will likely not be sufficient to arrest disease.

Besides insulin and IGFs, previous studies have suggested roles for impaired expression and function of other CNS trophic factors in the context of neurodegeneration. For example, the role of nerve growth factor [NGF] as a potential target for both diagnosis and treatment arose because NGF promotes survival and function of basal forebrain cholinergic neurons which undergo neurodegeneration early in the course of AD [212, 213]. However, interest in this concept initially waned, in part due to the finding that CSF and/or brain levels of NGF were not abnormal in AD [214–216]. Although subsequent studies utilizing more sensitive approaches, were able to detect significantly elevated levels of NGF in AD CSF or ventricular fluid [217, 218], similar abnormalities were observed in vascular dementia as well [219].

Other trophic factors of note include, transforming growth factor beta (TGFbeta) modulates responses to injury in the brain, acidic fibroblast growth factor (aFGF), which modulates cellular proliferation and differentiation, and neuronal thread protein (NTP), which accumulates in AD brains, is regulated by insulin, and physically interacts with phospho-tau [62, 220–222]. With regard to TGFbeta, CSF studies have produced mixed results with some reports showing no change [223, 224], and others demonstrating significantly elevated levels of TGFbeta [225, 226] in AD relative to controls. In two independent studies, elevated choroid plexus and CSF levels of aFGF distinguished AD from normal aging [227, 228]. Finally, a number of studies published in the last 10-15 years demonstrated the utility of neuronal thread protein (NTP) as a potential CSF biomarker of AD [229–234]. However, the lack of widely available reagents and poor understanding of its connection to AD, prevented its incorporation into mainstream concepts about neurodegeneration. Nonetheless, the aggregate findings with regard to AD-associated proteins other than phospho-tau and AβPP-Aβ, suggest that assays of NGF, TGFbeta, aFGF, and possibly NTP in CSF or ventricular fluid could be employed in multi-biomarker panels for detecting AD or monitoring responses to therapy.

Ideally, it would be most convenient and least costly to utilize peripheral blood or urine based biomarker assays to detect neurodegeneration. Such minimally invasive approaches have been considered and are still under scrutiny. For example, elevated levels of NTP are detectable in urine of AD patients, beginning early in the course of disease [230, 235–238]. Serum-based immunoassays have been used to detect oxidative injury pertinent to AβPP-Aβ and phospho-tau accumulations [198] or insulin/IGF-related metabolic impairments [210, 211] in AD brains. Paralleling observations with respect to CSF, investigators detected elevated levels of aFGF in AD sera [227]. However, attempts to extend these types of analyses to all potential biomarkers may not be feasible without substantial technical improvements in the sensitivity and specificity of detection methods. For example, even with regard to established abnormalities in AD, e.g. GLP-1, neuropeptide Y, and ghrelin-growth hormone expression, the levels detected in serum do not reliably distinguish patients with neurodegeneration from those with normal aging [239]. Another potential hurdle in designing serum-, plasma- or urine-based assays of AD is that certain neurodegeneration-associated abnormalities, even those that can be detected in CSF, may not be detectable in extra-CNS body fluids. Future studies should be directed toward correlating AD biomarker assay data from CSF, peripheral blood, and urine to establish non-invasive means of detecting and monitoring AD neurodegeneration and responses to therapy.

Rectifying Dementia Based on the Brain Insulin Resistance/Insulin Deficiency Disease Model to Prevent, Retard, Halt, and Cure AD-Type Neurodegeneration

