Alzheimer’s Disease: Current Options and Possible Treatment Approaches

Doc Gumshoe looks at "orange aspirin" and some progress in Alzheimer's trials

By Michael Jorrin, "Doc Gumshoe", December 1, 2015

[ed. note: Michael Jorrin, who I like to call “Doc Gumshoe,” writes about health and medicine for us from time to time. His columns are not generally focused on investments, though this one does include some commentary about a number of specific companies (most are not publicly traded). His words and opinions are his own, and he has agreed to our trading restrictions. Enjoy!]

The campaign to do something about Alzheimer’s disease (I won’t call it a war) moves forward on several fronts – forward, but with pretty frequent setbacks. We have to acknowledge that at this point, after having tried literally thousands of approaches, no drug or treatment modality reverses the course of the disease. That doesn’t mean that reversing or at least stopping disease progression is not the objective of a colossal amount of effort on the part of a great many entities of all types – academic centers, big and not-so-big pharma, biotechs of all sizes, government, foundations, and some individual scientists.

But it does mean that there is also a great deal of research into drugs and treatments that are not disease-modifying, but can to some degree mitigate the effects of Alzheimer’s disease (AD), specifically in the area of cognition. And, because the optimum time to start treating a person with AD would be as early as possible in the course of the disease so as to prevent irreversible cognitive damage, there is also a great deal of research directed at finding markers that could identify AD in the earliest stages.

In a way, the AD landscape resembles what was going on in rheumatoid arthritis treatment when I first started doing projects in that area. As in AD, there were no disease-modifying agents for RA; the best that could be hoped for was managing the patient’s worst symptoms as the disease marched on, leaving many patients severely disabled. Symptom management relied heavily on high-dose aspirin (this was before even ibuprofen became commonly available) with perhaps a steroid shot if Grandma wanted to get out on the dance floor at her grand-daughter’s wedding. A major difference is that current understanding of what happens in AD at the cellular and molecular level is far ahead of what was known about RA in those bygone days.

The short take is that even though there are no Alzheimer’s disease-modifying drugs available yet, the picture is not bleak. There are options that to some degree mitigate or delay cognitive decline in AD patients, and there are some strategies that appear to affect what are at least assumed to be some of the underlying causes. So there is hope!

How is treatment benefit in AD measured?

I trust that doesn’t sound like a dumb question. I can imagine loud answers from all quarters, amounting to, “If the treatment slows or reverses dementia, that’s a clear positive.” Yes, of course, I agree with that. A question is, are there any really objective and accurate ways of measuring the degree of dementia? And, yes, of course, when the husband fails to recognize his wife, that’s not so good (but remember that excellent book by Oliver Sacks, The Man Who Mistook His Wife for a Hat). But what about finer distinctions?

What they use in clinical trials to assess dementia, or the absence of dementia, are “validated instruments,” – i.e., the Mini Mental State Examination (MMSE), the Clinical Dementia Rating – Sum of Boxes (CDR-SB), and the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog). These, and others, are widely used and widely accepted. However, what is missing is an independent, objective measure. When an infection is being treated, it’s one thing when the symptoms go away, but you can always test to see if the pathogen has been vanquished. Currently, there is no such test in AD. Brain scans can detect the presence of amyloid plaque and analyses of cerebrospinal fluid can test for amyloid beta (Aβ) and tau protein, and these tests certainly provide valuable corroborative evidence, if not definitive proof. Also, many of the early-stage studies are not in humans, but in laboratory animals. There are supposedly ways of testing the cognitive capacities of mice – do they remember where the cheese is hidden? – but I hope I can be forgiven for questioning their reliability.

So let’s start out by checking on developments regarding the eleven pharmaceutical companies that I described in my 2013 piece, “Current Clinical Trials in Alzheimer’s Disease.” I am listing them by sponsor rather than by the name of the agent, mostly because several of the agents don’t have names as yet. And, as you’ll see, for several of these outfits, the news is not good, or, in some cases, there’s no news at all. I’m including the whole list as witness of the stuttering progress of investigational drugs for AD.

Accera, Inc
Broomfield, CO 80021

Accera’s AC-1202 is a medium-chain triglyceride that is metabolized into ketone bodies which provide nutrients to the brain. One of the hallmarks of AD progression is that the brain is prevented from using blood glucose for energy; AC-1202 is supposed to compensate for that. It’s marketed as a pharmaceutical under the name Ketasyn, and as a nutritional supplement as Axona. An agent with a similar mechanism, AC-1204, has enrolled about 75% of 480 subjects in a Phase 3 clinical trial, NOURISH-AD. Another Phase 3 trial is in the works.

This approach does not address the underlying disease process in AD, but likely has merit in slowing dementia. Researchers are looking into the possibility of using nasal insulin to boost glucose utilization in the brains of persons with AD, and the nutritional supplement faction has been quick to point out that the medium-chain triglycerides in Ketasyn and Axona are also present in coconut oil, so that might be a helpful dietary supplement.

Alzheimer’s Disease Cooperative Study (ADCS)
(in cooperation with the National Institute of Aging)
San Diego, CA

The resveratrol trial that I mentioned back in 2013 now has results, and they are at least somewhat promising. Resveratrol’s supposed mechanism is that it stimulates the activity of a class of enzymes called sirtuins, which are thought to mimic the anti-aging effects that caloric restriction has demonstrated in animals. This was supposedly why red wine drinkers (red wine, you certainly know, contains resveratrol) get a survival benefit – although the amount of resveratrol contained in red wine is nowhere near the amount that has been used in clinical trials. The Phase 2 trial enrolled 119 subjects with mild-to-moderate AD and assessed levels of amyloid beta (Aβ) 40 and 42 as well as tau protein in the cerebrospinal fluid. As you may remember from my previous piece, a higher proportion of Aβ42 to Aβ40 is associated with the progression of AD dementia. In this trial, patients taking up to 2000 mg of resveratrol per day maintained higher levels of Aβ40 (which we might dub “the good amyloid beta”) in proportion to Aβ42. There were no differences in tau protein, nor in the mini-mental state exam, but the treated subjects performed better on the activities of daily living scale. All in all, these results, published in September 2015, encourage further research.

