Alzheimer’s:  A Biological Model of Prevention – Finally!  (Part 3)

The Silent Flame

Theories abound on the origins of most major diseases, and many share one factor in common: inflammation. The biological consequences of inflammation are at the root of virtually every human malady from the common cold to cancer, allergies to arthritis, and headaches to heart disease. Yet inflammation is a natural, self-protective response of the body with the best of intentions. Inflammatory chemicals rush to the scene of injury or infection, and safeguards rein in the potent reaction before its benefits are outweighed by potential harm. When these defenses are compromised, immune responses lead to chronic inflammation, the root of major diseases.

Inflammation and the Brain

Just as the cells that make up our organs and tissues can be damaged by incessant inflammation, so too the cells that construct our brain experience its impact. Accelerated activity in the brain renders neurons even more vulnerable to inflammatory injury. Networks of neurons shape the nature and stability of our thoughts, moods, and behaviors; physical injury to these neurons has far greater implications for our health and well-being. In addition to neurological disorders such as Parkinson’s and Multiple Sclerosis and mental health conditions including depression and schizophrenia, Alzheimer’s Disease is one of several brain abnormalities highly associated with inflammation.

As we remarked in the last article in this series, the hallmark features of Alzheimer’s Disease—often called plaques and tangles—are accumulations of malformed protein fragments resulting from aberrant metabolic processes in the brain. Overactive enzymes, inefficient cellular waste removal, and biochemical imbalances caused by nutritional insufficiency and stress represent several research-supported mechanisms that underly the progressive neurodegeneration characterizing Alzheimer’s. In each of these models, inflammatory responses to injury play a major role in initiating and exacerbating the damage that kills neurons and severs the communication required for us to think, remember, and act. Thus, inflammatory status serves as a primary risk factor and measurable biomarker of short and long-term brain health. 

A Major Modifiable Risk Factor - Homocysteine

Predictably, high homocysteine is one of the most striking predictors of dementia and Alzheimer’s Disease, and one that is easily measured with a blood test.

Inflammatory status is routinely measured by medical practitioners to assess overall health and risk for chronic disease. Homocysteine levels in the blood are often assessed as sensitive measures of inflammation for screening of cardiovascular disease, as elevations are highly associated with heart attack and stroke. An intermediate amino acid derived from methionine, homocysteine holds a pivotal spot in the methylation cycle, a critical biological process that drives protein synthesis. Importantly, efficient operation of this cycle relies heavily upon Folate, Vitamin B-12, and Vitamin B-6. Elevated homocysteine is a beneficial indicator of deficiencies in these dietary essentials. The most severe symptoms of insufficient Folate, B-12, and B-6 are neurological in nature, and can produce debilitating motor and cognitive issues with potentially permanent consequences. Predictably, high homocysteine is one of the most striking predictors of dementia and Alzheimer’s Disease, and one that is easily measured with a blood test.

Though not initially designed to survey neurological outcomes, the multi-generational Framingham heart study, ongoing since 1946, published population data that revealed highly significant long-term correlations between blood levels of homocysteine, cognitive decline, and eventual Alzheimer’s Disease. Participants with homocysteine levels above normal doubled their chance of being diagnosed, with risk increasing by 40% at each incremental level. Remarkably, these associations were found several years before an official diagnosis and held independent of any other cardiovascular risk factors. A plethora of incontrovertible evidence has added to the Framingham report, leading researchers to formulate the “homocysteine hypothesis” as a leading theory to explain Alzheimer’s Disease. The statement endorsed by an international committee of experts reads “We conclude that elevated plasma total homocysteine is a modifiable risk factor for the development of cognitive decline, dementia, and Alzheimer’s disease in older persons.”

The theoretical basis behind the “homocysteine hypothesis” of Alzheimer’s suggests a similarity in the mechanisms tying homocysteine with cardiovascular disease: excessive inflammation as a result of oxidative stress. As chronically high homocysteine triggers an incessant immune response, brain cells are overstimulated to exhaustion and inundated with toxic levels of inflammatory chemicals causing injury and death. The consortium behind the “homocysteine hypothesis” also added greater beta-amyloid production and phosphorylation of tau, processes that encourage the growth and buildup of plaques and tangles. Synthesis of observational and laboratory data from men and women in middle age substantiates the striking relationship between this simple blood marker and progressive memory loss, cognitive decline, dementia, and Alzheimer’s Disease.

Bs for the Brain

With the recognition of such a strong predictor of neuroinflammation and risk for Alzheimer’s Disease, early detection and arrest of brain deterioration appears straightforward. Although high homocysteine was deemed a “modifiable risk factor”, ample intake of Folate, Vitamin B-12, and B-6 from food is often not a reliable gauge. The concept of biochemical individuality, a central tenet of integrative psychiatry, comes strongly into play. Inherent genetic variations in enzymes involved in the methylation cycle are particularly influential in determining B-vitamin needs, which can differ significantly from USDA recommendations and between individuals. 

Without adequate Folate and B-12 to sustain protein methylation in the brain, repair and regeneration of neurons is impaired.

