Alzheimer’s Disease

Neurodegenerative Diseases and Esssential Fatty Acids
A Chiro.Org article collection
This collection details research demonstrating the protective effects of omega-3 fatty acids on cognitive decline.

Alzheimer's Disease as a Systems Network Disorder:
Chronic Stress/Dyshomeostasis, Innate Immunity, and Genetics
Aging (Albany NY) 2020 (Sep 21); 12 (18): 17815–17844 ~ FULL TEXT
Ineffective results of clinical trials of over 200 anti-Alzheimer's drug candidates, with a 99.6% attrition rate, suggest that the current paradigm of Alzheimer's disease (AD) may be incomplete, necessitating exploration of alternative and complementary frameworks. Using algorithms for hypothesis independent search and expert-assisted synthesis of heterogeneous data, we attempted to reconcile multimodal clinical profiles of early-stage AD patients and accumulated research data within a parsimonious framework. Results of our analysis suggest that Alzheimer's may not be a brain disease but a progressive system-level network disorder, which is driven by chronic network stress and dyshomeostasis. The latter can be caused by various endogenous and exogenous factors, such as chronic inflammatory conditions, infections, vascular dysfunction, head trauma, environmental toxicity, and immune disorders. Whether originating in the brain or on the periphery, chronic stress, toxicity, and inflammation are communicated to the central nervous system (CNS) via humoral and neural routes, preferentially targeting high-centrality regulatory nodes and circuits of the nervous system, and eventually manifesting as a neurodegenerative CNS disease. In this report, we outline an alternative perspective on AD as a systems network disorder and discuss biochemical and genetic evidence suggesting the central role of chronic tissue injury/dyshomeostasis, innate immune reactivity, and inflammation in the etiopathobiology of Alzheimer's disease.

Transcriptional Effects of ApoE4: Relevance to Alzheimer's Disease
Molecular Neurobiology 2018 (Jun); 55 (6): 5243–5254 ~ FULL TEXT
The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the putative transcriptional role of ApoE4 and propose a model of Alzheimer's disease that focuses on the transcriptional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease.

Clinical Lifestyle Medicine Strategies for Preventing
and Reversing Memory Loss in Alzheimer's
American J Lifestyle Medicine 2018 (May 11); 12 (5): 391–395 ~ FULL TEXT
Alzheimer's disease (AD) is the most common form of dementia and currently affects over 5 million Americans and 30 million individuals worldwide. Unfortunately, the current approach to treating AD provides nothing more than a marginal, unsustained, symptomatic effect, with little or no effect on disease progression itself. To attain effective improvements in AD, one must determine risk factors, address the underlying causes, and focus on a combination of functional and lifestyle medicine strategies that provide a comprehensive, programmatic, and network-based approach that is sufficient to achieve epigenetic transformation and neurologic healing through its multiple and necessary synergistic components. Rather than normalizing metabolic parameters, the focus is on optimization of each metabolic parameter. Papers published by research neurologist, Dr Dale Bredesen have documented that symptoms of mild cognitive impairment and early AD may often be reversed within 6 months after initiating a comprehensive, functional and lifestyle medicine-focused program.

Evidence for Brain Glucose Dysregulation in Alzheimer's disease
Alzheimers Dement. 2018 (Mar); 14 (3): 318–329 ~ FULL TEXT
To the best of our knowledge, this report is the first to measure brain tissue glucose concentrations and assess glycolytic flux to demonstrate their relationships with both severity of AD pathology and the expression of AD symptoms. Including brain tissue samples from “asymptomatic Alzheimer’s disease (ASYMAD)” individuals who represent an intermediate group in the gradation of neuropathology from controls to AD patients in the absence of cognitive impairment during life allowed us to relate measures of brain glucose concentration and glycolytic flux to incremental levels of AD pathology and symptom expression. Equally importantly, by measuring glucose concentrations in brain regions both vulnerable to distinct pathological features of AD, that is, MFG (amyloid deposition) and ITG (tau accumulation) as well as in a region relatively resistant to AD pathology, that is, cerebellum [34], we were able to determine whether the observed alterations in brain glucose concentrations and abnormalities in glycolysis were related to defining pathological processes.

The Role of Reactive Oxygen Species in the Pathogenesis
of Alzheimer's Disease, Parkinson's Disease, and
Huntington's Disease: A Mini Review
Oxid Med Cell Longev 2016 (Dec 27); 2016: 8590578 ~ FULL TEXT
Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer's disease (AD), impairments in the movement, Parkinson's disease (PD), and the inability to walk, talk, and think, Huntington's disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases.