Bellus Health, Inc
Laval, Quebec, Canada, H7V4A7

Bellus’s principal candidate is Alzhemed, which is also marketed as a neutraceutical under the name Vivimind. Alzhemed is also known as tramiprosate and as homotaurine, and sometimes as 3APS. The supposed mechanism of action is that it binds to soluble Aβ, inhibiting formation of the sheet formations of Aβ that are found in Alzheimer’s patients. Clinical trials in this agent have failed to show any benefit thus far. Vivimind and another related agent, BLU8499, were licensed to a US company, Alzheon, in late 2013.

[ed. note: Bellus Health is tiny but publicly traded, BLU in Canada, and BLUSF OTC in the US.]

Biogen Idec (BIIB)
Cambridge, MA

In March 2015, Biogen’s AD drug, formerly BIIB037, now aducanumab, reported positive interim results in the PRIME study, a Phase Ib trial. What is particularly arresting about these results is that BIIB037/aducanumab is the first AD agent that has demonstrated both significant symptomatic benefit and significant benefit with regard to one of the presumed physiologic causes of AD, namely the deposition of amyloid plaque. BIIB037/aducanumab is a human recombinant monoclonal antibody (mAb) that targets aggregated forms of Aβ. The original antibodies on which the mAb is modeled came from the brains of individual donors who were thought to have successfully overcome AD.

The trial enrolled 166 patients with mild forms of the disease and followed them for one year. The symptomatic measures employed were the MMSE and the CDR-SB. Four dosage levels of BIIB037/aducanumab were assessed, and at the highest dose, subjects lost 0.58 points on the MMSE, while subjects on placebo lost 3.14 points. On the CDR-SB the scores were 0.59 points for BIIB037 versus 2.04 for placebo. Both differences were statistically significant.

Amyloid plaque deposition was measured by PET scans using the radiotracer florbetrapir 1, which binds to amyloid. In the two highest BIIB037 dose levels, 6 and 10 mg per kg of body weight, the differences in plaque deposition compared with placebo were both considered highly significant, P < 0.001. Another trial in the 6 mg/kg dose failed to reach clinical significance, which was considered a setback in the development program for aducanumab. Assessing dose levels lower than the 10mg/kg dose is important, because of a dose-related adverse effect called ARIA (amyloid-related imaging abnormalities) which can result in potentially dangerous swelling of the brain. The ARIA effect was more common in APOε4 carriers, who are also more likely to develop AD. Two Phase III studies in aducanumab are currently under way, with results not expected until sometime in 2020. In the meantime, Biogen has two more AD drugs in much earlier stages of development. One, labeled BAN2401, targets Aβ before it has aggregated into the forms that characterize AD. The other, E2609, is a β-secretase enzyme inhibitor (BACE), which targets the amyloid cascade upstream of Aβ peptide generation. Eight Phase 1 trials evaluating the safety and pharmacology of E2609 in nearly 500 healthy volunteers and people with early AD have been completed. The single oral ascending-dose study of 5 to 800 mg drug showed a reduction of Aβ levels in plasma; a 14-day ascending-dose study of 25 to 400 mg showed a dose-dependent reduction of up to 80% in Aβ levels in cerebrospinal fluid. Biogen is a major contender in the Alzheimer’s sweepstakes and is putting upwards of $2.5 billion on the line, with the expectation – or hope? – of a big-time payback, perhaps in the not-too-distant future. Curaxis Pharmaceuticals
Raleigh, NC 27614

Curaxis has declared bankruptcy and its stock is valued at much less than a penny a share. So it goes. I have seen no recent news about their AD drug, VP4896; it’s possible that they have licensed it to another biotech. VP4896 decreases the amount of luteinizing hormone released by the pituitary. There does appear to be evidence supporting the role of this hormone in both the cognitive deficits and molecular pathology that characterizes AD.

Elan Pharmaceuticals
Gainesville, GA
Now Perrigo (PRGO),
Dublin, Ireland

One of their AD drugs is ELND005, which prevents the aggregation of Aβ clusters. A Phase III trial at 62 locations failed to attain clinical significance, and in January, 2014 all further Phase III trials were suspended. Another Elan/Perrigo AD drug is bapineuzumab, which has been licensed to Janssen, a Johnson & Johnson subsidiary. Two Phase III trials in bapineuzumab have been conducted, only one of which reported any significant benefit. Bapineuzumab targets the accumulation of amyloid plaque, and in carriers of the APOε4 gene, PET scans demonstrated highly significant (P = 0.004) differences between patients who received bapineuzumab infusions compared with those who received placebo. There was no observed difference between treatment and placebo groups in patients without the APOε4 gene. Also, the treatment effect was more pronounced in patients with mild disease compared with those with moderate disease. However, no effects on either functional or cognitive outcomes were found, and all subsequent Phase III trials were suspended.