One of the most familiar and common classes of gene variants occurs in Methylene Tetrahydrofolate Reductase (MTHFR), a critical enzyme driving the metabolism of Folate which also requires Vitamin B-12 to function properly. MTHFR defects limit the activation of Folate to a form that can cross the blood-brain barrier.  Furthermore, disruptions in the methylation process allow homocysteine levels to build up, triggering its detrimental effects on delicate neurons. Without adequate Folate and B-12 to sustain protein methylation in the brain, repair and regeneration of neurons is impaired. Vitamin B-6 is required to neutralize homocysteine by converting it to the amino acid cysteine, an important factor in protein synthesis and detoxification. Individuals with defects in the Cystathionine-β-synthase (CBS) enzyme do not adequately use Vitamin B-6, leading to poor recycling of homocysteine.

Fortunately, at-risk individuals with and without genetic influences driving B-vitamin status can manipulate homocysteine with specific supplemental forms of Folate, Vitamin B-12, and Vitamin B-6 and adequately protect the brain from neurodegenerative disease. Patients with MTHFR variants respond remarkably well to L-methylfolate, the activated form of Folate that is highly bioavailable to the body and brain, or to 5-methyltetrahydrofolate, which bypasses the MTHFR impediment. Low B-12 responds most quickly and effectively to intravenous or sublingual delivery as either hydroxycobalamin or methylcobalamin. For individuals with a CBS gene mutation, Vitamin B-6 supplements in the bioactive form Pyridoxal-5-Phosphate (P5P or PLP) can kickstart the conversion of homocysteine and prevent its buildup.

Even healthy individuals who supplement with B-vitamins show improved measures of cognition that typically decline with age as well as superior integrity and maintenance of grey matter volume. In addition to showing a direct relationship to homocysteine levels, multiple research studies supply data showing an inverse relationship between B-vitamin status and cognitive decline, dementia, and Alzheimer’s Disease. Consistently, individuals with greater intakes of Folate, Vitamin B-12, and Vitamin B-6 have less brain atrophy and better neurological function over time. Beyond the methylation cycle, B-vitamins are key factors for the synthesis of red blood cells and maintenance of neurological processes throughout the body. Adequate B-vitamin intake from well-rounded diets and high-quality supplements is recommended for optimal health regardless of age or health status.

New Hope is Here

The most effective and unfailing treatment strategies are founded upon knowledge and understanding of the key biological processes involved and what is missing, out of balance, or not functioning correctly. At the same time, the answers to these questions should be reliably measured, precisely targeted, and easily monitored.  Homocysteine levels therefore represent a clear marker for early detection, prevention, and treatment of Alzheimer’s Disease, and B-vitamins offer a straightforward, safe, and effective solution for eliminating this substantial risk factor. With readily accessible genetic testing methods, we can even address the “unmodifiable” risk associated with poor B-vitamin metabolism in some patients, providing Folate and Vitamins B-6 and B-12 in ready-to-go forms that enable normal turnover of homocysteine. By providing ample supplies of easily recognizable, naturally present nutrients, cells can withstand the pressures of normal wear-and-tear and are more robustly equipped to combat oxidative stress and inflammation.

We don’t have to look far to sense the pessimism and loss of hope within the medical community as headlines stack up announcing another failed pharmaceutical drug trial in the search for an Alzheimer’s cure. Time ticks on as new diagnoses are charted by the seconds. With despair threatening Alzheimer’s patients and their loved ones, there is an urgent need for fresh news. The big business of conventional medicine ignores any non-lucrative treatment, yet billions are funneled into clinical trials doomed to fail. But wasted money is far from the greatest loss to society from Alzheimer’s; we are losing our parents, grandparents, and mentors far too early. And the cost of elderly care for Alzheimer’s patients is staggering.

After years of studying and practicing integrative psychiatry and following evolving research efforts, my perspective remains grounded in biological models of disease that arise from nutritional and genetic imbalances. Scientific evidence continues to deliver unmistakable confirmation that our diets, environments, and lifestyles have profound roles in determining our physical and mental health, and unseen consequences begin years before disease symptoms begin. This article series gives only a brief glimpse into the biochemical underpinnings of Alzheimer’s disease, but even a cursory glance supplies abundant pathways for prevention and treatment. We have the responsibility to use what we know, and we are privileged with unprecedented tools at our disposal. The future of successful Alzheimer’s treatment is now. As the truth about early detection and measurable risk unfolds and expands, we can reverse the prevailing cynicism and doubt and establish a new paradigm of triumph over this ruthless foe.

James M. Greenblatt, M.D.

Dr. James M. Greenblatt is chief medical officer and vice president of medical services at Walden. He provides medical management, leadership and oversight of Walden’s eating disorder and psychiatric programs in Massachusetts and Connecticut. Dr. Greenblatt is board-certified in child and adult psychiatry.

He received his medical degree and completed his adult psychiatry residency at George Washington University in Washington, D.C. He completed a fellowship in child and adolescent psychiatry at Johns Hopkins Medical School. In addition, Dr. Greenblatt is a clinical faculty member in the psychiatry department at Tufts Medical School as well as the Geisel School of Medicine at Dartmouth College in New Hampshire.  

He lectures extensively throughout the United States and Canada on integrative therapies for mental health. Dr. Greenblatt is the author of six books including one textbook and books on depression, eating disorders and ADHD. His latest book is on Integrative Therapies for Alzheimer’s disease, exploring the research on nutritional lithium. Dr. Greenblatt is the founder of Psychiatry Redefined, a healthcare education training program for integrative psychiatry.

He can be reached at: Walden Behavioral Care, 9 Hope Avenue, Suite 500, Waltham, Massachusetts, 02453; (781) 647-2901. For more information on Dr. Greenblatt please visit

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