The volume of literature supporting the concept that AD is associated with deficits in energy metabolism, glucose utilization, and insulin/IGF responsiveness in the brain has grown rapidly, causing the paradigm of AD pathogenesis to shift away from the overwhelmingly dominant amyloid and taupathy hypotheses. The attractiveness of the metabolic/brain insulin resistance hypothesis is that the impairments in brain insulin and IGF signaling caused by insulin/IGF resistance, together with the eventual depletion of trophic factors, could account for nearly all other abnormalities that occur in AD, including increased oxidative stress and ROS generation, mitochondrial dysfunction, cell death, loss of synaptic plasticity, deficits in cholinergic homeostasis, increase expression of AβPP, hyper-phosphorylation of tau, compromised myelin maintenance, and neuroinflammation. Another attractive feature of the metabolic/brain insulin resistance hypothesis is that it demystifies the pathophysiology of AD by relating it to other well-recognized systemic diseases, i.e. diabetes mellitus, non-alcoholic steatohepatitis, and metabolic syndrome. If indeed these diseases are all essentially the same except they involve different principal target organs, then the treatment and prevention approaches would also be similar or possibly the same. This concept is not far-fetched. For example, atherosclerosis can preferentially affect different major blood vessels and result in different patterns and distributions of tissue injury and disease, yet no one would regard each spectrum of disease as having a distinct pathogenesis. However, what does require further research is determining the degrees to which brain insulin resistance, cognitive impairment, and neurodegeneration are consequential to peripheral insulin resistance diseases, particularly type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome, or whether they constitute an intrinsic disease process equivalent to a brain form of diabetes mellitus. Although the above discussions culling human and experimental animal studies lend support to both arguments, epidemiological, clinical, and postmortem studies clearly show that sporadic AD develops primarily in the absence of obesity and T2DM. Nonetheless, with strong data coming from both points of view, it is likely that both concepts are correct. In fact, the existence of primary and secondary mechanisms of brain insulin resistance and neurodegeneration would help explain the heterogeneity of the AD phenotype. In the ensuing discussion of potential therapeutic targets for AD, emphasis will be placed on how current strategies address the brain insulin resistance/metabolic impairments in AD.

Potential Therapeutic Targets and Strategies for AD

Regarding potential strategies for treating sporadic AD, the major issues to be considered are: 1) Does hyper-insulinemia in obesity and T2DM cause oxidative stress and neurodegeneration; 2) does peripheral insulin resistance lead to increased cerebral micro-vascular disease and thereby cause brain atrophy and degeneration? 3) How do dyslipidemic states associated with T2DM, obesity, and non-alcoholic steatohepatitis (NASH) contribute to neurodegeneration? 4) does the overlap among T2DM, NASH, obesity, and neurodegeneration/AD reflect a single pathophysiological process that causes variable degrees of metabolic dysregulation in different target organs and tissues, e.g. brain, liver, and skeletal muscle? 5) To what extent is AD-type neurodegeneration primarily mediated by intrinsic impairments of brain insulin/IGF signaling, versus secondary effects of peripheral organ insulin resistance diseases, e.g. T2DM? In many respects, the appreciation that AD fundamentally represents a metabolic disease associated with the same molecular, biochemical, and cell signaling abnormalities identified in peripheral insulin resistance diseases, could simplify future approaches to treatment and prevention (Table 33). For example, pharmacotherapeutic concepts developed for T2DM and NASH may be adaptable to AD. Already, this concept has been tested, and under some conditional circumstances, positive responses to treatment with intranasal insulin and insulin sensitizer drugs have been observed in subjects with AD [66, 240–246]. However, in order to make real progress with respect to treatment, we must acknowledge that AD is the end result of a neurodegeneration cascade that progressively targets and cripples different aspects of cellular physiology and homeostasis. Therefore, one should anticipate that while mono-therapies may be appropriate early in the course of disease, over time, this approach will be doomed to failure [247]. Such lessons have already been learned in the field oncology. Unless we can completely prevent AD, multi-pronged approaches will be needed to support a range of cellular functions and minimize cellular injury and toxicity as the disease progresses. The rationale and targets of current and potential future therapies for AD are discussed below.