The bapineuzumab experience raises a serious and fundamental question. If a drug really does reduce the accumulation of amyloid plaque in at least a subset of patients, but this has no observable effect of symptoms, does this not imply that perhaps amyloid plaque is not the culprit? My skeptical nature prevents me from saying “yes” to that proposition. For one thing, as we have already learned, not all amyloid is the same. Assessing the differences between the two forms of Aβ – the 40 and 42 amino acid varieties, with Aβ42 dubbed “the bad amyloid” – was not part of the protocol. And it’s also possible that earlier intervention might have made a difference. In any case, bapineuzumab appears to have taken its place in the growing list of AD dead ends. Of the 14 clinical trials with bapineuzumab, 8 have been terminated, and 6 are completed. None are currently under way.

EnVivo Pharmaceuticals
Now Forum Pharmaceuticals
Waltham, MA 02451

EvVivo became Forum Pharmaceuticals in 2014. Clinical trials of their leading drug, EVP-6124, also called encenicline, are on hold due to a small number of serious gastrointestinal side effects, which caused the FDA to instruct Forum to interrupt their three ongoing AD studies. Encenicline is an alpha 7 nicotinic receptor agonist, which supposedly boosts neurotransmitter function, enhancing memory and executive function. Previous small trials with this agent had reported highly significant improvements in global cognitive function compared with placebo. Forum is currently making a case to the FDA to move forward with the planned Phase III trials. We should note that encenicline is not intended to be a disease-modifying agent, but may find a robust niche among the very few drugs that have a positive effect in terms of delaying the progress of AD-related dementia. Forum, by the way, at present is privately held.

Memory Pharmaceuticals
Now Roche Pharmaceuticals (RHHBY)
Basel, Switzerland

Roche’s motivation in acquitting Memory was to participate in the development of Memory’s AD drug, then dubbed MEM-3454 and now called RO5313534. It is a nicotinic acetylcholine receptor agonist, perhaps similar to Forum’s encenicline mentioned above. Acetylcholine is a neurotransmitter with a number of functions, one of which is enhancing cognitive processes in the brain. Early studies in this agent reported highly significant (P < 0.001) improvement in cognitive function as early as 8 hours post dosing. The results of a trial evaluating the effectiveness of this drug used on combination with donepezil, which is one of the very few drugs approved for treating the cognitive symptoms of AD, have not been announced as of 2 November 2015. Whether this is Roche keeping their cards close to their chest, or, alternatively, clamping the lid on the garbage can, is hard to know. In any case, even though RO5313534 is not a disease-modifying drug, it could well secure a prized space in the limited AD marketplace. Myriad Pharmaceuticals, now Myrexis (MYRX)
Salt Lake City, UT 84108

The last time I peeked, Myriad Pharmaceuticals had been spun out from test developer Myriad Genetics, and then changed its name to Myrexis, Inc. Their lead drug is flurizan or MPC-7869, which is the R-enantiomer of flurbiprofen, an NSAID similar to ibuprofen. Enantiomers are chemically identical but mirror image versions of the same molecule; the R-enantiomer is the right-handed version and the L-enantiomer is the left handed version. The two can behave differently because of how they fit to their targets; imagine a key cut to the same contours, but with the grooves on the opposite side – it just wouldn’t slide into the lock. Flurizan had been tested and failed in prostate cancer, but had shown promise in delaying cognitive decline in AD patients. However, more recent studies have reported that it does not pass the blood-brain barrier at sufficient concentrations for clinical use. So there’s another one that bites the dust.

Sonexa Therapeutics
San Diego, CA 92130

Sonexa is a very small private biotech with one product, ST101, aimed squarely at AD. ST101 is a small molecule that acts as a T-type calcium channel activator. In the brain, T-type channels regulate neuronal firing patterns.  They open in response to negative membrane potentials, and are thus suited for regulating neuronal activity.  Investigators at the University of California Irvine found that that ST101 induces cleavage of amyloid precursor protein (ABB) at a novel site, generating an APP cleavage product that does not appear to be a substrate for either of the enzymes that cleave APP forming amyloid beta (Aβ) and thus does not lead to formation of Aβ.  ST101 is orally active, efficacious at low doses, and improves memory function in mice and non-human primates. Two preliminary efficacy and safety studies in ST101 have been completed, one in conjunction with donepezil; results have not yet been published. From where I sit, this one is still alive and kicking.

Vivus, Inc (VVUS)
Mountain View, CA 94050

Vivus is a small pharmaceutical company with a couple of FDA approved agents and others in development in a number of treatment areas besides AD. Their AD drug is VI-1121, which targets acetylcholine release by altering the balance of two enzymes that regulate acetylcholine balance. The proposed mechanism is interesting – AD patients have a higher proportion of the enzyme butyrylcholinesterase (BuCheE) in proportion to acetylcholinesterase (AChE); thus targeting the former may increase the availability of acetylcholine, which is vital to cognitive function. But it doesn’t appear as though VI-1121 is going to do the trick; trials in VI-1121 have been discontinued.

What’s the score?

Of the 11 sponsors and their candidate drugs, none so far have hit the bulls-eye, meaning sufficiently robust Phase III clinical trial results to warrant an FDA submission, let alone fuel speculation of an early FDA approval. Six of the 11 are in the “maybe” category. Five are dead in the water. In the AD area, this is not a bad average at all, although what will happen to the six “maybe” candidates going forward is anyone’s guess. Biogen obviously has an edge because of their deep pockets, but deep pockets alone won’t be the deciding factor. Some of the “maybes” have interesting and possibly promising mechanisms, and even if they themselves don’t hit the jackpot, other agents using the same or similar mechanism may work a bit or even a lot better.

When I did my first Doc Gumshoe Alzheimer’s pieces way back in 2013, those 11 agents were the most promising ones I had spotted. They could be taken as a fairly representative sample of the universe of AD drug development, covering a range of mechanisms, including both disease-modifying and symptom-alleviating mechanisms. And what has happened with those development programs is very representative of what is going on in the AD world. There have been no clear wins.

