"Neurodegenerative disorders result in a progressive and irreversible loss of neurons and brain functioning," says the National Institute on Aging as the official prognosis for Alzheimer's and other dementias. However, some noteworthy medical scientist/clinicians (e.g., 1, 2) have offered evidence that Alzheimer's Dementia (AD) can be prevented and at least some individuals with AD can reverse the cognitive decline that is the hallmark of this disorder. Part 1 of this series will focus on the epidemiology and pathophysiology of AD, while Part 2 will describe the strategies for prevention and reversal that do not depend on a novel pharmaceutical, but rather on dietary and other lifestyle changes that alter the progression of AD in the brain.

AD is the most common among several major neurocognitive disorders (i.e., dementias). There are currently over 5 million people in the United States diagnosed with AD, with projections by the Centers for Disease Control and Prevention of over 8 million by 2030. Overall, Americans have about a 15% lifetime risk of acquiring AD, with most cases appearing after age 65. A variant of the gene for apolipoprotein, referred to as ApoE4, significantly increases the predisposition to AD. Those who carry one copy of this gene (i.e., heterozygous) have a two-fold increase in risk of acquiring AD, while those who carry two copies (i.e., homozygous) have a more than three-fold increase in risk, which usually onsets in their 40's or 50's (i.e., Early Onset AD). Beyond the genetics of AD, two important risk factors are advancing age and female gender. Women have a nearly two-fold increase in risk compared to men.

Any effort to prevent or reverse cognitive decline in AD must address the underlying neuropathology. Fundamentally, the neurons and their connections (i.e., synapses) are damaged in a way that progressively leads to brain atrophy. In most cases of AD the atrophy begins in the subcortical hippocampus - the primary memory structure – and, over time in years, sweeps throughout the brain. Two primary pathological processes are responsible for this atrophy: 1) the aggregation of beta-amyloid protein outside the neurons leading to synapse-destroying aggregations (i.e., plaques) , and 2) a structural change in tau protein associated with microtubules leading to the physical disruption of these vital transportation systems inside the neurons, referred to as neurofibrillary tangles (NFT's). The development of NFT's appears to be in response to the formation of beta-amyloid plaques. This pathological process often begins at least two decades before the subjective symptoms of cognitive impairment appear.

No pharmaceutical has been developed and FDA approved that prevents or reverses the cognitive decline of AD. The two approved AD medications are donezepil and memantine, which effect neurotransmitter systems unrelated to beta-amyloid accumulation and that only temporarily reduce symptoms but not the progression of cognitive decline.

The triggering mechanism for beta-amyloid accumulation and aggregation appears to be complex. Over the last decade, the AD research community has identified neuroinflammation as the most common underlying cause of over-production of beta-amyloid in AD. Neuroinflammation is basically the result of the immune system gone awry. Inflammation, in general, results from the immune system (think white blood cells) producing a class of polypeptides known as pro-inflammatory cytokines. Cytokines in the brain are produced by the glial cells that surround neurons. These pro-inflammatory cytokines interact with neurons in ways that alter the biochemical processes in the brain, such as promoting the over-production of beta-amyloid.

There are several situations that can cause neuroinflammation. Gene products from possessing the ApoE4 gene can elicit neuroinflammation. A leaky gut can allow undigested polypeptides to enter the bloodstream and promote an immune response - hence inflammation. Chronically high blood sugar can create unnatural glycoproteins that trigger an immune response. Chronic stress can promote neuroinflammation as well.

It is a relatively straight-forward process to determine if an individual's cognitive decline may be associated with an inflammatory process. One of the biomarkers of generalized inflammation is C-Reactive Protein (CRP), which is a protein produced by the liver in response to inflammation. CRP is often routinely measured in the lab work associated with regular physical exams and is usually included as a potential risk factor for cardiovascular disease. However, it is also often elevated in individuals diagnosed with cognitive impairment or AD. Additionally, there are two pro-inflammatory cytokines often found in individuals with AD – Tumor Necrosis Factor-alpha and Interleukin-6 – that can be measured in blood chemistries, but typically are not routinely included. The existence of multiple pro-inflammatory biomarkers is evidence that the cognitive impairment or diagnosed AD may be resulting from an inflammatory process in the brain.