Cholinergic Deficits and Glutamatergic Dysfunction as Targets

Acetylcholinesterase inhibitors are used to treat AD because acetylcholine levels are significantly reduced in the early stages of AD [75, 248], and the cholinergic system mediates cognitive function and neuronal plasticity. One of the major factors contributing to the acetylcholine deficits in AD is the loss of cholinergic neurons in the basal forebrain [213], as these neurons project widely to the cerebral cortex. A second factor is that choline acetyltransferase expression and activity are reduced even in viable neurons in brains with AD [7, 8]. It is noteworthy that choline acetyltransferase expression and activity are regulated by insulin/IGF stimulation [7, 249]. Although there is no evidence that acetylcholinesterase activity is significantly increased in AD brains, the rationale for treating patients with cholinesterase inhibitors is that such drugs could help sustain normal levels of acetylcholine by reducing the rates of its degradation. In addition, cholinesterase inhibitors may have off-target therapeutic effects by stimulating production of trophic factors, such as growth hormone and IGF-1 [250], which also support cognitive function. A third reason for administering acetylcholinesterase inhibitor drugs is that they may be protective against glutamate neurotoxicity and promote neuronal survival through activation of PI3 kinase-Akt [251]. Currently, the standard of care for AD includes the use of acetylcholinesterase inhibitors such as donepezil, aricept, tacrine, and rivastigmine [252].

The more recent addition of glutamate receptor antagonists to the AD treatment regimen is based on the concepts that L-glutamate functions as an excitatory amino acid neurotransmitter, and that glutamatergic dysfunction in AD leads to sustained excitotoxicity with attendant impairment of synaptic plasticity needed for learning and memory [253, 254]. Consequently, antagonists to the N-methyl-D-aspartate (NMDA) glutamatergic receptor, such as memantine (Nemenda), are used in conjunction with cholinesterase inhibitors to support memory in patients with mild to moderate AD [255, 256]. Although these approaches provide moderate symptomatic relief and delay disease progression in the early stages of AD, long-term therapeutic responses are limited at best, as these drugs do not arrest or reverse neurodegeneration [257–260]. Therefore, additional approaches are needed, and should include drugs that target various components of the neurodegeneration cascade. For example, there is evidence suggesting that the combined administration of a acetylcholinesterase inhibitors and anti-oxidants (Formula F or Ginkgo biloba-EGb 761) can more effectively improve cognitive performance than either compound alone [261,262]. Since NMDA can promote insulin resistance [263], and NMDA neurotoxicity can be attenuated or prevented by insulin stimulation [264]. Therefore, therapeutic measures to inhibit glutamate excitotoxicity may help restore brain metabolic functions, particularly in the context of insulin or insulin sensitizer treatments.

AβPP-Aβ Accumulation and Production as Therapeutic Targets

Research is extensively focused on finding safe and effective means of depleting the brain of toxic AβPP-Aβ deposits, reducing AβPP-Aβ fibrillarization and aggregation, and preventing abnormal cleavage and processing of AβPP [265]. The overarching hypothesis is that AβPP-Aβ peptides are neurotoxic, promote amyloid plaque formation, and mediate tau hyper-phosphorylation, fibrillarization, and neurofibrillary tangle formation [266]. Efforts to deplete the brain of toxic AβPP-Aβ led to the development of AβPP-Aβ-targeted immunotherapy. Although AβPP-Aβ active immunization with AβPP-Aβ peptides, or passive delivery of AβPP-Aβ-specific antibodies can effectively clear AβPP-Aβ plaques from brains of humans and experimental animals [267], the net outcomes are not very encouraging because the AβPP-Aβ instead accumulates in vessels, increasing propensity for micro-hemorrhage [268]. Even more disappointing were the findings that the effects of AβPP-Aβ clearance on cognitive function have been either modest or undetectable, and that patients receiving the vaccine still died with end-stage dementia and extensive neurofibrillary tangle and neuritic pathology in their brains [269, 270]. Moreover, amyloid vaccination produced unacceptable complications such as encephalitis mediated by auto-reactive T cell responses and vasogenic cerebral edema [267, 270].

Besides the neurological complications of brain swelling, particularly in subjects who did not have significant global brain atrophy, the root causes of vasogenic edema, i.e. pro-inflammatory responses with increased microglial activation, cerebral amyloid angiopathy, and accumulation of soluble neurotoxic oligomeric AβPP-Aβ [271], may have adversely influenced the clinical course of AD. Furthermore, studies examining therapeutic effects of passive humanized AβPP-Aβ antibody immunization demonstrated that despite AβPP-Aβ clearance and ample delivery of the antibodies to the brain [272], significant therapeutic responses such as improved survival or retarded progression from mild or moderate to severe dementia could not be demonstrated; consequently, those clinical trials were halted [273]. Altogether, the results of the AβPP-Aβ immunization trials suggest that, despite promising results in experimental animal models, this approach alone will not likely succeed for treating AD in humans. However, before this chapter can be closed, additional studies are needed to determine the degree to which pharmacological clearance of toxic AβPP-Aβ or preventing its formation and accumulation in brain can preserve or restore cognitive function and slow progression of AD neurodegeneration.