A common phenomenon in drug development is that many drugs in the early phases show promise. The biotechs and pharma outfits that are conducting the research evince optimism, but the stumbling blocks are multitudinous, and outright failure looms. Some of the smaller biotechs, for financial reasons, can only take the development program so far, and investors as well as Big Pharmas are understandably cautious. But the potential yields are huge. A small biotech scores good Phase II results, or even Phase Ib, and gets bought out by a Big Pharma. Then, even if later studies don’t pan out, investors can make a tidy profit. I won’t go on about that – as I’ve often said, that’s not my department.

A look at a drug with a completely different target

None of those 11 drugs targeted tau protein accumulation, even though the tau protein hypothesis was gaining prominence at the time. To review what was in the previous Doc Gumshoe piece about AD, the essential difference between the amyloid beta and tau protein hypotheses is that the Aβ structures impede communication between neurons by congregating in the synapses, whereas tau protein fibrils lead to neuron death by forming tangles in the axons that are the conduits for nourishment for neurons. In brief, Aβ works its mischief outside the neurons, while tau kills neurons from within.

TauRX Therapeutics, Ltd
Aberdeen, Scotland

TauRX is a biotech spun off from the University of Aberdeen in Scotland, where its clinical trials are being conducted, although its official headquarters are based in Singapore, likely for tax reasons. Their AD candidates are derived from a parent compound, methylene blue, which has been around for decades, and has been used to treat malaria and methemoglobinemia, a blood disease in which normal hemoglobin is replaced by a form containing ferric rather than ferrous iron, which is less able to transport oxygen. TauRX’s first formulation based on methylene blue (methylthioninium chloride) was Rember, which has been replaced by a successor, TRx0237. TRx0237 and Rember have the same mode of action, but TRx0237 is a stabilized, reduced form of the parent compound in order to improve the drug’s absorption, bioavailability, and tolerability. 

The most prominent advocate for the tau hypothesis is Prof. Claude M. Wischik, of the University of Aberdeen School of Medicine and Dentistry, and also of TauRX Therapeutics. He is unabashedly scornful of the Aβ hypothesis, and outspokenly positive about the prospects for TRx0237. For a taste of his rhetoric, here’s a bit from his paper in Biochemical Pharmacology (88: 2014):

“A recent meeting hosted by the New York Academy of Sciences had the title: “A Truce in the βAP-tist/Tau-ist War?” A truce only needs to be called when one side no longer sees any hope of outright victory. The extraordinary history of repeated clinical trial failures at phases 2 and 3 based on the β-amyloid hypothesis does suggest a need for βAP-tists to find a way out of an untenable situation. For long-term Tau-ists such as the authors, it is early days in the campaign, as we are only conducting the very first tau-based phase 3 clinical trial. It would be understandable that we would see no need for a truce at this stage.”

Dr Wischik is not content with expressing his support for the tau hypothesis – which, after all, is to a considerable degree his baby. No, he also takes out the cudgels and wallops the Aβ hypothesis. The paper I cited above lists 27 clinical trials targeting aspects of the Aβ hypothesis, and marking most of them as “failed.” Yes, it is true that most of these trials failed to meet their objectives, but that certainly does not put the Aβ hypothesis to rest. A distinct possibility is that by the time the subjects in these trials started treatment, the accumulation of Aβ had reached the point where prevention or slowing of further accumulation would not make much difference. One of the problems with treating AD is that by the time symptoms appear – that is, overt signs of dementia – treatment that addresses Aβ may just be too late. I do not accept Dr Wischik’s premise that the advocates of the Aβ hypothesis need “to find a way out of an untenable situation.”

This is not to say that the evidence for the tau hypothesis is not reasonably good. An exploratory study of TRx0237 in 321 persons with mild/moderate AD reported two types of treatment benefits. In a subset of patients with moderate AD, there was a significant (P = 0.047) difference between subjects treated with TRx0237 and placebo patients. Note, that P value just barely reaches the standard for significance, so this is far from a home run. But also, in a subset of patients with mild AD, there was a highly significant difference (P < 0.001) in cerebral blood flow, which is essential to neuronal function. While TauRX presses ahead with clinical trials in their proprietary formulation of methylthioninium, researchers are tinkering with the basic molecule to try to find structures that have a better pharmacodynamic profile – i.e., permit better absorption, reach higher concentrations – characteristics that lead to better efficacy. Currently, five clinical trials in TRx0237 are under way, plus one more in methylene blue and AD. Although TauRX appears to have an inside track with the methylene blue/ methylthionimium-based therapy, they by no means have an exclusive claim on that approach. The parent molecule is not subject to patent, and it wouldn’t surprise me in the least if other biotechs, or even piracy-inclined laboratories anywhere in the world, tried to cash in on what might be a lucrative product. Dr KSS and “the Manchurian Candida”

To learn more about this highly interesting and highly speculative theory about the pathology of AD, you will have to join the Irregulars and read Dr KSS’s superb post from a few weeks ago. I will say nothing about it beyond suggesting that it’s at least possible that the culprit referred to invades our poor vulnerable brains after and not before it is damaged by some of the other putative causes of AD.

… and one more for the road

This one’s about the “orange aspirin” that cures – yes, cures!!! – Alzheimer’s. Here’s part of the spiel:

“90 DAY ALZHEIMER’S TREATMENT:

“Could This Be The Biggest Breakthrough Health Experiment Since The Polio Vaccine?
“Research shows New ‘Orange Aspirin’ 
“Could End Alzheimer’s Disease

“Dear reader,

“It acts on your brain much like aspirin.