Reversal of Cognitive Decline in Alzheimer's Disease
Aging (Albany NY). 2016 (Jun); 8 (6): 1250–1258 ~ FULL TEXT
Alzheimer's disease is one of the most significant healthcare problems nationally and globally. Recently, the first description of the reversal of cognitive decline in patients with early Alzheimer's disease or its precursors, MCI (mild cognitive impairment) and SCI (subjective cognitive impairment), was published. [1] The therapeutic approach used was programmatic and personalized rather than monotherapeutic and invariant, and was dubbed metabolic enhancement for neurodegeneration (MEND). Patients who had had to discontinue work were able to return to work, and those struggling at work were able to improve their performance. The patients, their spouses, and their co-workers all reported clear improvements. Here we report the results from quantitative MRI and neuropsychological testing in ten patients with cognitive decline, nine ApoE4+ (five homozygous and four heterozygous) and one ApoE4–, who were treated with the MEND protocol for 5-24 months. The magnitude of the improvement is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. These results have far-reaching implications for the treatment of Alzheimer's disease, MCI, and SCI; for personalized programs that may enhance pharmaceutical efficacy; and for personal identification of ApoE genotype.

Enhancement of SAPP as a Therapeutic Strategy for Alzheimer’s and
Other Neurodegenerative Diseases
J Alzheimers & Neurodegenerative Diseases 2015 (Aug 3); 1 (1): 33–44 ~ FULL TEXT
Soluble, secreted Amyloid Precursor Protein-α (sAPPα), a product of α-secretase (ADAM10) cleavage of Full Length-APP (FL-APP), is a trophic factor critical for synaptic complexity and maintenance. As cleavage at the α-site of APP precludes the β-site cleavage that is the first step in Amyloid β (Aβ) production, enhancing sAPPα production may not only support and restore neuronal health, but may also decrease the generation of anti-trophic Aβ. Over-production or reduced clearance of Aβ is a hallmark of Alzheimer’s Disease (AD), and recent findings suggest it also plays a role in other neurodegenerative diseases and neurological conditions, such as Amyotrophic Lateral Sclerosis (ALS), Cerebral Amyloid Angiopathy (CAA), and Traumatic Brain Injury (TBI). Yet decades of focus on Aβ-lowering strategies alone including passive and active immunotherapy and γ-secretase and BACE1 (BACE) inhibition have yet to yield positive clinical results. Clinical trials of several BACE inhibitors are underway in AD patients, and although there is optimism about this strategy, there are also concerns about mechanism-based side-effects of these drugs. A truly effective therapy would not only slow the degenerative process underlying onset and progression of the disease, it should also restore healthy neuronal function. It is very likely this will comprise combination therapy utilizing more than one drug or intervention. Molecules that enhance sAPPα may be a safe, effective component of a multi-modal therapeutic approach to AD and other neurodegenerative diseases, and have the potential to increase neuronal health by providing trophic support and disrupting neurodegenerative mechanisms.

Metabolic Profiling Distinguishes Three Subtypes of Alzheimer's disease
Aging (Albany NY). 2015 (Aug); 7 (8): 595–600 ~ FULL TEXT
In summary, metabolic profiling of patients with cognitive decline, as described previously [5], reveals three readily distinguishable subtypes of Alzheimer's disease: inflammatory, non-inflammatory, and cortical. The distinctive features, presentation, lack of association with ApoE4, and marked hypozincemia, together suggest that the cortical subtype of Alzheimer's disease is a fundamentally different disease than the other two subtypes. This subtype deserves further genetic, epigenetic, and metabolomic studies.

Dynamic Self-guiding Analysis of Alzheimer's disease
Oncotarget 2015 (Jun 10); 6 (16): 14092–14122 ~ FULL TEXT
As constituents of a continuously remodeling tissue, neurons may undergo localized, transient, reversible, EMT-like, organizational transitions in response to a variety of physiological and non-physiological stimuli, such as growth factors, hormones, neuronal/brain stimulation/activity, learning, diet, physical activity, sleep, drugs, alcohol, smoking, hypoxia, and inflammation. In all likelihood, reversible organizational transitions occur continuously on multiple scales of space and time in synapses, neurites, neurons, and neuronal networks to enable neuronal plasticity, learning, memory, and cognition. They are expected to occur continuously throughout life throughout the body, with an especially high frequency and/or extent during developmental stages, active learning, regeneration, sleep-wake cycles, and in the regions of high neuronal plasticity/restructuring. However, when the (APP-associated?) signaling/metabolic network that controls these transitions is dysregulated, neurons/neurites/synapses may become locked in cancer-like, pro-secretion, pro-inflammatory modes/phenotypes, which are unable to support stable tissue architecture, thus leading to a progressive impairment of synaptic and neuronal functions, the accumulation and deposition of A-beta and neurofibrillary tangles, and impaired learning, progressive loss of memory, and cognitive decline. Similar to tumorigenesis, AD pathogenesis is expected to progress slowly and imperceptibly over time, accelerating non-linearly in the elderly and/or during the last stages of the disease, as an avalanche