When neuroinflammation is a prime suspect in the development of cognitive decline, there is an array of lifestyle changes that can be made to arrest the decline and even reverse it. Through case studies, a few pioneering clinicians have demonstrated that even early-stage diagnosed AD can be reversed through rigorous application of individualized lifestyle change protocols. These approaches to preventing and reversing AD will the emphasis in Part 2 of this series.

References
1. Bredesen, D. (2017). The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline. Avery:New York.
2. Sherzai, D & Sherzai, A. (2017).The Alzheimer's Solution: A Breakthrough Program to Prevent and Reverse Cognitive Decline at Every Age. HarperOne:New York

Alzheimer’s Dementia: Approaches for Prevention and Reversal
Part 2
James S. Graves, PhD, PsyD

Part 1 of this two-part article provided the background of the pathophysiology of Alzheimer’s Dementia (AD), which is considered a progressive neurodegenerative disease.  To recap the pathophysiology, the most popular theory involves the aggregation of beta-amyloid outside the neurons to form “plaques” and the disassembling of the microtubular system in the neurons resulting from the chemical change in tau protein (so-called neurofibrillary tangles). Efforts to develop a pharmaceutical that stops or reverses AD have so far failed in clinical trials or are currently in the early clinical trial process.  However, there is an emerging hypothesis that the development of neuroinflammation underlies the biochemical changes in the brain that results in plaques and tangles in most, but not all, cases of AD
In the last decade or so there has been an increase in interest regarding the effects of lifestyle practices on the onset and progression of AD.  In fact, the Alzheimer’s Association has recently launched a major research project in this area.  A few pioneering scientist/clinicians have provided evidence that lifestyle changes can frequently alter the progression of cognitive decline, especially in individuals with pre-AD Mild Cognitive Impairment (MCI).  In several case descriptions there appears to be some restoration of cognitive capabilities even in those with early-stage diagnosed AD. In these cases of so called “reversal” the process has required the rigorous application of individualized lifestyle change protocols.  
From the perspective of preventing the onset of AD, it is useful to know your family history or whether or not you are ApoE4 positive. With a genetic predisposition, it is important to  develop and implement lifestyle changes rigorously. The following are lifestyle strategies that, when implemented together, can lower your risk of acquiring AD:

• Start early. AD pathophysiology begins one to two decades prior to symptomatic onset.
• Maintain challenging mental activity. “Cognitive reserve” from years or decades of challenging learning experiences is a great protector against later-life cognitive decline. Engaging in complex problem solving or learning a new language or how to play a musical instrument rank high as the kinds of mental activities that promote cognitive reserve.
• Adopt an anti-inflammatory diet (related to the so-called Mediterranean Diet) in order to reduce neuroinflammation and, thus, beta-amyloid aggregation.  Such a diet is primarily plant based with substituting more fish or vegetable protein for meat of any kind. These foods provide anti-inflammatory phytonutrients (e.g., polyphenols), additional important vitamins and more anti-inflammatory Omega-3 fats than pro-inflammatory Omega-6 fats.  Also important is choosing sources of carbohydrates that have a low Glycemic Index (i.e., less rise in blood sugar), which usually means selecting brown or brightly colored sources over white. Frequent ingestion of simple sugars or refined carbohydrates can lead to chronically high blood sugar and insulin resistance.  This has led some authors to refer to AD as “Type-3 Diabetes.” This situation leads both to brain cells not receiving enough sugar for energy metabolism and less destruction and clearance of beta-amyloid.  
• Maintain a socially active lifestyle. Social interactions promote mental activities such as monitoring the flow of a conversation and calling up memories to participate in the conversation. 
• Maintain a physically active lifestyle.  Exercise has a variety of positive effects, including increasing blood flow and producing neurotrophic factors in the brain.  The most thoroughly studied neurotrophic protein, Brain Derived Neurotrophic Factor (BDNF), has been shown to increase the production of brain cells in the hippocampus, which is the memory-storing structure that is one of the first sites of atrophy in AD.
• Get sufficient quality sleep on a regular basis.  During several hours (typically 7-8) of sound sleep the brain clears out un-needed molecules, including beta-amyloid. 
• Manage stress.  Frequent or chronic stress causes the release of stress hormones (e.g., cortisol) that can be toxic to brain cells and can directly induce neuroinflammation. Engaging in calming lifestyle practices, such as meditation, yoga or other such activities, is an important part of a prevention plan.

