Vitamin B12 and Age-Related Cognitive Decline—Dementia and “Alzheimer’s Disease”

Abstract

This article is a commentary on the role of vitamin B₁₂ in age-related cognitive decline, with a meta-commentary on the misuse of the term “Alzheimer’s Disease.” The article describes the historical origins of the term “Alzheimer’s Disease” and argues that the term should be restricted to a narrower segment of the age-related dementia spectrum. The article also outlines the role of vitamin B₁₂ in age-related cognitive decline and outlines the rationale for the treatment of B₁₂ deficiency to address a potentially reversible factor in cognitive decline.

Review and Comments

Dementia is a spectrum disorder with several different presentations in the elderly. Age-related dementia and “Alzheimer’s disease” are not synonymous. Rather, Alzheimer’s disease is one component of late onset age-related (or senile) dementia (LOAD). There is a historical context to this misrepresentation of the term “Alzheimer’s Disease.” This starts with a report in 1907 of a 51-year-old woman who was hospitalized for what was called then “dementia” and died soon after. ¹ The leading neuropathologist in the world, Emil Kraepelin of Leipzig Germany, assigned his younger colleague, Alois Alzheimer, the task of doing the postmortem of the brain of this woman. Alzheimer’s description included terms that have made it into the modern lexicon as plaques and tangles and amyloid deposition. Kraepelin, who was widely influential in the world at the time, announced that this description of the pathology should be called Alzheimer’s disease. The brain pathology that Alzheimer described was not “senile dementia,” a term which dominated the growing field of age-related dementia in the first half of the 20th century. What Alzheimer described was rather pre-senile dementia in a 51-year-old, probably not even the same condition as LOAD. But Alzheimer’s name was later used as an umbrella term, after about 50 years to the increasingly recognized problem of age-related dementia or cognitive decline. Some enterprising clinicians and investigators realized that if they gave that condition a disease name (not just a condition of aging), that it would not only increase the interest in a condition that also it had an interesting metabolic underpinning (i.e., disordered amyloid metabolism), it would also stimulate research and funding. And in fact, there was a huge increase in research funding on both sides of the Atlantic, especially in the U.S. National Institutes of Health. Studies of “Alzheimer’s Disease” and investment by the pharmaceutical industry increased sharply, as the pharmaceutical industry was looking for a way to prepare drugs that would attack these plaques and tangles described by Alzheimer in that 51-year-old patient. That has led to hundreds of millions of dollars in investment in drugs that do not have much effect on senile dementia. And it also led to the use of the term “Alzheimer’s Disease” being applied to a larger proportion of patients with LOAD than is justified by rigorous diagnostic criteria. And in the process other pathogenetic contributors, especially cerebrovascular pathology, were sidelined in the rush to find a pharmaceutical cure or amyloid pathology. In the 1960s, many publications said that 90% of senile dementia was “Alzheimer’s Disease” and that only 10% may have been post-stroke, vascular, and some other conditions, such as frontal lobe dementia. But we now know, over the course of time and after considerable investment in largely negative trials, that age-related cognitive decline or LOAD is not a target for cure but rather for mitigation. Even the earlier descriptions of causes of dementia by Kraepelin and his colleagues was more focused on vascular pathology. Kraepelin wrote about the “strangulation of arteries” to the brain, and this is how vitamin B₁₂ and homocysteine feature in descriptions of pathogenesis of significant elements of cognitive decline. The contribution of vitamin B₁₂ deficiency to cognitive decline, dementia, and what we call Alzheimer’s disease (which in reality is a vascular dementia with prominent underlying cerebrovascular pathology) is both under-diagnosed and under reported. Cerebrovascular pathology, especially small vessel pathology in patients with cognitive decline and dementia is more prevalent than amyloid and tau pathology that often coexist. Vitamin B₁₂ deficiency in elders contributes to cognitive decline, memory impairment and dementia by affecting cerebrovascular integrity, in addition to direct brain and spinal cord neuronal damage with posterior column disease and spinal cord involvement with B₁₂ deficiency. There is growing evidence that one of the ways that B₁₂ deficiency affects the central nervous system (CNS) is at the level of the brain and cognitive function. This is where circulating homocysteine and methylmalonic acid (MMA) come in because both assays are underutilized in the workup of memory impairment and dementia. We need to use more of these tools in the diagnosis of B₁₂ deficiency and B₁₂ status in elders who present with cognitive decline. Elevated circulating homocysteine is an element in the diagnosis of vitamin B₁₂ deficiency because methylation of homocysteine is one of the two known coenzyme functions of Vitamin B₁₂. So, homocysteine can be one marker of B₁₂ status. Importantly, elevated homocysteine itself may contribute to vascular, including thromboembolic pathology, and possibly to direct neuronal toxicity. The earliest studies of hyper homocysteinemia were in children or patients with homocystinuria, a genetically determined condition. These children, some who died in