Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

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Greyhound
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Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

Post by Greyhound »

Looks promising?...

The psychiatric drugs improve cognition in AD patients
Peer-Reviewed Publication

University of Colorado Anschutz Medical Campus

Two commonly used psychiatric drugs show evidence of improving symptoms of Alzheimer’s disease including boosting cognition, according to a study from researchers at the University of Colorado Anschutz Medical Campus.

“The people who received these drugs developed better cognition and actually improved in their clinical diagnosis,” said the study’s senior author Huntington Potter, PhD, professor of neurology at the University of Colorado School of Medicine and director of the CU Alzheimer’s and Cognition Center. “Compared to those who did not take these drugs, they reverted from Alzheimer’s disease to mild cognitive impairment or from mild cognitive impairment to normal.”

The study was published today in the journal Alzheimer’s Research & Therapy.

The drugs, the antidepressant imipramine and antipsychotic olanzapine, are already approved by the Food and Drug Administration. And since depression and psychosis are common in those with Alzheimer’s disease (AD), many patients take other medications for these problems, providing a large control population for the scientists to evaluate the effects.

The CU Anschutz research team, led by Noah Johnson, PhD, were looking for drugs that block the effect of the apolipoprotein E4 protein or APOE4, which is encoded by a gene variant that when inherited, confers the strongest risk for developing late-onset Alzheimer’s.

“We took a unique approach by targeting APOE4 because the usual drug targets, amyloid-beta and tau, have not produced a convincingly effective drug for people with AD despite decades of work,” said Johnson.

The researchers screened 595 compounds in a drug library from the National Institutes of Health and identified several compounds that specifically blocked the effect of APOE4 on Alzheimer amyloid formation.

“We then looked into the huge National Alzheimer’s Coordinating Center (NACC) database and asked what happened when someone was prescribed these drugs for normal indications but happened to be Alzheimer’s patients,” Potter said.

That’s when they found that psychiatric patients with AD using imipramine and olanzapine showed significant improvement in AD symptoms.

“The only things these drugs have in common is that they block the catalytic effect of APOE4 on the formation of amyloids in the brain,” Potter said, referring to the proteins that form clumps and disrupt cell function in AD.

The results were surprising.

“Our analyses show that, compared to the control populations, subjects taking imipramine or olanzapine had improved cognition and diagnoses, which are direct clinical measures of disease severity,” the study said. “Notably, in our drug screen, we found that imipramine and olanzapine strongly inhibited the apoE4-catalyzed fibrillization of Aβ (amyloid beta), whereas none of the other antidepressants or antipsychotics whose use was reported in the NACC database had any such activity and none showed any benefit for AD patients.”

Potter cautioned that the study was retrospective, meaning they made the discovery while analyzing data collected for another purpose. The next step, he said, would be to test imipramine, which has fewer side-effects than olanzapine, on a rodent model and if successful conduct a clinical trial.

“The number of human drugs that have shown any benefit to AD patients are maybe one or two or three,” Potter said. “So this is a very promising advance.”
https://www.eurekalert.org/news-releases/957387
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

Post by NF52 »

Greyhound wrote: Wed Jun 29, 2022 5:55 pm Looks promising?......
Looks intriguing, at the very least!

Thanks for finding and sharing this, Greyhound.