“It’s quick, it’s painless, and it’s cheap…

“Yet what doctors are calling a ‘brain health miracle’ could be the final key to solving the Alzheimer’s mystery.

“Meet Linda — an 83 year old woman who could no longer cook, clean, or use the bathroom without help.

“Worse, she couldn’t remember her late husband or her family members.

“Was her life over? Some doctors would say yes.

“But in a research study, Linda was put on an unusual new treatment. A 90-day Alzheimer’s protocol that ended up generating huge buzz in the research community.

“And something incredible happened.

“After just 12 weeks of taking this ‘orange aspirin’, researchers from the National Center for Biotechnology Information were blindsided.

“As they reported,

“…her agitation, apathy, anxiety and irritability were all relieved. She began to tell about the need to urinate. Furthermore, she came to join in the laughter watching the TV comedy program, began to sing songs and do knitting which she used to do .’

“After one full year on the treatment they reported,

‘She came to recognize her family and remember her late husband. She now lives at home without significant symptoms!’

“Imagine that…”

… and it goes on from there. On and on and on, with more and more miraculous cures, attributed to “orange aspirin,” which some of you already know is curcumin, commonly found in the spice turmeric. Curcumin has been known as an anti-inflammatory for some time, and as such might be effective in preventing inflammation-associated changes in the brain. The “90 Day Alzheimer Treatment” goes on to contrast curcumin supplements, which is what they are touting, with expensive research on the investigational agent J147, derived from molecules found in curcumin, which has lately reported highly positive anti-aging and cognitive effects in mice.

The only problem with the curcumin supplement for AD is that it’s not too easy to sneak it past the blood-brain barrier; thus the need for painstaking research to develop a drug that might have some of those properties but does get past the blood-brain barrier. Of course, Big Pharma is accused of suppressing information about the curcumin supplement out of greed.

As we might expect, the “90 Day Alzheimer Treatment” goes on to pitch their “Little Bible of 77 Censored Health Cures” as well as several newsletters. The source is an outfit called “Natural Health Solutions.”

Doc Gumshoe strongly favors natural health solutions, without the capital letters, as long as they are really health solutions. J147 looks promising, and I’ll keep an eye on it. As for curcumin supplements, I remain, as usual, skeptical.

While I’m in skepticism mode, let me also express doubts that AD is a disease/condition with a unitary etiology, whether Aβ, tau, or any other single culprit. Many factors can cause the buildup of crud in our brains. Maybe we can slow some of them down; maybe we can find ways to continue putting our brains through their paces despite the crud. There’s lots to be learned.

And while working on this piece, I dug up so much more on AD treatment that I couldn’t cram it into this Doc Gumshoe blog. I will share it with you in an upcoming piece.

Forgive me if I pat myself on the back

A study published in JAMA on 17 November has borne out what I’ve been saying for years. Viz, after the U. S. Preventive Services Task Force issued its guidelines that men should not have PSA testing, the number of early stage prostate cancers dropped from 540.8 cases per 100,000 men aged 50 and older in 2008 to 416.2 per 100,000 in 2012. The total reduction in diagnoses of prostate cancer was 33,519 cases. While it’s true that many cases of prostate cancer are non-fatal – most men die with and not of prostate cancer – it’s virtually certain that some of those cases that escaped diagnosis will prove fatal. As with their recommendation that women under 50 should not have mammograms, what these green eyeshade types are doing is making more work for the undertaker.

* * * * * * *

As always, I look forward to receiving your comments. Best to all, Michael Jorrin (aka Doc Gumshoe)


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57 Comments on " Alzheimer’s Disease: Current Options and Possible Treatment Approaches"

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Dr. KSS MD PhD
Author
45029

Fine column Michael, and great synopsis of current companies with AD trials.

backoffice
Irregular
187

Dementia affects patients in vast majority of debilitating ways, there doesn’t see to be any predictable path it takes. It slowly robs you of your being. Sadly, the patient is unaware of what they are losing and the effect on those around them. This is I disease that I hope is cured within my lifetime. Are there even tests available to determine if an individual may be predisposed to Alzheimers?

Bradley Pigg
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Bradley Pigg
Anavex’s drug, ANAVEX 3-71, has tested to be a potent cognitive enhancer in Alzheimer’s disease models, Anavex said in a statement on Monday. The pre-clinical results for the drug will be published in the scientific journal “Neurodegenerative Diseases,” Anavex added. “At very low doses, it mitigates cognitive deficits and normalizes major pathological hallmarks in Alzheimer’s disease models indicating that ANAVEX 3-71 exerts a comprehensive disease-modifying effect,” study author Abraham Fisher said in a statement. “This data adds to the strong foundation of preclinical evidence to support the potential use of ANAVEX 3-71 in Alzheimer’s disease and a wide array of… Read more »
chauncey gardner
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chauncey gardner

a glaring and unfortunate omission on doc gumshoe’s part – Anavex (AVXL) is the Real Deal (thank you Evander Holyfield) notwithstanding the naysayers like adam feuerstein of The Street.com

Gui
Irregular
770
Gui

Nice article as usual, I see that you’ve left out some of the ‘popular’ usual suspects

which just confirms what I already was fairly convinced their prospects/motivations to be.

Thanks again.

Richard
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Richard
Using your brain to learn new languages , play high level chess, doing cross word puzzles, sudoku , etc. puts off the onset of the manifestations of dementia. Educating children well helps them much when they become 50 +. The nun studies where the nuns took cognitive tests yearly and brains examined when they died. Confirms this. Using you brian a lot to learn new stuff helps a lot more than some pills. Not all meds for dementia need to be expensive. Rationale for a trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular… Read more »
Ed Morgan
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Ed Morgan

Please revisit BIOZF (BITI). Also, I am receiving solicitations for CLBS (old NBS); any value? Thanks for sharing your expertise and time with us.

