New Medications Fail to Show Efficacy for Alzheimer’s Disease

While social and behavioral interventions consistently show preventative results, the hunt for a medicinal “magic bullet” for Alzheimer’s disease continues

Peter Simons
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Three phase III clinical trials assessing the efficacy of Lundbeck’s investigational drug idalopirdine for Alzheimer’s disease have failed, according to the pharmaceutical manufacturer’s annual report. The trials, titled STARSHINE, STARBEAM, and STARBRIGHT, included over 2000 participants and were designed to determine if adding idalopirdine to donepezil treatment for mild to moderate Alzheimer’s disease would improve scores on a cognitive functioning scale (ADAS-cog). All three trials showed a lack of efficacy for the new drug.

“We are disappointed about the outcome of this study,” said Dr. Anders Gersel Pedersen, EVP and Chief Scientific Officer at Lundbeck in a press release about the STARSHINE study. “The phase II data were very encouraging but unfortunately, these data failed to replicate those findings.”

Idalopirdine affects the 5-HT6 receptors in the brain, which have been associated with learning and memory. Several other pharmaceutical companies have also been researching this pathway, including Pfizer, whose own phase II trials of a 5-HT6 antagonist failed last year. Neuroscientists have explained these failures with the explanation that “5-HT6 receptor functionality is much more complex than initially defined.”

Photo Credit: Pixabay

Noted Alzheimer’s disease researcher Peter Whitehouse, MD, PhD, is a neuroscientist who helped to discover some of the known organic correlates of Alzheimer’s disease in the 1980s. This work, focusing on the cholinergic system in the brain, forms the foundation for most current pharmaceutical interventions for Alzheimer’s disease, including donepezil, which was utilized in Lundbeck’s phase III trials. However, these medications have proven ineffective, leading a group of researchers in 2010 to ask the question: “Do current drugs work in Alzheimer’s disease?” These researchers argue that the drugs may improve memory and cognitive function, but that their effect on complex and poorly understood brain systems cannot be described as targeting Alzheimer’s disease specifically.

Dr. Whitehouse went on to suggest in his book The Myth of Alzheimer’s: What You Aren’t Being Told about Today’s Most Dreaded Diagnosis (with Daniel George) that the search for medical interventions for Alzheimer’s disease is doomed to failure because Alzheimer’s is not a single organic disorder, but rather a cluster of symptoms that include aspects of the natural aging process. Certainly, there are brain changes that are associated with it, just as there are brain changes associated with human lifespan development. But these brain changes cannot be used to diagnose a disorder. After all, many of the brain changes discussed in this research cannot be observed until brains are examined after death. What is more concerning, though, is that research has identified people with many of the “telltale” organic signs of Alzheimer’s disease (“plaques and tangles”), that do not experience any cognitive decline, nor any Alzheimer’s symptoms.

In response, The National Institute on Aging, the government agency assigned to researching the disorder, acknowledged the difficulty in defining the disorder. In 2010, the institute explained that “there is an absence of highly reliable consensus-based diagnostic criteria for cognitive decline, mild cognitive impairment, and Alzheimer’s disease, and the available criteria have not been uniformly applied.”

In The Myth of Alzheimer’s, Dr. Whitehouse acknowledges the impact of what we call Alzheimer’s disease on the quality of life of elderly persons, but he argues that treating it as a disease obfuscates common-sense methods of maintaining engagement and quality of life, regardless of cognitive decline. Dr. Whitehouse’s later work involves elaborating on methods of caring for individuals with cognitive decline. In a recent TED talk, he argues convincingly for social connection as an easy-to-achieve element in appropriate care. Dr. Whitehouse leads a program of intergenerational schools which develop community engagement for elderly people with cognitive decline by incorporating them into a school with children. He argues that the results speak for themselves: both the elders and the children experience better learning and better quality of life.

The National Institute on Aging also states that “the existing evidence for drug, dietary, exercise, and other interventions is not yet sufficient to serve as the basis for clinical recommendations” for the prevention of Alzheimer’s disease. Yet researchers have found numerous links to prevention from outside the medical model.

One recent study, conducted in Finland, found that sauna bathing several times per week could reduce dementia risk by 70%. Studies have also found that “an active and socially integrated lifestyle in late life may protect against dementia,” “engagement in leisure activities may reduce the risk of incident dementia,”  and “a rich social network may decrease the risk of developing dementia.” Another study, which was published online last month in JAMA Neurology, found that elders who engaged in crafting, playing games, and using the computer were up to 30% less likely to develop mild cognitive impairment.

Current treatment of Alzheimer’s disease often consists of attempts to mitigate the symptoms after the disease has been diagnosed. Beyond the use of anticholinergic drugs, with limited effectiveness, another common approach is behavioral control via “antipsychotic” medication. This technique attempts to reduce aggressive and agitated behaviors in elders with dementia. However, a recent systematic review demonstrated that these medications do not work better than placebo.

Because mortality rate is significantly increased with the use of antipsychotics in the elderly, and there is little evidence of benefit, a number of guidelines have called for reduced use of antipsychotics in this population. In fact, in the US, antipsychotics have not been approved by the FDA for this purpose. Yet recent studies have indicated that antipsychotics are still being overprescribed to elders with dementia.

In fact, researchers in the UK recently stated that “. . .reductions in the prescribing of antipsychotics driven by the NDS (National Dementia Strategy) have not been sustained in care homes. Furthermore, we demonstrate that contrary to guidance, older antipsychotic agents are still being used extensively rather than safer SGAs (second-generation antipsychotics). We observed that most residents were prescribed antipsychotics within acceptable dosages; however, in the majority of cases, length of treatment was excessive.” In 2012, that “excessive” treatment occurred in 77.6% of cases, according to the researchers.