Neuroprotective Sirtuin Ratio Reversed by ApoE4
Aging (Albany NY). 2014 (Sep); 6 (9): 707–717 ~ FULL TEXT
The canonical pathogenesis of Alzheimer's disease links the expression of apolipoprotein E ε4 allele (ApoE) to amyloid precursor protein (APP) processing and Aβ peptide accumulation by a set of mechanisms that is incompletely defined. The development of a simple system that focuses not on a single variable but on multiple factors and pathways would be valuable both for dissecting the underlying mechanisms and for identifying candidate therapeutics. Here we show that, although both ApoE3 and ApoE4 associate with APP with nanomolar affinities, only ApoE4 significantly

(i)   reduces the ratio of soluble amyloid precursor protein alpha (sAPPα) to Aβ;

(ii)   reduces Sirtuin T1 (SirT1) expression, resulting in markedly differing ratios of neuroprotective SirT1 to neurotoxic SirT2;

(iii)   triggers Tau phosphorylation and APP phosphorylation; and

(iv)   induces programmed cell death.

We describe a subset of drug candidates that interferes with the APP-ApoE interaction and returns the parameters noted above to normal. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aβ, SirT1:SirT2, APP:phosphorylated (p)-APP, and Tau:p-Tau, is programmatically altered by ApoE4 and offer a simple system for the identification of program mediators and therapeutic candidates.

Next Generation Therapeutics for Alzheimer's disease
EMBO Mol Med. 2013 (Jun); 5 (6): 795–798 ~ FULL TEXT
However, if the optimal therapeutic approach to AD does indeed turn out to involve a multi-component cocktail, an obvious consideration relates to the development and approval processes required for a cocktail approach: in the case of HIV treatment, each of the cocktail's constituents exerts a significant, albeit modest, effect on HIV infection. However, considering the numerous mechanisms identified as underlying AD pathogenesis, it is conceivable that many more than three different therapeutic agents will be required for optimal treatment of AD. Of even greater concern is the possibility that none of the components of the optimal therapeutic cocktail will turn out to exert a significant therapeutic effect when administered alone. How, then, would the optimal combination be identified, and ultimately approved for clinical use? Significant modernization of the current translational approach, clinical trial methodology and approval process may be required to render the optimization and approval of such a therapeutic cocktail feasible.

Nutrient Biomarker Patterns, Cognitive Function, and
MRI Measures of Brain Aging
Neurology. 2012 (Jan 24); 78 (4): 241–249 ~ FULL TEXT
Research investigators at the Department of Neurology of the Oregon Health & Science University reveal that higher blood levels of omega-3 fatty acids, vitamin B, vitamin C, vitamin D and vitamin E are associated with better mental functioning in the elderly.
You may want to review this New York Times review of this study.

Novel Mediators of Amyloid Precursor Protein Signaling
Journal of Neuroscience 2009 (Dec 16); 29 (50): 15703–15712 ~ FULL TEXT
Multiple recent reports implicate amyloid precursor protein (APP) signaling in the pathogenesis of Alzheimer's disease, but the APP-dependent signaling network involved has not been defined. Here, we report a novel consensus sequence for interaction with the PDZ-1 and PDZ-2 domains of the APP-interacting proteins Mint1, Mint2, and Mint3 (X11alpha, X11beta, and X11gamma), and multiple novel interactors for these proteins, with the finding that transcriptional coactivators are highly represented among these interactors. Furthermore, we show that Mint3 interaction with a set of the transcriptional coactivators leads to nuclear localization and transactivation, whereas interaction of the same set with Mint1 or Mint2 prevents nuclear localization and transactivation. These results define new mediators of the signal transduction network mediated by APP.

Neurodegeneration in Alzheimer's disease:
Caspases and Synaptic Element Interdependence
Molecular Neurodegeneration 2009 (Jun 26); 4: 27 ~ FULL TEXT
We present here a model for Alzheimer's disease that is based not on chemically and physically-mediated toxic effects of Aβ, but on imbalanced signal transduction. The model suggests that the imbalance lies in the ratio of the signals that mediate synaptic maintenance, neurite extension, and cell survival vs. those that mediate synaptic reorganization, neurite retraction, and programmed cell death – essentially, memory retention vs. forgetting and memory reorganization. This model suggests that Aβ has a physiological function as a neuromodulatory peptide, and at least in some cases that it functions as an anti-trophin – competing, for example, with netrin-1 for binding to APP. Whether it has analogous functions related to its described interactions with other receptors, such as PrP, p75NTR, and RAGE, remains to be determined. This model also proposes that synaptic element interdependence is a critical factor in synaptic maintenance vs. reorganization, with associated effects on memory retention vs. loss. Both pre-synaptic and post-synaptic elements exert trophic and anti-trophic influences on each other, and the balance determines whether synaptic maintenance or reorganization will occur. The molecular details of the model are summarized in Figure 4.