Below is an excerpt from the open access article Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer’s disease cognition.
As some background, the patients being studied were followed for years and had diagnoses of Alzheimer's disease (but without confirmation of amyloid or tau PET). They were seen from 2005-2020 in US academic research centers that belong to the National Alzheimer’s Coordinating Centers project, which is an impressive 20 year plus collaboration (see here for more info: https://naccdata.org through the National Institute on Aging. People in the NACC databased are all going to memory care clinics, so tend to skew more heavily to those with ApoE4 and be diagnosed as at a younger age, compared to population-based studies like the Framingham Heart Study or others. Tne NIA is itself funding studies that look at approved drugs and botanical and other compounds because researches now have the computing ability to do studies that find gems like this:
We acquired longitudinal data from the National Alzheimer’s Coordinating Center (NACC) on 42,661 subjects who were seen at 39 different ADRCs [Alzheimer's disease Research Centers] in the USA since 2005. We searched the prescription drug histories of the subjects in the NACC dataset and found that 40 subjects had taken imipramine, an antidepressant, and that 94 subjects had taken olanzapine, an antipsychotic. We then identified “control” subjects who had been prescribed any antidepressant (n = 6233 subjects) or any antipsychotic (n = 798 subjects) medication other than imipramine or olanzapine, which are listed in Additional file 11. We first evaluated changes in cognition in all of the subjects over time as measured by the MMSE [Mini-Mental Status Exam]. Controlling for age and sex, we found that the subjects who took imipramine had a significantly greater change (i.e., improvement) in MMSE score over time compared to subjects who took any other antidepressant medication (P = 0.0490) (Table 2). Likewise, subjects who took olanzapine had a significantly greater change (i.e., improvement) in MMSE score over time compared to subjects who took any other antipsychotic medication (P = 0.0310) (Table 2). Notably, our results show that imipramine use corresponded to an estimated increased score of 0.4186 points (out of 30) per year and that olanzapine use corresponded to an estimated increased score of 0.4937 points per year, relative to their respective control groups (Table 2). Because we identified imipramine and olanzapine as specific inhibitors of the apoE4-Aβ interaction, we also determined whether APOE genotype might influence their effects on cognition. When the subjects who took imipramine were segregated into APOE4 carriers and APOE4 non-carriers, both groups showed improvement on imipramine by estimate compared to control, and the estimate for APOE4 carriers was larger, but none of the contrasts were statistically significant (Table 2). Subjects carrying at least one APOE4 allele who took olanzapine had a significantly greater change (i.e., improvement) in MMSE score over time (P = 0.0235), whereas subjects carrying no APOE4 allele who took olanzapine showed improved cognition by a lower estimate, and it was not statistically significant
At the very least, it argues for recognition and treatment of mental health disorders such as depression., anxiety, bipolar disorder and schizophrenia, with studies looking at using these two drugs to reduce the risk of AD.
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

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It seems like a good avenue to explore as imipramine is already approved by the FDA.
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

Post by Greyhound »

"imipramine is the obvious choice due to less side effects.

Call me skeptical at worst. Why are they slow pacing the research by first going the long route with a mouse model?
Let us pretend they think it is the safe and best way to do things or is it that it will funds a pet project? Rather strange that is could not be suggested to recommend the drug rather than all the other useless antidepressants which are no better than a placebo <20% effective with multiple side effects and only recommended for short term use. I can quote a study on antidepressants but we all can wait and be hopeful someone in the medical field will have an enlightened idea that will not offend medical sensibilities. There is no profit in an already patented drug and it will be hard to find research dollars although I have recently seen a few tens of million being donated. Maybe there are some advocacy groups that can pass and push this along.
Alzheimer's can be so severe and deceiving and such was the case of my late aunt who had it and was depressed prior to getting it but ended up dying of undetected cancer. That was the source of her screaming and pain which no one could figure out. Her son sacrificed most of his productive life taking care of her. Thanks for the attention.
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

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Greyhound wrote: Thu Jun 30, 2022 11:04 am Alzheimer's can be so severe and deceiving and such was the case of my late aunt who had it and was depressed prior to getting it but ended up dying of undetected cancer. That was the source of her screaming and pain which no one could figure out. Her son sacrificed most of his productive life taking care of her. Thanks for the attention.
Oh, Greyhound, my heart goes out to you and your family. Your late aunt’s situation sounds absolutely devastating. How terrible that she had to suffer so much.

I appreciate your posting the article. Seems very promising.
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

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Greyhound wrote: Thu Jun 30, 2022 11:04 am "imipramine is the obvious choice due to less side effects.

Call me skeptical at worst. Why are they slow pacing the research by first going the long route with a mouse model?
Let us pretend they think it is the safe and best way to do things or is it that it will funds a pet project? ...There is no profit in an already patented drug and it will be hard to find research dollars although I have recently seen a few tens of million being donated. Maybe there are some advocacy groups that can pass and push this along.
Alzheimer's can be so severe and deceiving and such was the case of my late aunt who had it and was depressed prior to getting it but ended up dying of undetected cancer. That was the source of her screaming and pain which no one could figure out. Her son sacrificed most of his productive life taking care of her. Thanks for the attention.
Greyhound, I'm so sorry for the suffering that your aunt and your cousin went through both with her cancer and with her Alzheimer's .