In response to the results of the pharmaceutical industry’s failed trials, the limited effectiveness of anticholinergic medications, and the dangerous inefficacy of antipsychotics for elders with cognitive decline, Dr. Whitehouse writes in the Journal of Alzheimer’s Disease:

 “It seems quite clear that attention to diet, exercise, cognitive activity, and social engagement has already reduced the incidence of dementia (as evidenced by falling dementia rates in countries like Sweden, Norway, and the UK) and that there is still much more progress to be made in this area […] And we have learned that hundreds of billions of dollars invested in medications has led to very little except exaggerated false promises. Perhaps this reflection should lead to a little more humility.”

 

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Full Text: http://files.shareholder.com/downloads/AMDA-GGC00/3860200189x0x926925/C05FC4E6-75BB-4467-881D-53786BFBE2DD/LUNDBECK_ANNUAL_REPORT_2016.pdf

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Peter Simons
MIA-UMB News Team: Peter Simons comes from a background in the humanities where he studied English, philosophy, and art. Now working on his PhD in Counseling Psychology, his recent research has focused on conflicts of interest in the psychopharmaceutical research literature, the use of antipsychotic medications in the treatment of depression, and the general philosophical and sociopolitical implications of psychiatric taxonomy in diagnosis and treatment.

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12 COMMENTS

  1. That such medicines are not effective does not surprise me. From my own perspective, seniors do better when they are able to face and engage with the challenges of life.

    When they are tuned out, out of touch with their feeling, out of touch with reality, they go fast.

    The worst, from my perspective, are usually the people who have abused their children.

    And then likewise, any one in Therapy or Recovery, is also going to be harmed.

    Nomadic

  2. Don’t forget this: lawsuit says Prevagen doesn’t boost memory
    http://www.usatoday.com/story/money/2017/01/09/dont-forget-lawsuit-says-prevagen-doesnt-boost-memory/96357742/
    Jan 9, 2017 – The marketer of nationally-advertised memory supplement Prevagen was sued by the Federal Trade Commission and New York Attorney …
    The agencies are seeking refunds for consumers who bought the deceptively marketed product. http://www.google.com/search?q=prevogen+lawsuit

    Doesn’t matter, they say the secret to happiness is good health and a bad memory.

    Nothing is as irritating as those Liberty Mutual car insurance commercials but getting rid of those Prevagen ads will be nice.

  3. A company called TauRx has had some interesting results with a drug that untangles the Tau proteins that also characterize the brains of AlzD individuals. The study was roundly criticized because the finding occurred in an unplanned analysis, but it was a reasonable analysis that should have been planned. It is certainly worth doing again, properly.
    http://taurx.com/press-releases/

    Alzforum.org provided critical coverage, so critical that it quoted an amyloid-b proponent’s suggestion that it could have been a placebo effect…

    …reducing brain atrophy as a placebo effect?

    “In First Phase 3 Trial, the Tau Drug LMTM Did Not Work. Period.”
    http://www.alzforum.org/news/conference-coverage/first-phase-3-trial-tau-drug-lmtm-did-not-work-period

  4. There have been anecdotal reports that coconut oil or mct oil have helped. If I had a relative with Alzheimers, I would certainly give it a try since there aren’t any risks I am aware of. And it sure beats trying drugs that have proven to be useless.

  5. Due to oxidation, many g protein-coupled receptors are damaged in Alzheimer’s disease. This includes not only serotonin receptors, but also receptors that affect the retrieval of short-term memory, smell, sleep, social recognition, and alertness. Using agonist to try to activate these receptors is like trying to open a lock that is jammed. You have to unlock the jam before a key will work.

    Amyloid is a somewhat more complicated case. Various forms of amyloid (excess amounts of the amyloid precursor protein, c-terminal fragments, monomers, and oligomers, but apparently not plaques) will increase oxidation before and during the early stages of Alzheimer’s disease via g protein signalling. But there are two critical points. First, amyloid does no damage if oxidative and nitrostative damage does not occur. Prevent and reverse that damage and amyloid is harmless. Secondly many other factors cause oxidative stress including various environmental toxins (air pollutants, industrial solvents, mercury, and pesticides), an unhealthy diet (high in sugar, carbohydrates, high fructose corn syrup, and salt, for instance), psychological stress, and chronic smoking. If you remove various forms of amyloid, you are only slowing down the damage done by oxidation and nitration in the brain. You may briefly delay the onset of the disease and slightly slow down its early progression, but in the end you do not alter the ultimate trajectory of the disease.

    The key to treating Alzheimer’s disease is to remove the nitro-oxidant peroxynitrite and to repair part of the damage that it has done to the brain. This can be done with cannabidiol and THC in CBD oil, with essential oils high in eugneol (such as clove, bay laurel, rosemary, and lemon balm), and ferulic acid, syringic acid, vanillic acid, p-coumaric acid, and maltol in panax ginseng. In a non-placebo controlled study with heat processed ginseng (steamed at very high temperatures) there were improvements in cognition and behavior at 12 weeks that were sustained at 24 weeks. In the case of Korean red ginseng, there were improvements in cognition at 24 weeks that were sustained for two years.

    Alzheimer’s diseases is caused by oxidation, nitration, lipid peroxidation, and DNA damage (all due directly or indirectly to peroxynitrite). Peroxynitrite contributes to the formation of amyloid and tau tangles, both of which can contribute to the disease, but are not the primary cause of the disease. The best peroxynitrite scavengers not only stop the progression of Alzheimer’s disease, they partially reverse the disease.