Berthe
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0

Very interesting summary, but it looks like you missed one “natural health solution” that is coconut oil. And I am not kidding. Doctor Mary Newport wrote a book on it after applying this solution to her husband. I only know the title in french : « Maladie d’Alzheimer, Et s’il existait un traitement », éditions Josette Lyon, 2014.

Michael Jorrin,
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Michael Jorrin (aka Doc Gumshoe)

Berthe, I did mention coconut oil in the bit about Accera. If it works, it’s because it provides nutrition to the brain which is not able to get sufficient nourishment from glucose. Please see my fuller comment at the end of the comments thread. Thanks, MJ

Paul
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Paul

Interesting article in Nature (journal) regarding BRCA1 protein deficiency in AD patients -by the Gladstone Instituit. Maybe one more piece in this very complex puzzle. Nice article Doc Gumshoe!

Myron Martin
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I will admit I have not read 77 censured health cures, but I have considered ordering it as I believe cures for every disease can be found in nature and are more effective, cheaper and safer than chemicals concocted in a laboratory. I myself take turmeric among several other herbs (cinnamon in particular) said to be helpful in diabetes. So far i can report that I have been able to reduce my insulin intake by almost 50% with much more stable blood sugar levels. I have also been able to cease several drugs originally prescribed and reduce others from weekly… Read more »
Ken
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Ken
This is the problem with one payer systems as it locks all patients into the the allopathic, patentable drug business model. Evolution has provide us with millions of natural molecules, many with health benefits, which the pharma business model necessarily ignores. This goes back to the Rockefeller Foundation’s funding of medical schools with the condition that tha the Rockefeller Foundation be able to place some its “medical doctors” on the boards of the medical schools starting about 1910. Before that medicine in the USA had two streams, one allopathic which focused on surgury and patent medicines (often toxic and some… Read more »
Dave
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Dave
Thanks for the very informative article. I am very concerned about AD because my mother, her sister and my grandmother all had AD. Therefore I am taking supplements that may have some preventative effects. I am skeptical about whether slowing the progress of AD is beneficial. My mother had AD for an unusually long time, about 19 or 20 years. After she could no longer live alone she was in a board and care home for 10 years and then in a nursing home for 5 years before her death at age 89. She did not know that I was… Read more »
ron korody
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ron korody
While I myself do try most if not all natural cures, health store delights, naturopath goodies, etc. I am very skeptical and have not seen many of these have any real effects other than placebo effects. And THAT is the major difference between the “greedy and corrupt” world of big pharma”. While many of the big pharma cures have ridiculous side effects, costs, etc. – MOST of these drugs have very noticeable and immediate effects i.e. CURES or proven “efficacy” (I hate that Dr. medical B.S. power word “efficacy” … when “effective” would do nicely). By the same token, 98%… Read more »
Patricia
Member
686
I’ve certainly never taken that approach of trying “most if not all” natural cures – what a waste of money. Word of mouth, via people I know who’ve tried things with good results, has been my own best source. Researching some traditional remedies has been my second-best method of finding the ones that consistently work. Medicine was practiced for thousands of years using natural substances with medicinal properties, and still is. Of course those who are anti-natural want to lump them all together with the many silly ones, like the Chinese use of ground tiger penis for virility. Here’s the… Read more »
armitage
Irregular
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armitage

Excellent article as usual.
It seems that a common problem is accessing the brain for drug delivery. Are you aware of the potential breakthrough announced on that front earlier this month?
http://sunnybrook.ca/media/item.asp?c=1&i=1351&f=blood-brain-barrier-focused-ultrasound-chemo

prorsum
Irregular
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Always an informative read. This one especially as wife has been diagnosed with early onset. Tried both of the go to chemicals that they all prescribe (Donepezil, Namenda) just so they can say they did something with disasters results! Read about some naturals that help as much without the side effects. One is a prescription called Cerefolin NAC and the other is Huperzine A. Any info on either would be appreciated.

finder0522
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finder0522

I use Super Huperzine A. It works really well. Now if I can only remember where I put it!

DBMD
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DBMD
Great review and interesting. I am skeptical about tau and Aβ peptides as we have been chasing this for awhile, and not much fruit really. The hypothesis about Candida was interesting, but I think the root is cytokines. I have observed an interesting phenomenon among the most clear cut AD patients: though they can be old many are otherwise healthy. On occasion, out of porportion to the general population, they will be on no meds for other conditions nor will they have had any surgeries. I believe many diseases are due to an imbalance in cytokines which can even lead… Read more »
Michael Jorrin,
Guest
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Michael Jorrin (aka Doc Gumshoe)
I knew it! The many interesting comments & suggestions from Gumshoeland Denizens will require a fuller answer! I was going to do yet another AD follow-up, because there’s lots of new ideas & leads popping up, but your suggestions will be sleuthed. Re Anavex, I’ve looked at that & will report. Re cytokines, I attended a meeting on autoimmune diseases, where inflammation plays a major part, and there was a presentation on cytokines. As the presentation went on, the slides showing the immense vast huge number of cytokines finally began to elicit laughter from the assembled gurus. There are just… Read more »
Brian Smith
Guest
0
While you are at it, look at Neurotrope (NTRP) …juts raided $15.4 million for a phase 2a study on 150 people worldwide…has shown very good results in some people as it has been approved for compassionate use…Neurotrope, Inc. is focused on developing two product platforms, a drug, bryostatin, for the treatment of Alzheimer’s disease (AD) and its diagnostic test for the detection of AD, both of which are still in the clinical testing stage. Its lead product candidate is bryostatin, which is a natural product isolated from a marine invertebrate organism, a bryozoan called Bugula neritina. Bryostatin is a protein… Read more »
Laden Sieber
Guest
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Laden Sieber

