{"id":428,"date":"2015-09-25T12:24:20","date_gmt":"2015-09-25T12:24:20","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=428"},"modified":"2015-09-25T12:24:20","modified_gmt":"2015-09-25T12:24:20","slug":"promise-of-novel-alzheimers-treatments","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/09\/25\/promise-of-novel-alzheimers-treatments\/","title":{"rendered":"Promise of Novel Alzheimer&#8217;s Treatments"},"content":{"rendered":"<p><span style=\"font-weight: 400\">Last year, <\/span><a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2014\/03\/12\/mitigating-risk-of-alzheimers-disease-more-important-than-we-thought\/\"><span style=\"font-weight: 400\">I blogged<\/span><\/a><span style=\"font-weight: 400\"> on a CDC report that Alzheimer\u2019s Disease is more prevalent than previous epidemiology had acknowledged. \u00a0Last month at the Rejuv Biotech conference, I heard <\/span><a href=\"http:\/\/www.ndm.ox.ac.uk\/principal-investigators\/researcher\/chas-bountra\"><span style=\"font-weight: 400\">Chas Bountra<\/span><\/a><span style=\"font-weight: 400\"> tell us that <\/span><\/p>\n<ul>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Alzheimer\u2019s Disease is currently #3 among diseases of old age<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Demographics are increasing the prevalence of AD at an inexorable rate<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Far more than cancer and vascular diseases, AD is unknown to us&#8211;medical science really doesn\u2019t have a clue<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400\">Boutra is in a position to direct many millions of research dollars for AD, and he says he won\u2019t go near either of the two large branches of research on the disease. \u00a0Study of (1) beta amyloid plaques and (2) tau proteins has absorbed tens of billions of research dollars over half a century, and yet there is no agreement even about what ultimately causes AD, let alone a program for cure. \u00a0So he will only fund long-shot ideas at the fringes of Alzheimer\u2019s research. <\/span><\/p>\n<p><span style=\"font-weight: 400\">There is no shortage of dark horses in this field. \u00a0In recent blog posts, I described two: \u00a0<a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/08\/24\/report-from-rejuvention-biotech-2015\/\" target=\"_blank\">Tony Wyss-Coray<\/a> is beginning clinical trials using plasma transfusions from young donors, and <a href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/03\/18\/tomorrows-anti-aging-therapy-available-today\/\" target=\"_blank\">Bioviva<\/a> will soon be trying gene therapy to activate telomerase.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Further along than either of these is <\/span><a href=\"http:\/\/www.impactaging.com\/papers\/v6\/n9\/full\/100690.html\"><span style=\"font-weight: 400\">Dale Bredesen\u2019s innovative approach<\/span><\/a><span style=\"font-weight: 400\"> based on the\u00a0sustained\u00a0application of common sense. \u00a0Bredesen reports on a trial with just 10 patients, but 9 of them showed major improvement. \u00a0This was not the kind of result that you need a cognitive test to measure; the patients came out of nursing care and went back to their jobs. \u00a0He calls the program MEND, for <\/span><b>M<\/b><span style=\"font-weight: 400\">etabolic <\/span><b>E<\/b><span style=\"font-weight: 400\">nhancement for <\/span><b>N<\/b><span style=\"font-weight: 400\">euro<\/span><b>d<\/b><span style=\"font-weight: 400\">egeneration. \u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400\">Bredesen\u2019s starting point is a model in which AD results from a change in hormonal signaling. \u00a0There is turnover of neurons throughout our lives (this alone is a relatively new acknowledgment), and late in life, the destruction of neurons outpaces the growth of new ones. \u00a0Bredesen defines AD as the tail of the distribution, in which the destruction of neurons has become so severe as to precipitate\u00a0obvious cognitive decline. \u00a0He draws an analogy to osteoporosis, which is understood as a loss of the healthy balance between the creation and destruction of bone cells (osteoblasts) that renews bone tissue and keeps bones strong. \u00a0Nerve cells in the brain do not turn over as frequently as bone cells, but the principle is the same.