Many repurposed drugs are already in human clinical trials; here's a May 2022 article on that:
Alzheimer's disease drug development pipeline: 2022
As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease-modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty-seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials.
Much of the initial funding for work to identify these drugs, either from looking at medical records or using sophisticated machine learning programs to predict good candidates is already supported bt the NIA, which has multi-year "high priority research topics", like the"Alzheimer's Drug Development Program", with starting dates of 2022 through late 2025 (later grants likely ending in 2028) for numerous grants:
Alzheimer's Drug Development Program (ADDP)...offers researchers funding for drug development activities that can be conducted in their own laboratories, in collaboration with contract research organizations (CROs)...including: medicinal chemistry; pharmacokinetics (PK); Absorption, Distribution, Metabolism, Excretion, Toxicology (ADMET); formulations development; efficacy in animal models; chemical synthesis under Good Manufacturing Practices (GMP); Investigational New Drug (IND) enabling safety-toxicology; and initial Phase I clinical testing.[/b]
https://grants.nih.gov/grants/guide/pa- ... 2-047.html

Here's why Pharma companies are willing to fund AD clinical trials, from a 2020 article:
Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry....Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.
. Repurposed agents in the Alzheimer's disease drug development pipeline

An example of a re-purposed substance is the projected Phase 3 clinical trials of ALZ-801, a re-formulated version of tramiprosate, also known as homotaurine, which is found in seaweed. ALZ-801 seems to be especially effective in ApoE 4/4 and is likely to be in a trial with those with normal cognition and elevated amyloid or tau in the next year or so. https://alzheon.com/pipeline/alzheon-alz-801/

So I still think imipramine and others drugs may be in clinical trials sooner that other drugs starting from scratch!
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

Post by Theresa.J »

mgrant6053 wrote: Wed Jun 29, 2022 7:17 pm It seems like a good avenue to explore as imipramine is already approved by the FDA.
Welcome to the ApoE4.info website, mgrant6053!

This study showing an association between imipramine and improvement in AD symptoms is certainly positive news. Let's hope that clinical trials to further explore its usefulness in ApoE4 carriers are fast-tracked.

You've likely been following the site for a while now. However, as a Support Team intern, I'll take this opportunity to let you know about several tools/resources you may not have come across yet.

If you haven't already looked at it, the Primer is a detailed and informative resource written by a practicing M.D. with ApoE4/4. It includes information about the biochemistry of the ApoE4 gene and offers a variety of research-based prevention strategies.

Additionally, the How to Guide offers tips on how to navigate forums and respond to posts. In particular, you can use the quotation icon in the upper right of any post to begin a reply. This will quote the member and trigger an email notification to them telling them you've responded to their post. The " How to Guide" also describes how to use the Search function to locate topics, and how to subscribe to topics of interest in the forums.

Finally, if you would like to learn more about other community members' experiences, you can link to Our Stories. You are welcome to share your story there as well if you feel comfortable doing so.

I hope you find these tools useful as you navigate the site. Please reach out if you have any questions regarding using the site or need assistance.

Take care and be well!

Warmly,
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Re: Researchers find two FDA-approved drugs that curb symptoms of Alzheimer’s disease

Post by Greyhound »

NF52 wrote: Thu Jun 30, 2022 12:31 pm
Greyhound wrote: Thu Jun 30, 2022 11:04 am "imipramine is the obvious choice due to less side effects.

Call me skeptical at worst. Why are they slow pacing the research by first going the long route with a mouse model?
Let us pretend they think it is the safe and best way to do things or is it that it will funds a pet project? ...There is no profit in an already patented drug and it will be hard to find research dollars although I have recently seen a few tens of million being donated. Maybe there are some advocacy groups that can pass and push this along.
Alzheimer's can be so severe and deceiving and such was the case of my late aunt who had it and was depressed prior to getting it but ended up dying of undetected cancer. That was the source of her screaming and pain which no one could figure out. Her son sacrificed most of his productive life taking care of her. Thanks for the attention.
Greyhound, I'm so sorry for the suffering that your aunt and your cousin went through both with her cancer and with her Alzheimer's .

