Tag: Alzheimer’s Disease

What you don’t eat can’t hurt you

Many people in the life extension community follow some kind of diet. Historically, caloric restriction (CR) has been the most popular and most discussed option. Other popular diets include the Mediterranean diet and the Paleolithic diet.  In one sense, comparing these diets is like comparing apples and pears. The emphasis of caloric restriction is on how much we eat (given adequate nutrition) and the other diets are more concerned with what we eat. People who follow certain diets may also have different aims. In the case of CR, life extension. In the case of the Mediterranean diet, preventing and delaying cardiovascular and neurodegenerative diseases. And many who adopt a low-carb diet are (initially) motivated by securing sustainable weight loss.

Assuming that diet plays some role in longevity and disease, it is rather obvious that cryonicists should take a strong interest in choosing the right diet. As it looks to me, there are a number of important considerations.

1. The most important aim of a diet for cryonicists should be to avoid, or delay, neurodegenerative diseases. Extending your life and ending up with advanced Alzheimer’s Disease is worse than dying young and being cryopreserved under circumstances that optimize preservation of personal identity.

2. The choice to follow a particular diet should work for your genotype. Admittedly, nutrigenetics is a very young field but there is a growing recognition that human evolution has not stopped since the start of agriculture and that different populations respond differently to certain diets. And even within these populations we should expect individuals to respond differently to diet.

3. A decision to follow a certain diet should be based on empirical evidence, not on intuition, abstract theories, or thought experiments. In the case of choosing diets, this  means identifying a diet that has shown a favorable ratio of good outcomes in experimental studies, and humans in particular.

Putting this all together, it seems to me that a low calorie diet remains the most defensible choice for most cryonicists because it has been studied longer, studied more extensively, and has the most robust favorable outcomes. CR also seems to stand out favorably in that there are relatively few studies that find detrimental outcomes and its benefits seem to embrace many species and populations. Another advantage of CR is that it can capture all the important goals that life extentionists seeks from a diet: longevity, weight loss and prevention (or delay) of neurodegenerative diseases.

It may be the case that many of the benefits of CR actually come from a reduction of carbohydrates. But one of the problems with a paleolithic diet is that it may be more beneficial for certain populations than others. As Gregory Cochran and Henry Harpending demonstrate in their seminal book The 10,000 Year Explosion: How Civilization Accelerated Human Evolution, human evolution did not stop when hunter gatherers started agriculture, and some populations are more adapted to agricultural products (such as milk) than others. Another concern about the paleolithic diet is the controversy surrounding saturated fat. For life extentionists who carry one or two copies of the ApoE4 gene, a diet high in saturated fat may actually increase the probability of Alzheimer’s disease. Others dispute this and recommend a diet high in (saturated) fat to prevent dementia.  In light of this uncertainty, the most prudent course of action may be to incorporate the emerging evidence against carbohydrates into a CR diet without emphasizing saturated fat.

There is an ongoing debate whether the longevity benefits of CR will be as great in humans as in lower species but the evidence so far seems to be that there are at least benefits in terms of delaying the onset of age-associated diseases. Whether these benefits are conferred through a change in gene expression or because they reduce the amount of chemicals that can participate in pathological events is not clear, but our incomplete knowledge about the mechanisms involved should not deter anyone from following CR. As I currently see it, the role of ongoing research into nutrigenetics and other diets should be to further calibrate and refine a low calorie diet to optimize it for a specific individual and to further delay the onset of neurodegenerative diseases.

CR seems to come closer to being a universal diet than other diets but it may be contra-indicated for some people, such as certain athletes and extreme ectomorphs. There are also cases in the life extension community of people who pushed it too hard (or neglected good nutrition), offsetting all the gains from the diet, or even endangering their own health. A diet that does not make a person feel good, is generally not a diet that is good, let alone one that can be sustained over time.  The aim of a diet should not be to conform to an impersonal set of recommendations, but to monitor your own response and increase the chance for personal survival.

ApoE4 – The Ancestral Allele

Reportedly, when James Watson and Steven Pinker had their genome sequenced, they declined to know their risk for Alzheimer’s disease. Clearly this is not an option for life extensionists and cryonicists, who are better off knowing whether they have a copy or, worse, two copies of the ApoE4 gene.