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Body homeostasis is maintained generally by signaling with negative feedback loops. \u00a0Biology derives its robustness from \u00a0processes that are self-limiting. \u00a0But positive feedback loops act like \u201cswitches\u201d; they can take the body from one state to another. \u00a0Beta amyloid is at the center of a positive feedback loop; it is a mis-folded protein that tends to cause more proteins to misfold, similar in dynamics to a <\/span><span style=\"font-weight: 400\"><a href=\"https:\/\/en.wikipedia.org\/wiki\/Prion\">prion<\/a>, though the feedback\u00a0of beta amyloid is not so direct as in prion diseases.<\/span><\/p>\n<p><span style=\"font-weight: 400\">In the case of beta amyloid, the protein that is misfolded is called APP, for amyloid precursor protein. \u00a0Bredesen sees APP as a switch that turns AD on, and can just as well turn AD off. \u00a0It is both a signal protein and the gunk that accumulates around neurons in the Alzheimer\u2019s brain.<\/span><\/p>\n<p><b>The (missing) punch line<\/b><\/p>\n<p><span style=\"font-weight: 400\">So what is the program that Bredesen has used so successfully to reverse Alzheimer\u2019s symptoms in ten patients? \u00a0It is multi-faceted, not easily summarized, addressing multiple risk factors through multiple modalities. \u00a0The program is also personalized, as a doctor works with each patient\u2019s particular symptoms and particular strengths, desiging a program the patient can commit to. \u00a0This is not traditional allopathic medicine, and prescription drugs play a minor role. \u00a0Bredesen describes a program for one of the 10 patients.<\/span><\/p>\n<blockquote><p><span style=\"font-weight: 400\">(1) she eliminated all simple carbohydrates, leading to a weight loss of 20 pounds; (2) she eliminated gluten and processed food from her diet, and increased vegetables, fruits, and non-farmed fish; (3) in order to reduce stress, she began yoga, and ultimately became a yoga instructor; (4) as a second measure to reduce the stress of her job, she began to meditate for 20 minutes twice per day; [<\/span><a href=\"http:\/\/www.impactaging.com\/papers\/v6\/n9\/full\/100690.html#bibl_5\"><span style=\"font-weight: 400\">5<\/span><\/a><span style=\"font-weight: 400\">] she took melatonin 0.5mg po qhs; (6) she increased her sleep from 4-5 hours per night to 7-8 hours per night; (7) she took methylcobalamin 1mg each day; (8) she took vitamin D3 2000IU each day; (9) she took fish oil 2000mg each day; (10) she took CoQ<\/span><span style=\"font-weight: 400\">10<\/span><span style=\"font-weight: 400\"> 200mg each day; (11) she optimized her oral hygiene using an electric flosser and electric toothbrush; (12) following discussion with her primary care provider, she reinstated HRT (hormone replacement therapy) that had been discontinued following the World Health Inst report in 2002; (13) she fasted for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime; (14) she exercised for a minimum of 30 minutes, 4-6 days per week. <em>[<\/em><\/span><em><a href=\"http:\/\/www.impactaging.com\/papers\/v6\/n9\/full\/100690.html\"><span style=\"font-weight: 400\">same ref above<\/span><\/a><span style=\"font-weight: 400\">]<\/span><\/em><\/p><\/blockquote>\n<p><span style=\"font-weight: 400\">(Do you ever wonder about the code language used by doctors on their prescription pads, that only pharmacists can read? \u00a0\u201cpo qhs\u201d is prescription-ese for \u201cby mouth at bedtime\u201d. \u00a0Methyl cobolamin is vitamin B12.)