childhood were found to have thromboembolic cerebrovascular abnormalities, with thromboembolic changes, in brain pathology levels on autopsy. ² It is likely that subclinical vitamin deficiency plays a role in the pathogenesis of decline in cognitive function. ³ There is a gradation of developmental of functional responses to vitamin B₁₂ deficiency. Vitamin B₁₂ deficiency is not a binary phenomenon. What about the association of low normal B₁₂ levels with CNS abnormalities? We know that there can be degenerative changes in the spinal cord, an increased risk of neural tube defects, risk of stroke, risk of depression, risk of cognitive impairment, damage to white matter, and atrophy of the brain. Damage to white matter is part and parcel of some of the diagnostic approaches that we and others, especially in the Rotterdam Scan studies, have been making since we have been able use magnetic resonance imaging (MRI) scans of the brain in vivo to explore the underlying causes of dementia. The Rotterdam scan study emphasized that white matter hyper intensities on MRI are indicative of small vessel vascular disease. ^4,5 In community dwelling elderly comparing the quartiles and plasma levels of B₁₂, in the lowest quartile there was a significant relationship between low B₁₂ and cognitive impairment. ⁶ There is evidence about how MMA and total homocysteine could be used in relation to cognitive impairment and in the plasma levels of both MMA and homocysteine. In the study, the third and fourth quartiles of homocysteine elevation are associated with cognitive impairment as measured by the mini mental status examination. Now in another longitudinal study, cognitive decline was relating to the mini mental status examination over the years and that with higher holo-transcobalamin (TC) the cognitive decline was considerably slower than at lower levels of cognitive holo-TC over a 10 year span. ^7,8 So there is ample longitudinal evidence now of the association of low B₁₂ and cognitive decline. Serum B₁₂ and change in brain volume was measured in the OPTIMA study, and others, by Smith and others, where the annual change in total brain volume over 5 years in relation to the Vitamin B₁₂ levels, that there was a significant relationship between higher B₁₂ levels and change in brain volume. ⁹ There is evidence that atrophy rate in the brain over time with enlarged ventricles and loss of brain matter compared to the atrophy rate of less than about a quarter than with B₁₂ levels that were 3 times as high. An important question is, is this reversible? And in another study, brain scans were performed in patients with B₁₂ levels under 114 µmoles before and after treatment containing vitamin B₁₂. There was a sign of positive change 4 months after B₁₂ treatment. So unlike changes that we were unable to see with the use of these expensive anti-amyloid antibody drugs in an Alzheimer’s disease, there is actually evidence that fairly early in the course of the condition there was reversibility. By reversing B₁₂ deficiency, we are improving the pathogenetic factors, including small vessel disease that was shown in the white matter changes. This is also dependent on the original baseline homocysteine levels. In work by David Smith, over the course of time you can see some changes in the rate of atrophy that are influenced by the starting levels of homocysteine. ¹⁰ Vitamin B₁₂ treatment influenced brain shrinkage and plasma homocysteine and cognitive decline was slowed. So, the main effect is a highly significant slowing of the rate of whole brain atrophy. Using the National Health and Nutrition Examination Survey (NHANES) data in the United States, there is a significant difference between the relationships of B₁₂ and high folate, but much more with cognitive impairment than with anemia. In our recent work, which showed that small vessel cerebrovascular pathology identified by MRI is prevalent (in what was called Alzheimer’s disease by consensus diagnosis of clinicians) and that both this study and other studies have shown that early cognitive impairment and B₁₂ is associated also perhaps with some evidence of vascular pathology. ¹¹ With white matter intensities absent or present, there’s a difference in brain atrophy grade across homocysteine quintiles due to effect of small vessel infarcts in relation to different homocysteine levels. White matter hyper intensities are much more related to peri ventricular findings rather than subcortical, as seen in the Rotterdam scan studies. ⁴ Executive function across the gradations of homocysteine quintiles was significant in our study. I emphasize executive function because that probably is one of the better tests in our armamentarium of looking at cognitive function, and it tracks quite successfully with vascular abnormalities that we can show on MRI.

In summary, it is my recommendation that elders, with or without anemia, should be screened for B₁₂ deficiency because that may be one of the reversible factors in their cognitive decline. In the absence of their diagnosis, treatment of B₁₂ deficiency in appropriate dosage and mode of administration should lead to benefits. If we do this right, there may be some effect on both prevention of decline or at least modification of further decline and maybe even some reversibility of early findings.

Supplemental Material

Supplemental Material, sj-pdf-1-fnb-10.1177_03795721241228060 - Vitamin B12 and Age-Related Cognitive Decline—Dementia and “Alzheimer’s Disease”

Supplemental Material, sj-pdf-1-fnb-10.1177_03795721241228060 for Vitamin B12 and Age-Related Cognitive Decline—Dementia and “Alzheimer’s Disease” by Irwin H. Rosenberg in Food and Nutrition Bulletin