Patri Friedman, son of the libertarian economist David Friedman (who in turn is the son of the Nobel laureate Milton Friedman), recently learned that he has two copies of the ApoE4 gene when 23andMe updated their reports. Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing Alzheimer’s by 75 years of age, as compared to those not carrying any E4 alleles. Patri is a life extensionist, practitioner of the paleo diet, and recently made cryonics arrangements with his whole family at Alcor – and is thus far more prone to a pro-active course of action.

When he realized that there was no good central resource for people with copies of the ApoE4 gene he started a new blog called ApoE4 – The Ancestral Allele, which aims to share practical information and research for health-conscious E4 carriers. The first posts discuss some of the benefits of having the E4 gene (better episodic memory) and what kind of diet is recommended for E4 carriers. He also encourages guest posts and other co-bloggers to help run the website.

No disease in the brain of a 115-year old woman

In August 2008, Neurobiology of Aging published the interesting observations of den Dunnen, et al. of the post-mortem body of a 115 year old woman, which showed no evidence of atherosclerosis. Her brain was devoid of the amyloid plaques characteristic of Alzheimer’s disease and neural density was on par with healthy persons 60-80 year of age. Pre-mortem psychological testing of the woman at ages 112 and 115 found her cognitive abilities to be well above average, scoring better than the average healthy 60-75 year old. Indeed, the authors describe her repeatedly as “alert and attentive” and interpret their findings as follows:

“Our observations indicate that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable.”

This lack of pathophysiology and retention of mental abilities in old age is encouraging and should motivate us to take the best care of our bodies as possible, so that our latest years remain some of our best ones. However, it should be noted that while the woman’s Mini Mental State Examination (MMSE) score only dropped one point (from 27 to 26) from age 112 to 115, and her immediate recall ability and orientation did not deteriorate, she performed worse at age 115 at more complex tasks such as those testing working memory and mathematical calculation skills. In addition, though no amyloid deposits were found in her brain, the other hallmark of AD, neurofibrillary tangles, were observed in the medial temporal lobe, possibly indicating the very earliest stages of AD.

While brain disease at 100 may not be inevitable, and we will certainly enjoy our healthy lives as long as we have them, ultimately even the healthiest supercentenarians succumb to the progression of aging and its entourage of aging-related diseases. Cracking the mystery of aging will require multiple approaches, and studies of the oldest-lived among us provide clues as to which lines of inquiry are the best leads to follow.

Recent developments in the treatment of Alzheimer's

The full text of the Life Extension Foundation magazine article (August 2008) describing the use of Enbrel for the treatment of Alzheimer’s disease and announcing LEF’s new Enbrel trial, is now available. As previously discussed, Enbrel (entanercept) has been shown to provide immediate benefits in Alzheimer’s patients, improving memory performance and less frustration and agitation within minutes of treatment.

The more recent publication (pdf document) of additional data from the same patients in the previously reported six month Phase II trial adds further evidence to these results, specifically noting a rapid improvement in the verbal fluency of patients undergoing weekly perispinal Enbrel injections. Additionally, case studies of two more patients are given in the text of the report, and a stronger case for carrying out larger scale studies (including Phase III clinical trials) is made.

A blog post at Al Fin reports on other promising Alzheimer’s treatments such as the drug Rember, which “appears to target ‘Tau tangles’ in the portion of the brain most active in memory formation.”

TNF-alpha modulation in Alzheimer's patients

More than a decade of basic research and clinical evidence now implicates inflammatory processes in the pathogenesis of Alzheimer’s disease (AD). TNF-alpha is a pro-inflammatory cytokine, also known as the “master regulator” of the immune response, and is the key initiator of immune-related inflammation in the brain. Much evidence has linked excess TNF-alpha to the development of AD, including the demonstration of 25-fold elevated levels of TNF-alpha in the cerebrospinal fluid of AD patients and the finding that beta-amyloid (the main constituent of the amyloid plaques found in the brains of AD patients) stimulates the secretion of TNF-alpha, which in turn induces beta-amyloid production in a vicious positive-feedback loop. This beta-amyloid-induced neuroimflammation has been shown to result in neurotoxicity and to upregulate other inflammatory mediators in the brain, including interleukin (IL)-1 beta, IL-6, and nitric oxide.