<\/span><\/p>\n<p><b>Bredesen\u2019s results<\/b><\/p>\n<p><span style=\"font-weight: 400\">The good news is that AD was dramatically reversed, especially in its early stages, with a low-cost program that does not require superhuman life style changes. \u00a0This worked in 9 cases out of 10, and the 10th case was advanced AD. \u00a0The bad news is that crafting an individualized program for the patient requires a doctor with broad knowledge both of medicine and of the patient\u2019s history and temperament, as well as blood tests and cognitive tests. \u00a0Patience. \u00a0This is likely to be expensive and difficult to replicate in modern, assembly-line medicine where doctors are fungible cogs in a health care factory. \u00a0But then, perhaps the bad news isn\u2019t bad&#8211;it\u2019s pointing in the direction of the future of medicine.<\/span><\/p>\n<p><b>Ultrasound<\/b><\/p>\n<p><span style=\"font-weight: 400\">This is just vibration, but at a higher frequency than human ears can hear. \u00a0Ultrasound is commonly used (at low intensity) as an imaging tool <\/span><\/p>\n<p><span style=\"font-weight: 400\">Prof. J\u00fcrgen G\u00f6tz and Gerhard Leinenga of the Clem Jones Centre for Ageing Dementia Research, Queensland, Australia have pioneered the use of ultrasound at higher intensity to break up the beta amlyloid plaques in the brain, with dramatic benefits in mice. \u00a0Mice normally don\u2019t get AD, but they can be genetically engineered to come down with AD reliably. \u00a0It was these mice that the Queensland doctors worked with, and in most mice they were able to clear up the plaques. \u00a0There is still controversy (after 40 years) whether amyloid plaques actually cause AD or whether they are a symptom or side-effect. \u00a0So it was important to verify that the mice showed actual memory improvements, and not just better results on the diagnostic tests. \u00a0The next step is to get experience in larger animals, before the first human trials. \u00a0[Read more from <\/span><a href=\"http:\/\/www.medicalnewstoday.com\/articles\/290801.php\"><span style=\"font-weight: 400\">Medical News Today<\/span><\/a><span style=\"font-weight: 400\">] \u00a0[In-depth nterview with <\/span><a href=\"http:\/\/www.abc.net.au\/radio\/programitem\/peOWD0e2P3?play=true\"><span style=\"font-weight: 400\">Norman Swan<\/span><\/a><span style=\"font-weight: 400\">. \u00a0The episode also includes an interview with Saul Vileda of Stanford about planned plasma transfusion experiments in Alzheimer\u2019s patients.]<\/span><\/p>\n<p>&nbsp;<\/p>\n<p><b>Alzheimer\u2019s as an Immune Disorder<\/b><\/p>\n<p><span style=\"font-weight: 400\">A promising line of research regards AD as an immune attack on nerve cells that producers amyloid plaques as a side-effect. \u00a0It is not the neurons byt <\/span><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/11596127\"><span style=\"font-weight: 400\">glial cells<\/span><\/a><span style=\"font-weight: 400\">, the \u201cin-between\u201d cells in the brain, that trigger the immune attack. \u00a0In active brains with lots of nerve firings, the glial cells are kept in check, while inactive neurons allow the neighboring glial cells to turn themselves into immune provocateurs.<\/span><\/p>\n<p><span style=\"font-weight: 400\">This is a link between decline of the immune system with age, increase in inflammation, and AD. \u00a0Strong circumstantial support for this perspective comes from the fact that anti-inflammatories such as NSAIDs and curcumin offer some of the best protection against Alzheimer\u2019s risk that we currently have available.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Conversely, the healthy immune system <\/span><b><i>attacks<\/i><\/b><span style=\"font-weight: 400\"> amyloid beta and breaks it up. \u00a0Biogen Corp purchased a drug based on antibodies produced by healthy humans that attacks A-beta. \u00a0Just this year, a new drug called <\/span><a href=\"http:\/\/www.alzforum.org\/therapeutics\/aducanumab\"><span style=\"font-weight: 400\">Aducanumab<\/span><\/a><span style=\"font-weight: 400\">, aka BIIB037, was <\/span><a href=\"http:\/\/www.alzforum.org\/news\/conference-coverage\/biogen-antibody-buoyed-phase-1-data-and-hungry-investors\"><span style=\"font-weight: 400\">reported<\/span><\/a><span style=\"font-weight: 400\"> to be effective in reversing cognitive decline in small, initial trials with human trials&#8211;not just mice. <\/span><\/p>\n<p>&nbsp;<\/p>\n<p><b>DFMO and