For someone already experiencing cognitive decline with MCI or early-stage AD , case reports suggest that the lifestyle changes must be implemented extensively and rigorously in order to improve the likelihood of restoring some cognitive capacities.  First, it is important to obtain a baseline of cognitive capabilities through an assessment battery or at least a mental status assessment, such as the Montreal Cognitive Assessment.  It is then important to engage medical experts in the field to implement the diagnostic process and to prescribe potential medical interventions and, importantly, to define the appropriate lifestyle change protocol based on diagnostic data. There are multiple neurology clinics across the US that specialize in the diagnosis and treatment of neurocognitive disorders.  In Southern California, Drs. Dean and Ayesha Sherzai have a Brain Health and Alzheimer’s Prevention Program at Loma Linda University Medical Center. You can read the Sherzaiz’s story at: https://news.llu.edu/clinical/prevention-new-treatment-for-alzheimer-s-disease.

Alzheimer’s Dementia: Reasons for Hope
James S. Graves, PhD, PsyD

The official prognosis for Alzheimer’s and other dementias according to the National Institute on Aging is: “Neurodegenerative disorders result in a progressive and irreversible loss of neurons and brain functioning,” However, some noteworthy medical scientist/clinicians (e.g., Bredesen, 2017; Sherzai & Sherzai, 2017) have offered evidence that Alzheimer’s Dementia (AD) can be prevented and, based on anecdotal case descriptions, at least some individuals with early-stage AD may show stabilization or even restoration of some cognitive capabilities.  This article will describe the epidemiology and pathophysiology of AD. It will also identify some of the strategies for prevention and for possible amelioration of cognitive decline that do not depend on a novel pharmaceutical, but rather on dietary and other lifestyle changes that may alter the progression of AD in the brain. 

AD is the most common among several major neurocognitive disorders (i.e., dementias).  There are currently over 5 million people in the United States diagnosed with AD, with projections by the Centers for Disease Control and Prevention of over 8 million by 2030. Overall, Americans have about a 15% lifetime risk of acquiring AD, with most cases appearing after age 65 (Alzheimer’s Association, 2018). A variant of the gene for apolipoprotein, referred to as ApoE4, significantly increases the predisposition to AD.  Those who carry one copy of this gene (i.e., heterozygous) have a significant increase in risk of acquiring AD, while those who carry two copies (i.e., homozygous) have a greater increase in risk, which usually onsets at an earlier age (Qian, et al, 2017).  Beyond the genetics of AD, two important risk factors are advancing age and female gender.  Women have a nearly two-fold increase in risk compared to men (Alzheimer’s Association, 2018). 

Any effort to prevent or reverse cognitive decline in AD must address the underlying neuropathology.  Fundamentally, the neurons and their connections (i.e., synapses) are damaged in a way that progressively leads to brain atrophy.   In most cases of AD the atrophy begins in the subcortical hippocampus - the primary memory structure – and, over time in years, sweeps throughout the brain. Two primary pathological processes are responsible for this atrophy: a) the aggregation of beta-amyloid protein outside the neurons leading to synapse-destroying aggregations (i.e., plaques) , and b) a structural change in tau protein associated with microtubules leading to the physical disruption of these vital transportation systems inside the neurons, referred to as neurofibrillary tangles (NFT’s). The development of NFT’s appears to be in response to the formation of beta-amyloid plaques (.  This pathological process often begins at one to two decades before the subjective symptoms of cognitive impairment appear (Alzheimer’s Association, 2018; Musiek & Holtzman, 2012).