One potential approach to preventing the formation and build-up of toxic AβPP-Aβ is to inhibit the expression or activity of enzymes responsible for aberrant processing and cleavage of AβPP. AβPP-Aβ is generated by sequential proteolysis, first with beta secretases, then gamma-secretases [274]. Presenilins, which are often mutated in early onset familial AD, form the catalytic component of gamma-secretases, which mediate intramembranous cleavage of type 1 transmembrane proteins, including AβPP [275]. Mutation of presenilin genes leads to accumulation of AβPP-Aβ in AD, as well as other aging-associated neurodegenerative diseases, including fronto-temporal lobe and Lewy body dementias [275]. To inhibit abnormal processing of AβPP and the attendant accumulation of toxic AβPP-Aβ, efforts have been focused on targeting gamma secretases, including for the treatment of sporadic, late-onset AD [276, 277]. Although the pharmacological effects of gamma secretase inhibitors proved promising with regard to their ability to effectively lower plasma, CSF, and brain AβPP-Aβ burden [274, 278], the disappointing result was that objective clinical therapeutic responses to these agents proved to be minimal or undetectable [276, 279,280]. Worse yet, the compounds proved to be highly toxic due to concurrent inhibition of Notch signaling pathways [274, 277]. In the adult brain, Notch signaling mediates neuronal plasticity, cognition, and long-term memory [281].

To circumvent toxicity-related problems, efforts are underway to develop Notch cleavage-sparing gamma secretase inhibitor drugs [282, 283]. Results of clinical trials that may be underway are not yet known. However, besides toxicity, the potential therapeutic effectiveness of gamma secretase inhibitors has been drawn into question because the net effects of these agents on AβPP-Aβ levels may be too low to improve clinical outcome [277]. The same problem exists regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs), which have Notch-sparing gamma secretase inhibitory effects, but they produce weak clinical therapeutic responses [277, 284]. Nonetheless, the potential still exists to develop drugs that reduce AβPP-Aβ burden and toxicity by other mechanisms such as, inhibiting beta site AβPP cleaving enzyme 1 (BACE1), increasing expression of alpha secretase, or blocking AβPP-Aβ peptide fibrillization [252].

With regard to insulin resistance and the potential contributions of Aβ toxicity, since insulin accelerates trafficking of Aβ from the trans-Golgi network to the plasma membrane, and extracellular secretion of Aβ [63], and impaired insulin signaling disrupts the processing of AβPP and clearance of Aβ [66], it seems likely that by addressing the underlying causes of insulin/IGF resistance, we may be able to effectively and safely reduce AβPP-Aβ burden in the brain. This point is reinforced by the finding that IGF-1 and IGF-2 are neuroprotective as they reduce the neurotoxic effects of AβPP [70–73]. On the other hand, the fact that AβPP oligomers inhibit neuronal insulin-stimulated signals, blocking PI3 kinase activation of Akt, which leads to impaired survival signaling, increased activation of GSK-3β, and resultant hyper-phosphorylation of tau, argues in favor of pursuing measures that reduce AβPP oligomer fibrillarization as a means of restoring brain insulin sensitivity.

Therapeutic Targeting of Tau Hyper-Phosphorylation

Hyperphosphorylation of tau leads to misfolding and aggregation of oligomeric fibrils, followed by ubiquitination and generation of dementia-associate paired helical filaments. Paired-helical filaments form the cores of neurofibrillary tangles, neuropil threads, and dystrophic neurites, which are structural hallmarks of AD neuropathology. Tau hyperphosphorylation is mediated by inappropriate and sustained activation of kinases, including GSK-3β [285], cyclin-dependent kinase -5 (cdk-5), p38 MAPK, and c-jun kinase (JNK) [286, 287], and inhibition of phosphatases that mediate physiological dephosphorylation of tau, e.g. protein phosphatase-2A [287]. Therefore, treatment with chemical inhibitors of one or more of these disease- relevant kinases, or phosphatase activators, may reduce the rates of neurofibrillary pathology in AD. Among these potential targets, somewhat greater attention has been paid to the role of GSK-3β because, in addition to promoting tau hyper-phosphorylation, high levels of GSK-3β activity lead to alterations in AβPP processing and increased neuronal death [285, 288–290].