Netrin-1 Interacts with Amyloid Precursor Protein and
Regulates Amyloid-beta Production
Cell Death Differ. 2009 (May); 16 (5): 655–663 ~ FULL TEXT
The beta-amyloid precursor protein (APP) is an orphan transmembrane receptor whose physiological role is largely unknown. APP is cleaved by proteases generating amyloid-beta (Abeta) peptide, the main component of the amyloid plaques that are associated with Alzheimer's disease. Here, we show that APP binds netrin-1, a multifunctional guidance and trophic factor. Netrin-1 binding modulates APP signaling triggering APP intracellular domain (AICD)-dependent gene transcription. Furthermore, netrin-1 binding suppresses Abeta peptide production in brain slices from Alzheimer model transgenic mice. In this mouse model, decreased netrin-1 expression is associated with increased Abeta concentration, thus supporting netrin-1 as a key regulator of Abeta production. Finally, we show that netrin-1 brain administration in Alzheimer model transgenic mice may be associated with an amelioration of the Alzheimer's phenotype.

Reversal of Alzheimer's-like Pathology and Behavior in
Human APP Transgenic Mice by Mutation of Asp664
Proc Natl Acad Sci U S A. 2006 (May 2); 103 (18): 7130–7135 ~ FULL TEXT
The deficits characteristic of Alzheimer's disease (AD) are believed to result, at least in part, from the neurotoxic effects of beta-amyloid peptides, a set of 39-43 amino acid fragments derived proteolytically from beta-amyloid precursor protein (APP). APP also is cleaved intracytoplasmically at Asp-664 to generate a second cytotoxic peptide, APP-C31, but whether this C-terminal processing of APP plays a role in the pathogenesis of AD is unknown. Therefore, we compared elements of the Alzheimer's phenotype in transgenic mice modeling AD with vs. without a functional Asp-664 caspase cleavage site.

Surprisingly, whereas beta-amyloid production and plaque formation were unaltered, synaptic loss, astrogliosis, dentate gyral atrophy, increased neuronal precursor proliferation, and behavioral abnormalities were completely prevented by a mutation at Asp-664. These results suggest that Asp-664 plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP transgenic mice, possibly as a cleavage site or via protein-protein interactions.

Misfolded Proteins, Endoplasmic Reticulum Stress and Neurodegeneration
Curr Opin Cell Biol. 2004 (Dec); 16 (6): 653–662 ~ FULL TEXT
The ER is very sensitive to changes in its environment, and such changes may lead to disruption of its normal homeostasis. A variety of environmental insults, as well as genetic diseases associated with the accumulation of misfolded proteins, can all affect the ER structure, function and integrity, leading to ER stress and contributing to the pathogenesis of different disease states. Prolonged stress leads to organelle damage and dysfunction, and ultimately triggers PCD. The accumulation of misfolded proteins seen in various neurodegenerative diseases leads to an ER stress response, irrespective of whether the misfolded proteins build up within the ER or outside the ER. Further insights into the pathways triggered by misfolded proteins, ER stress responses and cell death programs should facilitate the development of new therapeutic strategies for neurodegenerative disorders and other disorders that feature misfolded proteins.

Amyloid Beta Protein Toxicity Mediated by the Formation of
Amyloid-beta Protein Precursor Complexes
Annals of Neurology 2003 (Dec); 54 (6): 781–789
The amyloid-beta protein precursor, a type 1 transmembrane protein, gives rise to the amyloid beta-protein, a neurotoxic peptide postulated to be involved in the pathogenesis of Alzheimer's disease. Here, we show that soluble amyloid beta protein accelerates amyloid precursor protein complex formation, a process that contributes to neuronal cell death. The mechanism of cell death involves the recruitment of caspase-8 to the complex, followed by intracytoplasmic caspase cleavage of amyloid precursor protein. In vivo, the levels of soluble amyloid beta protein correlated with caspase-cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects. These findings suggest that soluble amyloid beta protein-induced multimerization of the amyloid precursor protein may be another mechanism by which amyloid beta protein contributes to synapse loss and neuronal cell death seen in Alzheimer's disease.