If its possible that anti-inflammatory products produce positive results against AD then please into Antabine citrate and the company Rock Creek Pharmaceuticls. They’ve conducted a study with mice and anatabine that is very promising

Dave
Guest
0
Dave
I have been taking anatabine (Anatabloc) for a couple of years and I own some stock in the company. Unfortunately for those currently taking it the company has decided to seek approval to sell it as a pharmaceutical rather than as a supplement. It will take a few years to get FDA approval for it as a pharmaceutical as they need to run more formal tests required for FDA approval. In the meantime they have withdrawn the supplement from the market to avoid the supplement conflicting with the FDA approval process. I bought a fairly large supply when they announced… Read more »
Alden Sieber
Guest
0
Alden Sieber
Unfortuneately, anatabine is currently off the market due to some issues with the FDA. Hopefully these issues will be cleared up in the near future. In the meanime, Dr. Mullen at Rock Creek Pharmaceuticals is studying it’s effect on AD, as well as its use against other diseases. Some s documented studies have been conducted with anatabine that show promise. And there are some videos on YouTube of Drs. Mullen and Fiona Crawford of Rock Creek Pharmaceuticals talking about the benefits of anatabine towards various ailments, one of which is about how anatabine attacks AD. And with no side effects.… Read more »
Mark Mark
Guest
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Mark Mark

Hi Doc great article as usual. I would like to point out that Merck has a BACE inhibitor in late stage clinical trials (Ph3) for mild-moderate AD which they are optimistic about. Keeping our fingers crossed! Mark

Gui
Irregular
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Gui
There’s been a lot of chatter recently on the use of the diabetes drug metaformin as an anti-aging treatment and also slowing down aging diseases including dementia and alzheimers. Recently it’s been shown that metformin prolongs the lifespan and health of certain species of roundworms and mice researchers at Cardiff University have shown that diabetic patients treated with metformin, who typically have shortened lifespans, often live longer than non diabetics. The U.S. Food and Drug Administration has ok’d trials to proceed’ “Researchers plan to conduct the first clinical trials of the project, dubbed Targeting Aging with Metformin (TAME), next year… Read more »
Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)

Quick note – I discussed the metformin – lifespan matter at some length in the Aug 2 Doc Gumshoe piece on Aging – as well as some other possible strategies for living a long & healthy life. Good luck!

Gui
Irregular
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Gui

oops, kindly let me know when there is a breakthrough for memory retention,

tia

chibana
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chibana

Michael,
Great article as always!
V/R
Tom

Harold Hansen
Guest
0
Thank. You! I wanted to promote myself once again. It was determined that I had Cancer, and j would like to ask all you good guys/ gals to go to : ” gofundme “/ Harold and if you can make a Donation, it would so help me. I just got hit with CPS, a dehabilitating nerve disease lthat I’ve been living with and you should see what Medicare charges for my pills. So living on Disability is tough. If you can, I’d sure appreciate it, And if not, well, that’s ok too! Thanks to Everyone! Again it’s ” gofundme “/… Read more »
Vance
Guest
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Vance

Great article/post Michael.
Does anyone on here have background and interest in bringing proprietary supplements to market?
I have many years of research on a wide array of vitamins, minerals, and herbal supplements. A few years ago, I was near placing an initial order for my own blend to be produced and packaged….but, decided to hold off at that time as I have also experienced the darker side of supplement use.
Thanks

Gui
Irregular
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Gui

Currently ClinicalConnections.com lists 77 trials in the U.S. for Alzheimers, unfortunately you have to click on each to get an idea who the sponsor is.

Multi-Site Clinical Trial Search
http://www.clinicalconnection.com/clinical_trials/condition/alzheimers_disease.aspx

SoGiAm
Irregular
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512 studies found for: alzheimers | Open Studies at https://clinicaltrials.gov/ct2/results?term=alzheimers&recr=Open Thank you Michael Best2ALL!-Ben

Gui
Irregular
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Gui

Well, now I see why you have 4 times as many ‘likes’ as me,

7 times as much data found – well done. 😉

jblynch
Irregular
12

Thanks for continuing to provide us the quality of info so consistently reported!

jl

edski
Guest
0
edski
I must relate this story to all of the above and to those seeking answers to AD. My mother died after 11 years of being diagnosed. I spent plenty of time daily with her the last five years of her life, which consisted of closing her eyes and rubbing them, and never talking…. not a word from her, which may have been pure stubbornness. Two years before her death, she fell out of her wheelchair and hit her head on the floor. I got the call, and went over there to check her out in two minutes time. A nice… Read more »
SoGiAm
Irregular
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Thank you for sharing this event Edski. Interesting as it supports exercise and move-it-or-loose-it 🙂 Best2U-Ben

Dave
Guest
0
Dave
Edski, when my mother was about half way through her 19 year Alzheimer’s she started having seizures. The first time it happened they put her in the hospital and did and MRI on her brain. The doctor reading the MRI was not told she had Alzheimer’s but after examining the MRI he said “does this patient have Alzheimer’s”. So at that point there was enough damage to the brain that it was readily visible on the MRI even though the Alzheimer’s Institute says that it can only be diagnosed during autopsy. So IMO if there is that much damage to… Read more »
edski
Guest
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edski
Thank you for the suggestion. I think that the Alzheimers Institute means that the only “true” way to diagnose it is via autopsy. Brain scans have shown clear shrinkage of the brain in AD patients over time. Left lobe/Right lobe……they may even be “short circuited” so to speak. I do believe that activity, exercise, using your muscles, makes a big difference in the way our bodies change, especially in our evolutinary path. We have gone so far in such a short period of time, that our bodies were used to hard work, and now….most of us have it easy at… Read more »
Dave
Guest
0
Dave