Approaches to therapeutically inhibiting GSK-3β activity have mainly included the use of lithium chloride, and to a lesser extent, indigoids [285, 288–291]. Experimentally, lithium chloride treatment of Swedish AβPP transgenic mice reduced GSK-3β-induced AβPP-Aβ accumulation [292, 293], and treatment of mutant AβPP and tau double transgenic AD mice with the NP12 GSK-3 inhibitor, significantly reduced brain amyloid burden, tau alterations, and neuronal survival [294]. In contrast, lithium treatment of aged 3xTg-AD mice reduced tau phosphorylation, but did not alter AβPP-Aβ load or improve performance on working memory tasks [295]. Therefore, in several well-characterized experimental models, therapeutic inhibition of GSK-3β prevented certain aspects of AD-type neurodegeneration, although the results varied, depending on the underlying gene abnormalities.

In several uncontrolled or retrospective human clinical studies, it was demonstrated that prior use of lithium therapy in psychiatric patients was protective against dementia and associated with better performance on cognitive tests [296–299]. In addition, among individuals at risk for early onset familial AD, chronic lithium treatment reduced the prevalence rates of AD and the brain activity levels of GSK-3β, and it increased the levels of brain-derived neurotrophic factor (BDNF) [300]. However, a subsequent randomized, single-blind, short-term (10 weeks) placebo-controlled multicenter trial proved disappointing in that performance on standardized cognitive function tests was not significantly improved, and no significant reductions in CSF GSK-3β activity were detected [301]. However, those findings ought to be interpreted with caution, given the relatively short duration of the trial compared with earlier (uncontrolled) retrospective studies.

Altogether, the effects of GSK-3 inhibitor treatments on neurodegeneration and cognitive performance in both human and experimental animal studies have been mixed. Variability in the diminution of GSK-3β-induced pathology, i.e. tau phosphorylation, AβPP-Aβ load, and cognitive function, could be attributed to the inadequacy of controls, differences in the durations of treatment and observation, nature of the underlying mechanisms of neurodegeneration, and variability in outcome measurements. Therefore, it may be premature to abandon this approach without further systematic investigation, particularly since the scientific basis for the overarching hypothesis is sound. Nonetheless, an important caveat with regard to going forward with this therapeutic strategy is that efforts should be made to target only the GSK-3β activity that is aberrantly increased in the CNS, rather than broadly inhibit GSK-3β throughout the brain and body. Since GSK-3β is a broadly acting kinase that regulates signaling through critical pathways such as Wnt and Notch [302, 303], which in the adult CNS are crucial for neural stem cell homeostasis [304,305], chronic global inhibition of GSK-3β could have unintended consequences with regard to regenerative and repair mechanisms in brain cells that are not targeted for neurodegeneration.

Insulin Therapy

The proposed used of anti-diabetes, hypoglycemic drugs to treat AD is based on the findings that: 1) AD is associated with brain insulin resistance and insulin deficiency (reduced brain and CSF levels), with or without associated systemic insulin resistance or T2DM; 2) diabetic patients that are well-managed with insulin or hypoglycemic medications exhibit significant improvements in memory and slowing of AD progression; 3) treated elderly diabetics have lower densities of AD lesions compared with non-diabetic controls; 4) insulin administration improves cognition and memory in AD, and insulin stimulated cognition is correlated with increased levels of norepinephrine in both plasma and CSF [306]; 5) hyper-insulinemic euglycemic clamping enhances cognition and attention in patients with AD; and 6] experimental intracerebral or intravenous treatments with insulin improve memory, cognition, evoked brain potentials, and neurotransmitter function [66]. Although attractive and seemingly simple, a foremost consideration is the fact that the target population consists of elderly individuals who probably have other chronic diseases and who are at increased risk for problems related to inadvertent bouts of hypoglycemia, e.g. traumatic falls that could be debilitating or life-threatening, and metabolic insults to various organs, including brain. Moreover, the effectiveness of insulin therapy may be dependent upon simultaneously increased levels/availability of glucose, and it may not be effective in facilitating memory if CSF AβPP-Aβ42 levels are markedly elevated due to insulin resistance [307]. Therefore, the routine use of systemic insulin therapy for patients with AD would be impractical and probably ill-advised, if not unacceptable.