Arginine<\/b><\/p>\n<p><span style=\"font-weight: 400\">Arginine is one of the 20 amino acids used to build proteins, and it has been found that the AD brain <\/span><a href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC2600464\/\"><span style=\"font-weight: 400\">consumes inordinate quantities of arginine<\/span><\/a><span style=\"font-weight: 400\">. \u00a0This begs the question whether arginine is part of the problem or part of the body\u2019s natural solution. \u00a0Carol Colton and her Duke Univ lab are betting on the latter. \u00a0DFMO=difluoromethylornithine is a drug that blocks arginase, the enzyme that breaks down arginine. \u00a0In case that\u2019s too many negatives for you: more DFMO means more arginine. \u00a0DFMO has already been approved as a cancer treatment, and now it has been tested in mice, and found to both decrease plaques and improve cognitive performance. [<\/span><a href=\"http:\/\/www.medicaldaily.com\/alzheimers-may-be-linked-arginine-deprivation-supplements-wont-help-329248\"><span style=\"font-weight: 400\">News article<\/span><\/a><span style=\"font-weight: 400\">, <\/span><a href=\"http:\/\/www.jneurosci.org\/content\/35\/15\/5969.short\"><span style=\"font-weight: 400\">Research article<\/span><\/a><span style=\"font-weight: 400\">]<\/span><\/p>\n<p><span style=\"font-weight: 400\">Another protein component called taurine was found last year to be beneficial for the mice genetically engineered for susceptibility to AD. \u00a0Taurine was added to their drinking water in quantities huge by human standards, equivalent to more than 2 ounces per day of pure taurine. \u00a0But improvements in cognitive performance were dramatic. \u00a0Results were <a href=\"http:\/\/www.nature.com\/articles\/srep07467\" target=\"_blank\">reported<\/a> from the Korean lab of YoungSoo Kim<\/span><span style=\"font-weight: 400\">. \u00a0\u00a0<\/span><\/p>\n<p>&nbsp;<\/p>\n<p><b>Current \u201cbest practices\u201d<\/b><\/p>\n<p><span style=\"font-weight: 400\">There are currently 5 FDA-approved drugs for AD, but all of them provide symptomatic relief only, and work only for a few months. \u00a0None is able to slow progression of the disease. \u00a0[Read more from <\/span><a href=\"http:\/\/csundquist.peachpuff-wolverine-566518.hostingersite.com\/49\/\"><span style=\"font-weight: 400\">Carl Sundquist<\/span><\/a><span style=\"font-weight: 400\">] \u00a0Last year, there was a breathless announcement by Eli Lilly about early successes with a new drug called solanezumab, but later results <\/span><a href=\"http:\/\/www.bmj.com\/content\/351\/bmj.h4064\"><span style=\"font-weight: 400\">deflated the bubble<\/span><\/a><span style=\"font-weight: 400\">. <\/span><\/p>\n<p>&nbsp;<\/p>\n<p><b>What you can do to lower your long-term risk of AD<\/b><\/p>\n<ul>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Regular and sufficient sleep<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Anti-inflammatories: NSAIDs, fish oil, curcumin=turmeric<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Weight control<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Mental and emotional engagement<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Yoga and meditation<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Vigorous exercise<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">mega-doses of Vitamin D<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Melatonin at bedtime<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">DHEA, Vit B12 and SAMe, especially for people with MTHFR genetic risk<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Low carb diet<\/span><\/li>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">CoQ10<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400\">Fortunately, the greatest risk factors for AD are the same as for other diseases of old age, so there are broad benefits from the above program. \u00a0General risk factors are cholesterol levels in the blood, insulin resistance, and inflammation.