BTW, when my mother was in the last 5 years of her life my sister-inlaw used a CD player to play 1940’s music and my mother seemed to respond to that, much like the people in some of the YouTube videos.

kirt germond
Guest
0
kirt germond

just saw a program with Dr. perlmutter and research he has done and has seen is now relating a healthy gut to the reduction of body-wide inflammation which affects brain malfunctions. it is probably worth a look. you can google his name and find him.

larrys
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larrys
I am curious about the root cause of AD. Like Autism it seems to be on the increase. In Veterinary medicine I see a lot of disease states related to nutrition but in many instances the underlying problem is mycotoxins. This is not the live fungus but the residual toxin that is a by-product of their metabolism. These toxins are numerous and prevalent in grain products and their presence seems to be increasing.. We feed binding agents and enzymes in an attempt to mitigate their effects on a routine basis. We also reject shipments that test highly positive and they… Read more »
SoGiAm
Irregular
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larrys and others please feel free to join us (biotech-team) on http://www.stockgumshoe.com/2015/11/the-manchurian-candida We could sure benefit from your knowledge in Veterinary medicine. Also there is a conference call at 2 p.m. eastern TODAY if you’d like to join us. Best2All-Ben

Gui
Irregular
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Gui

Aspirin: The little white pill that keeps on giving.

We can only hope new derivatives of salicylic acid should be a helper in some serious degenerative diseases.

A key ingredient in aspirin blocks cell death from Alzheimer’s and Parkinson’s disease – ScienceAlert
http://www.sciencealert.com/a-key-ingredient-in-aspirin-blocks-cell-death-from-alzheimer-s-and-parkinson-s-disease

hblytt
Member
9
hblytt
Michael, I want to thank you for your stand on PSA testing. I was diagnosed with prostate cancer 7 years ago, and am currently cancer-free, by a urologist. Based on my rising PSA (from 2.8 to 4.1) and a DRI (digital rectal exam. Sorry, it’s not charming but it’s life-saving.) he ordered a prostate biopsy. It came back positive, with a Gleason score of 7. So he suggested surgery. If the diagnosis had been delayed, my future would be a lot bleaker. Early diagnosis is key. Once the cancer metastasizes, the situation is irremedially worse. I vividly remember that Dr… Read more »
Craig
Guest
0
Craig
More and more ‘preliminary’ trial results continue to accumulate indicating that Anavex’s (AVXL) A2-73 is the real deal for Alzheimer’s Disease; latest being the January 11th update re. positive dose escalation response data from their ongoing P-2a/b trial. At around $150M MC, AVXL is an unbelievable bargain – IF further reports (next one expected within weeks) continue to demonstrate the sig. disease modifying benefits which earlier reports seem to indicate….you could eventually see AVXL sporting a M.Cap well into the $ billions; numerous analysts have projected that a truly effective, safe and durable-response Alzheimer’s drug (and there aren’t any to… Read more »
SoGiAm
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Marysquitieri
Guest
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Marysquitieri

Hi, I read all about this orange aspirin so, my question is where do I buy it.
Let’s cut the red tape, where do I purchase it and how much is it.
Thank you

Mary squitieri-lebda

arch1
Irregular
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Mary that was a snakeoil Ad and there is no evidence cucurmin does anything for Altzheimers. If you want to obtain cucurmin just buy the spice Cumin at any grocers and now in healthfood stores,,, or just eat lots of curry.

Travis Johnson, Stock Gumshoe
Admin
6448

Well put arch1, though curcumin is actually the “active ingredient” in turmeric, not in cumin.

arch1
Irregular
7459

Travis You are right. Early AM Senior moment,,,,brainfart. Thank you for catching that.

Marysquitieri
Guest
0
Marysquitieri

Let’s cut the red tape, where do I purchase it and how much is it.
Thank you

Mary squitieri-lebda

siff
Irregular
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Mary – Solaray – Curcumin Extract 250 Mg and I think other firms sell this – Katerina

stan
Irregular
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stan
Mary, I am just turning 75 and have been ingesting curcumin for 6+ years pretty regularly. I actually take a table spoon of coconut oil with a 500 mg Doctors Best C3 cap along with a Swanson 200 mg grape seed extract cap. The extra virgin oil (I believe) acts or reacts to provide a total system carrier for those products that then (counterbalance the products of arthritis, namely joint pain and stiffness). This all comes from early on using daily doses of grape seed extract to help with nightly aching knee joints I seemed to get every time I… Read more »
siff
Irregular
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Mary and stan
I know that ground pepper enhances the effect of curcumin –
Katerina

Michael Jorrin,
Guest
0
Michael Jorrin (aka Doc Gumshoe)

I’m taking a look at yet another curcumin/turmeric-promoting piece. This one claims it cures all 619 known diseases, or words to that effect. We can be quite sure it doesn’t do that – the question is whether curcumin has any genuine health benefits of any kind at all. Look for it in a week or so. Best to all, MJ

Dave
Guest
0
Dave

For real information on the value of curcumin by UCLA Dept. of Neurology, including references to double-blind studies, see http://alzheimer.neurology.ucla.edu/Curcumin.html. I take the NOW brand of curcumin which contains the curcumin longvida described in the link. That is more bioactive than other forms of curcumin. The Now product is named “Curcubrain”. You can buy that a http://www.swansonsvitamins.com or http://www.vitacost.com.

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