To examine the effect of downregulating this inflammatory process, a group of researchers performed a 6 month pilot study in 2006 to determine the effect of modulating TNF-alpha in AD patients using the specific anti-inflammatory agent entanercept (Enbrel). Enbrel selectively inhibits the biologic activity of TNF-alpha by binding to TNF-alpha and preventing its interaction with cell-surface TNF receptors.  Entanercept is already FDA approved for the treatment of such diseases as rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Fifteen patients with mild to severe AD were evaluated before treatment began and once a month thereafter for six months using three standard measures of cognition: the AD Assessment Scale-Cognitive subscale (ADAS-Cog), the Severe Impairment Battery (SIB), and the Mini-Mental State Examination (MMSE). Treatment consisted of a total dose of 25 to 50 mg of Enbrel in sterile water per week via interspinous injection. This injection between two cervical vertebrae is hypothesized to improve flow of the drug to the central nervous system (CNS). All patients in this pilot study improved significantly on all assessments of cognitive ability, which is particularly amazing given the cognitive decline that would normally be expected of an AD patient over the course of six months.

As mentioned, this pilot study was approved to evaluate patients only at monthly intervals. However, during this six-month study and over the course of their clinical experience since the pilot study, the researchers noted “an unexpected and largely unprecedented clinical phenomenon… a noticeable clinical improvement within minutes of perispinal entanercept administration.” To validate these observations, the researchers performed a case study in 2008 in which a patient with severe AD was evaluated prior to, ten minutes after, two hours after, and one week after Enbrel administration.

Prior to treatment the patient had been unable to recall his birthday, his father’s occupation, or the names of any of the physicians treating him. He was not oriented to the calendar date, day of the week, year, place, city, or state. Ten minutes after receiving an injection of Enbrel, the patient correctly identified the state as California and his demeanor was observed to be calmer and more attentive. His responses to questions were less effortful, as well.

At the 2-hour post-evaluation, the patient was able to recall the name of his evaluator and was able to identify the month, day of the week, place, and name the state of California. He was slightly off on the calendar date and year, but “appeared more aware of his deficient performance.” The patient’s scores on all mental tests also improved dramatically. These improvements were maintained over the course of a week, whereupon he was evaluated again before receiving his next Enbrel dose. The patient continued to receive a weekly dose of Enbrel for a total of 5 weeks and was re-evaluated at 7 weeks (fourteen days after his last dose). His improvement in all areas of cognitive performance was marked and significant.

An important consideration when treating a patient with Enbrel, however, is that it is immunosupressive and as such leaves the patient at high risk of morbidity if they acquire an infection. This is especially important in late-stage Alzheimer’s patients, who are generally elderly, frequently visit hospitals/treatment centers, and live in community environments, making them particularly susceptible to community-acquired infection.

Following up on the publication of these unprecedented findings, the Life Extension Foundation recently published a review of both Enbrel pilot studies and the initial results of their own pilot study involving a 91-year-old female AD patient with severe cognitive deficits, who has also shown marked improvement in cognitive ability. The Life Extension Foundation is now eager to “launch an expanded study with the objective of measuring the long-term effects of weekly Enbrel injections plus nutrients that help suppress the production of excess TNF-alpha.” These trials are aimed at treating early-stage AD patients, and weekly Enbrel injections will be given in the Fort Lauderdale area.

To inquire about enrolling in this new study, contact the Life Extension Foundation.

Enbrel reverses Alzheimer's cognitive deficits

The latest issue of Life Extension Magazine (August 2008) contains an encouraging report about off-label use of etanercept (commercial name: Enbrel) to reverse the cognitive deficits associated with Alzheimer’s disease. Etanercept is a tumor necrosis factor (TNF) blocker that is used to treat diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, and rheumatoid arthritis. Pilot studies and case reports not only reported improved cognitive function after weekly perispinal administration (injection  into the back of the neck) of etanercept, but rapid clinical improvements have also been observed within minutes of administration of the drug in at least one person, a result that the Life Extension Foundation (LEF) reportedly was able to reproduce in a pilot study of a 91-year-old female patient with advanced Alzheimer’s disease.

The Life Extension Foundation (LEF) is currently seeking to launch an expanded study to investigate the effects of weekly Enbrel injections plus nutrients that help suppress the production of excess TNF-alpha in people who have early-stage Alzheimer’s disease. Although the normal costs of weekly injections is around $675, LEF will not charge people enrolled in the studies for these treatments. Patients who have, or people who know someone with, early-stage Alzheimer’s disease are encouraged to contact LEF for enrollment. The study will be conducted in the Fort Lauderdale area in south Florida.

Future installments of this blog will review the research on TNF-alpha modulation for the treatment of Alzheimer’s disease in more technical detail. We also recommend a recent article on long-term brain maintenance on the blog Existence is Wonderful, which also discusses cryonics in a favorable context.