<\/span><\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Last year, I blogged on a CDC report that Alzheimer\u2019s Disease is more prevalent than previous epidemiology had acknowledged. \u00a0Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that Alzheimer\u2019s Disease is currently #3 among diseases of old age Demographics are increasing the prevalence of AD at an inexorable rate Far &#8230; <a title=\"Promise of Novel Alzheimer&#8217;s Treatments\" class=\"read-more\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/09\/25\/promise-of-novel-alzheimers-treatments\/\" aria-label=\"Read more about Promise of Novel Alzheimer&#8217;s Treatments\">Read more<\/a><\/p>\n","protected":false},"author":65,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[1],"tags":[],"class_list":["post-428","post","type-post","status-publish","format-standard","hentry","category-uncategorized"],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v27.4 (Yoast SEO v27.4) - https:\/\/yoast.com\/product\/yoast-seo-premium-wordpress\/ -->\n<title>Promise of Novel Alzheimer&#039;s Treatments - Josh Mitteldorf<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/09\/25\/promise-of-novel-alzheimers-treatments\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Promise of Novel Alzheimer&#039;s Treatments\" \/>\n<meta property=\"og:description\" content=\"Last year, I blogged on a CDC report that Alzheimer\u2019s Disease is more prevalent than previous epidemiology had acknowledged. \u00a0Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that Alzheimer\u2019s Disease is currently #3 among diseases of old age Demographics are increasing the prevalence of AD at an inexorable rate Far ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. This makes the mechanism challenging to understand and to model. more at http:\\\/\\\/mathforum.org\\\/~josh\",\"sameAs\":[\"http:\\\/\\\/AgingAdvice.org\"],\"url\":\"https:\\\/\\\/scienceblog.com\\\/joshmitteldorf\\\/author\\\/joshmitteldorf\\\/\"}]}<\/script>\n<!-- \/ Yoast SEO Premium plugin. -->","yoast_head_json":{"title":"Promise of Novel Alzheimer's Treatments - Josh Mitteldorf","robots":{"index":"index","follow":"follow","max-snippet":"max-snippet:-1","max-image-preview":"max-image-preview:large","max-video-preview":"max-video-preview:-1"},"canonical":"https:\/\/scienceblog.com\/joshmitteldorf\/2015\/09\/25\/promise-of-novel-alzheimers-treatments\/","og_locale":"en_US","og_type":"article","og_title":"Promise of Novel Alzheimer's Treatments","og_description":"Last year, I blogged on a CDC report that Alzheimer\u2019s Disease is more prevalent than previous epidemiology had acknowledged. \u00a0Last month at the Rejuv Biotech conference, I heard Chas Bountra tell us that Alzheimer\u2019s Disease is currently #3 among diseases of old age Demographics are increasing the prevalence of AD at an inexorable rate Far ... 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The surprising fact that our bodies are genetically programmed to age and to die offers an enormous opportunity for medical intervention. It may be that therapies to slow the progress of aging need not repair or regenerate anything, but only need to interfere with an existing program of self-destruction. Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for vigorous self care, including exercise, meditation and caloric restriction. After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle and Temple University. He is presently affiliated with MIT as a visiting scholar. In private life, Mitteldorf is an advocate for election integrity as well as public health. He is an avid amateur musician, playing piano in chamber groups, French horn in community orchestras. His two daughters are among the first children adopted from China in the mid-1980s. Much to the surprise of evolutionary biologists, genetic experiments indicate that aging has been selected as an adaptation for its own sake. This poses a conundrum: the impact of aging on individual fitness is wholly negative, so aging must be regarded as a kind of evolutionary altruism. Unlike other forms of evolutionary altruism, aging offers benefits to the community that are weak, and not well focussed on near kin of the altruist. 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