No pharmaceutical has been developed and FDA approved that prevents or reverses the cognitive decline of AD.  The two approved AD medications are donezepil and memantine, which affect neurotransmitter systems unrelated to beta-amyloid accumulation and that only temporarily reduce symptoms but not the progression of cognitive decline (Alzheimer’s Association, 2018).

The triggering mechanism for beta-amyloid accumulation and aggregation appears to be complex.  Over the last decade, the AD research community has identified neuroinflammation as the most common underlying cause of over-production of beta-amyloid in AD (Heppner, et al., 2015).  Neuroinflammation is basically the result of the immune system gone awry. Inflammation, in general, results from the immune system (think white blood cells) producing a class of polypeptides known as pro-inflammatory cytokines.  Cytokines in the brain are produced by the glial cells that surround neurons.  These pro-inflammatory cytokines interact with neurons in ways that alter the biochemical processes in the brain, such as promoting the over-production of beta-amyloid.

There are several situations that can cause neuroinflammation. For people who possess the ApoE4 gene, expression of that gene can elicit neuroinflammation.  A leaky gut can allow undigested polypeptides to enter the bloodstream and promote an immune response - hence inflammation.  Chronically high blood sugar can create unnatural glycoproteins that trigger an immune response.  Chronic stress can promote neuroinflammation as well (Bredesen, 2017; Sherzai & Sherzai, 2017).  

It is a relatively straight-forward process to determine the likelihood that an individual’s cognitive decline may be associated with an inflammatory process.  One of the biomarkers of generalized inflammation is C-Reactive Protein (CRP), which is a protein produced by the liver in response to inflammation. CRP is often routinely measured in the lab work associated with regular physical exams and is usually included as a potential risk factor for cardiovascular disease.  However, it is also often elevated in individuals diagnosed with cognitive impairment or AD.  Additionally, there are two pro-inflammatory cytokines often found in individuals with AD – Tumor Necrosis Factor-alpha (Chang, et al., 2017) and Interleukin-6 (Cojocaru, et al., 2011) – that can be measured in blood chemistries, but typically are not routinely included. Elevated homocysteine is also considered a biomarker for inflammation (Bredesen, 2017; Sherzai & Sherzai, 2017). The existence of multiple pro-inflammatory biomarkers is evidence that the cognitive impairment may be resulting from an inflammatory process in the brain.  

When neuroinflammation is a prime suspect in the development of early-identified cognitive decline, there is an array of lifestyle changes that, at least in some cases, can lead to arrest the decline or even restore some cognitive capabilities (Bredesen, 2017, Bredesen, et al., 2015; Sherzai & Sherzai, 2017).  From the perspective of preventing the onset of AD, it is useful to know your family history or whether or not you are ApoE4 positive.  Beyond that, the following are lifestyle strategies, when implemented together, can greatly lower your risk of acquiring AD:

• Start early: AD pathophysiology begins one to two decades prior to symptomatic onset.
• Maintain challenging mental activity. “Cognitive reserve” from years or decades of challenging learning experiences is a great protector against later-life cognitive decline (Stern, 2012).
• Adopt an anti-inflammatory diet (related to the so-called Mediterranean Diet) in order to reduce neuroinflammation and, thus, beta-amyloid aggregation (Alzheimer’s Association, 2018; Bredesen, 2017, Bredesen, et al., 2016; Sherzai & Sherzai, 2017). Such a diet is primarily plant based with substituting more fish for red meat. These foods provide anti-inflammatory phytonutrients (e.g., polyphenols) and more anti-inflammatory Omega-3 fats than pro-inflammatory Omega-6 fats.  Also important is choosing sources of carbohydrates that have a low Glycemic Index (i.e., less rise in blood sugar, which usually means selecting brown or brightly colored sources over white. 
• Maintain a socially and physically active lifestyle with routine exercise.  Social interactions promote mental activity.  Exercise has a variety of positive effects, including increasing blood flow to the brain (Sherzai & Sherzai, 2017).
• Get sufficient quality sleep on a regular basis.  During several hours of sound sleep the brain clears out un-needed molecules, including beta-amyloid (Yo-El, et al., 2014). 
• For someone already experiencing significant cognitive decline, based anecdotal case studies with variable measurements of outcomes (Bredesen, 2017, Bredesen, et al., 2016; Sherzai & Sherzai, 2017), the evidence suggests that some people with early-stage AD may experience some restoration in cognitive capabilities.  In such cases the diagnostic testing is more exhaustive, and the lifestyle changes are implemented more extensively and rigorously (Bredesen, et al., 2016). In any such case it is important to obtain a baseline of cognitive capabilities through an assessment battery or a mental status assessment, such as the Montreal Cognitive Assessment, that can be retested after a period of treatment.  To implement the diagnostic process and to prescribe the appropriate lifestyle changes and potential medical interventions, it is necessary to engage medical experts in the field.  In the Los Angeles area, Drs. Dean and Ayesha Sherzai (Sherzai & Sherzai, 2017) have a Brain Health and Alzheimer’s Prevention Program at Loma Linda University Medical Center. You can read their story at: https://news.llu.edu/clinical/prevention-new-treatment-for-alzheimer-s-disease.