Many repurposed drugs are already in human clinical trials; here's a May 2022 article on that:
Alzheimer's disease drug development pipeline: 2022
As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease-modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty-seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials.
Much of the initial funding for work to identify these drugs, either from looking at medical records or using sophisticated machine learning programs to predict good candidates is already supported bt the NIA, which has multi-year "high priority research topics", like the"Alzheimer's Drug Development Program", with starting dates of 2022 through late 2025 (later grants likely ending in 2028) for numerous grants:
Alzheimer's Drug Development Program (ADDP)...offers researchers funding for drug development activities that can be conducted in their own laboratories, in collaboration with contract research organizations (CROs)...including: medicinal chemistry; pharmacokinetics (PK); Absorption, Distribution, Metabolism, Excretion, Toxicology (ADMET); formulations development; efficacy in animal models; chemical synthesis under Good Manufacturing Practices (GMP); Investigational New Drug (IND) enabling safety-toxicology; and initial Phase I clinical testing.[/b]
https://grants.nih.gov/grants/guide/pa- ... 2-047.html

Here's why Pharma companies are willing to fund AD clinical trials, from a 2020 article:
Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry....Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.
. Repurposed agents in the Alzheimer's disease drug development pipeline

An example of a re-purposed substance is the projected Phase 3 clinical trials of ALZ-801, a re-formulated version of tramiprosate, also known as homotaurine, which is found in seaweed. ALZ-801 seems to be especially effective in ApoE 4/4 and is likely to be in a trial with those with normal cognition and elevated amyloid or tau in the next year or so. https://alzheon.com/pipeline/alzheon-alz-801/

So I still think imipramine and others drugs may be in clinical trials sooner that other drugs starting from scratch!
My detailed rebuttal got timed out and wiped out.
That is only a summary of the work being done and does not address the issues I have raised.
It is just a database summary and they admit it has omissions. On repurposed drugs we all know how the drug companies extend their patent by making a small change and then filling a new patent.
Yes work is being done. It is just the way the research industry works. It is its own way of doing things.
Can a doctor look something up from this database without much trouble and find something useful he might look up and try? I doubt it so that is my point. There needs to be some reform and advisory group to spread some of the best ideas to the community. Thanks for your personal concern but that situation is still ongoing and was to get attention to the slow pace of progress when all the research wheels are spinning but we are not seeing the progress.
https://www.livescience.com/8365-dark-s ... sions.html

edit will add this section.

So why did it take 20 years to develop with failed drug..that is not useful and too expensive.
https://theconversation.com/a-slow-and- ... rug-162603

There actually is an academic paper explaining why the research is not successful and quotes Daniel Kahnman author of Thinking Slow & Fast fame but when moving from ipad to laptop I cannot find it..
so here is something on funding
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118094/

https://www.sciencedaily.com/releases/2 ... 104219.htm

edit 2

"Because of the high risk and lack of commercial success associated with CNS drug development, many pharmaceutical companies have drastically curtailed their investments in CNS diseases over the past 20 years.3-5 Such measures likely reflect concerns regarding the limited availability of target engagement biomarkers, complex clinical trial designs, imprecise clinical measures, heterogeneous symptoms, limited ability to affect the underlying causes of CNS diseases, and the lack of predictive animal models 6, 7—all of which contribute to high risk with uncertain future revenues. AD drug development is the canonical example of this predicament. AD drug trials cost more per patient than trials in any other therapeutic area, with 50% to 70% of the cost devoted just to patient screening.8 Recruiting for AD trials is difficult, and participant attrition is high since the trials are often longer than trials in other therapeutic areas—especially for trials attempting to demonstrate disease modification and those focusing on secondary prevention."
https://alz-journals.onlinelibrary.wile ... /alz.12450

"Dark Side of Medical Research: Widespread Bias and Omissions"
notice the bias and concealment with anti-depressant drugs, this is a widespread continuing problem that never has addressed and has led up the the last questionable Alz drug.
https://www.livescience.com/8365-dark-s ... sions.html

I am a realist and when the Alzheimer community recognizes the lay of the land and decides to do something then we all can be optimistic. Now there are choloregenic drugs available and the guidelines seem to force doctors to encourage their usage whether it is good the patient or not.
I will take a break from posting.
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