Feb 19, 2012

Current Science, Dementia in the 21st Century

Despite all efforts to the contrary, as the second decade of the 21st century dawns, biomedical efforts to delay, prevent, or cure dementia are showing no significant success.

By Stephen Post


Current Science,  Dementia in the 21st Century
Stephen G. Post
Despite all efforts to the contrary, as the second decade of the 21st century dawns, biomedical efforts to delay, prevent, or cure dementia are showing no significant success.

The history of science is of course replete with surprising examples of victory plucked from the wings of despair, and indeed “serendipity favors the prepared mind.”

Without giving in to scientific defeatism, it does seem fitting to focus our hope on care itself, and on how we can create cultures that value people who are so deeply forgetful.

There is no magic bullet for dementia, but we can place hope in these three things:
  1. the compassionate carers who manifest our deepest sense of a shared humanity despite cognitive decline;
  2. the increasing evidence for enduring selves beneath the chaos of neurological devastation;
  3. and the possibilities of a spiritual-cultural evolution toward acceptance, affirmation, and connection with the deeply forgetful.

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Current Science

In the United Kingdom there is wisdom in speaking of “dementia” rather than of “Alzheimer’s disease,” since dementia as a syndrome has so many causes, and any single case may be of mixed causality.

No doubt there exists a progressive, intractable, and irreversible form of dementia that is characterized through brain imaging as an atrophy of the hippocampus, that part of the brain most involved with memory, and this may be described as dementia of the “Alzheimer’s type,” or even as Alzheimer’s disease. But it is by no means agreed upon anymore that the disease is caused by beta-amyloid protein plaques that develop between neurons.

In a recent study, Eli Lilly’s compound, Semagacestat, successfully reduced beta-amyloid plaques in the brains of people with a diagnosis of probable Alzheimer’s, but this seems to have worsened cognitive function and activities of daily living in subjects when compared with placebo.

Contrarian basic scientists then quickly asserted their view that beta-amyloid build-up is the body’s protective reaction to Alzheimer’s, rather than a causative agent to be eliminated. In a spinal fluid test for Alzheimer’s based on beta-amyloid and tau protein levels was media hyped as “100 percent accurate” in predicting onset of Alzheimer’s, when in fact, such tests are still lacking in their sensitivity (ability to diagnose Alzheimer’s when it exists) and specificity (ability to only diagnose those with the disorder). It is not the case that persons with normal memories who have these proteins will go on to develop Alzheimer’s. Even if elevated beta-amyloid levels are associated with Alzheimer’s to a significant extent, this by no means is a certain marker for disease, nor is it necessarily causal.

True, then, there is an epidemiology of an irreversible, intractable, and progressive form of senile dementia that it quite heterogeneous in manifestation, marked by hippocampal atrophy, and that we call Alzheimer’s despite the fact that in 1907 Dr. Alzheimer himself did not think he was discovering a disease, but simply observing brain plaques that might or might not be associated with the senile dementia that we would probably all succumb to if we just lived long enough.

Indeed, the major prevalence study of persons 90 years of age or older indicates a 61.1 percent prevalence rate of the syndrome of dementia among women 100 years of age or older, some of which is due to hippocampal atrophy, but that may equally well be due to limited blood flow or small stroke-like events in the white matter of the brain (i.e., multi-infarct dementia). More frequently than not, these “mixed” causes occur together. Maybe dementia just comes with the territory of growing very old as the vasculature system declines and the brain ages. If so, then the primary cause of dementia is age, which we are not likely to eradicate, although a great deal of effort is being spent on research into the basic science of aging in the hopes that the process can be delayed.

Dementia associated with hippocampal atrophy can occur in early onset families, caused by rare autosomal dominant mutations, especially the presenilan genes PS1 and PS2 (disease onset is typically in the early forties and is especially rapid in progression). It is possible to speak of these genetic diseases as Alzheimer’s disease, but they might be better referred to as PS1 and PS2 diseases, although it is also plausible that they could be very pure or “unmixed” examples of Alzheimer’s disease.

Plural biologies, plural genetics, plural ages of onset, plural progressions, and probably plural diseases are apparent in dementia, and Alzheimer’s is a label being used too widely. As the basic science of Alzheimer’s disease has become confused, scientists have a hard time being able to pick out the right targets for new compounds to attack.

There is to date no successful compound, natural or unnatural, that delays, prevents, slows, or cures this atrophy of the hippocampus that we call Alzheimer’s disease. If, on a scale of one to ten, insulin is a ten for the treatment of diabetes, these cholinesterase inhibitors are a 1 at best, and probably a .05.

The legacy of disappointment is clear. Back in the late 1980’s, Whitehouse and others put forward the cholinergic hypothesis, and quickly the hype evolved to a point where cholinesterase inhibitors were going to “cure” “Alzheimer’s disease.” The results of this entire line of compounds over the past two decades have been so limited that many clinicians still do not prescribe them, or would not were there no pressure from families to do so.

As for delay and prevention, hormonal replacement in post-menopausal women not only failed, but actually contributed to dementia levels. Anti-inflammatory drugs have little or no impact. Cholinesterase inhibitors have no demonstrated delaying or preventive impact at all, and their impact on those with PD is slight even in the best case scenarios. Vitamin E has shown no benefits, though for a while many neurologist friends were gulping down pills.

A 2010 National Institute of Health panel, after reviewing the world’s scientific literature, found that “Currently, no evidence of even moderate scientific quality exists to support the association of any modifiable factor (such as nutritional supplements, herbal preparations, dietary factors, prescription or nonprescription drugs, social or economic factors, medical conditions, toxins, or environmental; exposures) with reduced risk of Alzheimer’s disease”. Such honesty is laudable, although the panel errs in downplaying the studies on diet, exercise, and social engagement, which are alluded to in the next section.

Note: We will publish the full, unabriged, version of Stephen Post's article, Five Sources of Hope for the Deeply Forgetful, Dementia in the 21st Century, on February 21th.

Also see:

Best-selling author of The Hidden Gifts of Helping (2011), Stephen Post is Director of the Center for Medical Humanities, Compassionate Care and Bioethics at Stony Brook University. His book
The Moral Challenge of Alzheimer Disease: Ethical Issues from Diagnosis to Dying was selected as a “Medical Classic of the Century” by the British Medical Journal (2009). He received the Distinguished Service Award from the National Board of the Alzheimer’s Association “In recognition of personal and professional outreach to the Alzheimer’s Association Chapters on ethics issues important to people with Alzheimer’s and their families” (1998).

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Original content Stephen Post, the Alzheimer's Reading Room