References
Alzheimer’s Association. (2018).  Alzheimer’s & Dementia. Retrieved from: https://www.alz.org/alzheimer_s_dementia
Bredesen, D. (2017). The End of Alzheimer’s: The First Program to Prevent and Reverse Cognitive Decline. New York :Avery.
Bredesen, D. (2015). Metabolic profiling distinguishes three subtypes of Alzheimer’s disease.  Ageing (Albany NY). 7(8), 595-600.
Bredesen, D. E., Amos, E. C., Carnick, J., Ackerley, M., Raji, C., Fiala, M., & Adidan, J. (2016). Reversal of cognitive decline in Alzheimer’s disease. Ageing (Albany, NY). 6. 1250-1258.
Chang, R. Yee, K-L., & Sumbria, R. K. (2017). Tumor necrosis factor-alpha inhibition in Alzheimer’s disease. Journal of Central Nervous System Disease. 9, 11795735177009276. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436834/
Cojocaru. I. M., Cojocaru, M., Miu, G., & Sapira, V.  (2011). Study of Interleukin-6 in Alzheimer’s disease. Romanian Journal of Internal Medicine. 49(1),  55-58.
Heppner, F.L., Ransohoff, R.M., & Becher, B. (2015). Immune attack: the role of inflammation in Alzheimer Disease. Nature Review Neuroscience. 16, 358-372. 
Musiek, ES. & Holtzman, DM. (2012). Origins of Alzheimer’s disease: Reconciling CSF biomarker and neuropathology data regarding temporal sequence of A-beta and tau involvement. Current Opinion in Neurology. 25(6), 715-720.
Qian, J., Wolters, F. J., Beiser, A., Ikram, M. A., Karlawish, J., Langbaum, J. B. . . . . .  Blacker, D. (2017). APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts. PloS Medicine, 14(3), e1002254. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/?term=APOE-related+risk+2017+Qian
Sherzai, D & Sherzai, A. (2017).The Alzheimer’s Solution: A Breakthrough Program to Prevent and Reverse Cognitive Decline at Every Age. New York:HarperOne.
Stern, Y. (2012). Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurology. 11(11), 1006-1012.
Yo-El, S.J., Lucey, B. P., & Holtzman, D. M. (2014). Sleep and Alzheimer’s disease pathology – a bidirectional relationship.  Nature Review Neurology. 10(2), 115-119.

The Gut-Brain Connection in Alzheimer’s and Major Depression
James S. Graves, PhD, PsyD

Our gastrointestinal system (GI tract) contains about 100 trillion microorganisms – mostly bacteria with a few fungi, protozoa, and viruses thrown in.  That number is ten times the number of cells that make up our body. The roughly 1000 species of microbiota and their vast array of genetic material (about 10 - 100 quadrillion genes) are collectively known as the microbiome. 