However, another approach taken that avoids potentially harmful side-effects is to administer intranasal insulin. Intranasal insulin increases brain insulin levels and improves performance on declarative memory tasks while having little effect on plasma glucose and insulin levels [308]. In addition, intranasal insulin delivered via an electronic atomizer, improves attention and increases the AβPP-Aβ 40/AβPP-Aβ42 ratio [245]. Reducing the relative amounts of AβPP-Aβ42 should be neuroprotective as AβPP-Aβ42 is the neurotoxic form of the secreted peptide. In a controlled clinical trial, ApoE-ϵ4-negative individuals were demonstrated to benefit significantly from intranasal insulin, as manifested by improvements in cognitive performance [308]. The fact that ApoEϵ4+ subjects did not benefit from the same treatment suggests that intranasal insulin, as well as other pro-metabolic therapies for AD, may have to be tailored according to particular genetic risk factors and biomarkers of disease.

Anti-Hyperglycemic Agents

Metformin is a biguanide anti-hyperglycemic drug that is used to treat T2DM. Metformin functions by suppressing gluconeogenesis and enhancing glucose uptake and insulin sensitivity. Metformin treatment is protective against neurological complications of T2DM, including cognitive impairment and cerebral vascular disease [324]. Although metformin treatment was found to increase the generation of both intra- and extracellular AβPP-Aβ due to increased expression of BACE1, suggesting that metformin and insulin may have opposing effects on AβPP-Aβ accumulation, the administration of both insulin and metformin provided significant neuroprotection. Importantly, the combined treatments reduced AβPP-Aβ levels, the severity of AD pathology, including AβPP-Aβ neuritic plaques, and oligomeric AβPP-Aβ-mediated down-regulation of the insulin receptor. These findings suggest that metformin mono-therapy may be harmful due to exacerbation of AD-type neurodegeneration [325], whereas the combined use of insulin and hypoglycemic drugs may benefit elderly patients in the early stages of AD by significantly improving cognitive performance and slowing the rate of neurodegeneration.

Insulin Sensitizers

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 [326–329]. 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, 83, 149]. PPAR agonist treatments improve cognitive performance in experimental animal models [83, 330] and in humans with AD or MCI [148, 150, 331]. 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.

Antioxidant and Anti-Inflammatory Drugs

Antioxidant functions help maintain mitochondrial homeostasis, neuronal activities, and cell survival. Oxidative stress plays a pivotal role in the pathogenesis and progression of AD-type dementia. Sources of oxidative stress include, impairments in insulin signaling, fibrillarization of oligomeric AβPP-Aβ and tau, mitochondrial dysfunction, micro-vascular disease, increased accumulation of ROS, RNS and inflammation [353]. Although it has not yet been determined which source of oxidative stress in most critical to neurodegeneration and cognitive impairment, some doubt has been cast upon the role of AβPP-Aβ since in a longitudinal analysis, significant reductions in plasma AβPP-Aβ42 in subjects treated with various anti-inflammatory agents, was not associated with improvements in cognition [354]. Nonetheless, the interest in reducing oxidative stress in the brain is justified as a treatment approach because this type of injury could, at the very least, serve as a co-factor mediating AD progression. Potential approaches to reduce oxidative stress include the use of anti-oxidants, anti-inflammatory agents, radical scavengers, transition metal chelators, and non-vitamin anti-oxidant polyphenols.

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, 459]. Observational studies provide positive evidence that chronic omega-3 ingestion is beneficial to cognitive function [458, 460, 461], 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, 436, 465–470] and AD is mediated in large measure by brain insulin resistance and impaired energy metabolism [7, 8]. 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, 474], 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.

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