Our gut microbiota play important roles in both health and disease, which relies on the proportions of “good” bacteria versus less favorable strains.  When this balance tilts toward the more pathogenic strains, referred to as a state of dysbiosis, the microbiota may contribute to a variety of disease states, particularly autoimmune diseases such as intestinal bowel disease, type I diabetes, and rheumatoid arthritis.  Dysbiosis may be caused by GI infections (e.g., periodontitus), antibiotics, dietary factors (e.g., high fat diet), obesity, parasites and aging, itself. 

This disturbance in the microbial communities can lead to auto-inflammatory diseases. Under stable, favorable conditions, the gut microbiota and the large molecules they secrete remain inside the GI tract to be excreted in the stool.  The epithelium (i.e., a layer of specialized cells) which lines the gut forms a barrier by virtue of tight junctions between the epithelial cells that prohibit the passage of large molecules and the bacteria themselves.  However, in the condition of dysbiosis, secreted bacterial toxins cause these tight junctions to loosen, thereby allowing larger molecules and some bacteria to pass through the epithelium into the circulatory system.  This “leaky gut” phenomenon triggers the immune system to be activated and results in a systemic inflammation.

But, how does this inflammatory response have an effect on brain disorders like Alzheimer’s Dementia (AD)? Under healthy conditions the brain is protected from the invasion of blood-borne microbes, immune cells or proteins and other large molecules by the Blood Brain Barrier (BBB). The BBB is comprised of the cells lining the vascular system’s capillaries that also have tight junctions, unlike capillaries in the rest of the body. However, with a leaky gut the same molecules that disrupted the gut epithelial tight junctions now have the same effect on the tight junctions of the BBB, allowing the immune white blood cells and pro-inflammatory proteins to pass into the brain tissue.  The brain’s immune system then becomes activated, producing a state of neuroinflammation. 

Neuroscience research in recent years has implicated neuroinflammation in the etiology of Alzheimer’s Dementia (AD) and Major Depressive Disorder (MDD).  The most popular hypothesis of the development of AD is the “Amyloid Cascade Hypothesis,” in which there is an overproduction of the protein, beta amyloid, in the brain resulting in toxic aggregations known as “neuritic plaques” on the outside of brain neurons. These plaques appear to work in concert with an abnormal variety of tau protein, an important component of the microtubular system, which is like a railroad system transporting vital materials inside the neuron.  The abnormal variety of tau protein physically disrupts the microtubular system to form “neurofibrillary tangles,” which leads to synaptic malfunction and cell death.

Beta amyloid protein is produced by the cleavage of a membrane protein that is sensitive to the extracellular environment.  In the presence of an inflammatory environment in the brain, that cleavage process is distorted to form greater amounts of beta amyloid and more plaques.  The relationship between neuroinflammation and abnormal tau protein is less well understood. Nonetheless, it appears that neuroinflammation facilitates the production of abnormal tau and the tangles it creates.  Aging is the greatest risk factor for AD, and its role in dysbiosis may be a significant factor in the development of AD, especially for those without a genetic predisposition. 

Neuroinflammation is also a significant factor in the development of Major Depressive Disorder (MDD) in some people. There are at least three areas of evidence supporting this theory: 1) People with MDD often have biomarkers of ongoing systemic inflammation; 2) Administration of inflammation-inducing compounds (e.g, LPS) causes depression in both animals and humans; 4) Administration of anti-inflammatory drugs (e.g., celecoxib), either as monotherapy or as an add-on to standard antidepressant therapy, have significant antidepressant effects. Because dysbiosis is a significant cause of neuroinflammation, it may also be playing a role in the development of MDD, at least for some people. 

What is a person to do if a leaky gut is suspected to be at work?  Systemic inflammation can be detected with standard lab tests ordered by a physician. Dysbiosis can be identified by determining the proportions of different species of bacteria in stool samples.  If these tests point to a leaky gut, the microbiome can be modified by a regimen of GI specific antibiotic treatment and repopulation of the gut with probiotics to correct the imbalance of bacteria leading to dysbiosis. There is also evidence that a plant-based diet, stress management and exercise may help to normalize gut microbiota.