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TIME’s short memory on Alzheimer’s drug failures

The following guest post is from one of our contributors, Dr. Susan Molchan, a psychiatrist in the Washington D.C. area.


TIME alzheimers- 2016 coverTIME 2010 Alzheimers coverAs half of the face of a pretty middle-aged woman dissolves into the background of an October 2010 TIME magazine cover, the headline proclaims, “At last, some progress against the most stubborn disease — Alzheimer’s.”

Cover articles in TIME magazine have always been — and still are, even in a changing media landscape — a big deal. But as someone who follows research on Alzheimer’s disease closely, I have to wonder: Did the message that was conveyed merit such a prime piece of cultural real estate?

That 2010 cover article focused primarily on drugs that target pathological deposits of the protein amyloid. Since that article’s publication, these drugs have been tested in large studies that have so far ended in crushing disappointment. And yet this week, TIME’s cover again dramatizes potential Alzheimer’s treatments with a silhouetted face in profile about to swallow a glowing blue capsule. Is the magazine building up hopes that are likely to get dashed once again by an encounter with reality?

The story promises “a radical new approach,” and quotes Dr. Frank Longo of Stanford University as being frustrated (to the point of tears) “that we’ve cured Alzheimer’s in mice many times.” Yet the only shred of evidence given for the promise of Dr. Longo’s new drug, referred to as LM11A-31, is that it has positive effects in mice. The drug is just now being tested in people with Alzheimer’s disease, in phase II trials. Many drugs have gotten through phase II trials, only to fail in the larger, longer phase III trials.

Dr. Longo’s drug doesn’t target amyloid, and the story does a good job of explaining this. It quotes a well-known Alzheimer’s researcher, Dr. Ronald Petersen of the Mayo Clinic, who speculates the drug may stimulate growth factors to help preserve connections among nerve cells. For anyone quoted, though, it’s important to establish if they have a financial conflict of interest in either Dr. Longo’s company, PharmatrophiX, or any other drug company. And in Dr. Petersen’s case, he has previously disclosed relationships with a number of companies developing Alzheimer’s drugs including Roche, Merck, and Genentech. Billions continue to be funneled into drug development for Alzheimer’s disease because it’s projected to be a $20 billion/year market. Like Dr. Petersen, most academics doing clinical Alzheimer’s research are paid consultants to pharmaceutical companies. We only hear the rosy side of the story in TIME, with no comments on drawbacks or possible side effects. If the rosy bit warrants a cover story, balance demands a comment regarding possible downsides. Growth factors, for example, can promote cancer.

The researchers interviewed also surmised that this new drug, targeting its cascade of badness, might be swallowed together with a drug targeting amyloid, and yet a third targeting the tangles of the protein tau — creating a “new Alzheimer’s cocktail.”

I would definitely toast any drug or drugs that halted the progression of the disease with tolerable side effects, but the prospects for this are poor. Most older people already take several drugs, and are particularly susceptible to side effects, a significant cause of hospitalization and death. Also, with the way prices of new drugs are running, we may be talking hundreds of thousands of dollars a year. Young people will need a cocktail or two when they see what Medicare is costing, if it even survives the potential “game changers” described by TIME.

A drug may be approved by the FDA that doesn’t even work, or work very well, but which still costs hundreds of thousands of dollars a year. This might be fine for Dr. Longo and his company, which if it makes it through phase II may well be purchased by a large pharmaceutical company for further development and marketing of the drug.

Ineffective drugs are approved on the basis of “surrogate endpoints,” which we hope are indicators or markers for what will actually help people. Cholesterol levels are one example where these work, as lower levels predict less heart disease. But as journalist John Fauber has pointed out, many cancer drugs shrink tumors but end up not affecting survival or quality of life. (We profiled Fauber recently in one of our podcasts on health journalism standouts.)

This is a boon for drug companies, but not for patients, and some scientists think it discourages innovation, as companies tend to continue to take this easy route to approval, a sort of “teaching to the test” of FDA approval rather than towards clinically meaningful benefits.

As the TIME article notes, of 200 drugs tested none have materialized as the “silver bullet.” Traditionally Alzheimer’s has been considered as the most common cause of dementia, responsible for 60-70% of cases. Most people with dementia are in their 80s (the 2010 TIME cover and movies like “Still Alice” aside). According to most dementia experts, “the vast majority of dementia cases, especially those occurring late in life, tend to involve a mixture of Alzheimer’s disease, vascular disease, and other degenerative factors.” No wonder no drug has worked.

This week’s TIME article notes interesting results from a longitudinal study at Rush University Medical Center indicating that increasing levels of the nerve growth factor BDNF might be helpful for Alzheimer’s disease. Although TIME notes, “There is no drug that boosts BDNF levels . . . ” it is a well known effect of anti-depressants and thought to be involved with their mechanism of action. They unfortunately have not been found to help with memory problems in Alzheimer’s disease. Another way to increase BDNF: exercise. This is very well documented in studies of mice and rats, and understandably harder to document in the brains of humans, so results are more mixed.

The article mentions exercise, but only in two sidebars entitled “Longevity Pro Tips”, and it only offers anecdotes from scientists saying what they do for exercise. It makes one wonder, do they know something the author isn’t telling us? In a larger sidebar, “Other strategies for fighting Alzheimer’s,” we have more drugs, drugs, and drugs, even though there’s good evidence that non-drug interventions (exercise is one) may be helpful via the same mechanisms proposed, such as fighting inflammation and improving blood sugar regulation.

This month scientists from Boston University published findings from the Framingham Heart Study, showing that the number of new cases of dementia decreased by 44% in recent years compared with the late 1970s. Many other studies, especially from developed countries in Europe, have also shown that dementia rates are dropping. Researchers think part of this is due to improved heart and blood vessel health as people smoke less and control blood pressure and cholesterol levels. Education and/or socioeconomic class also appear to have something to do with it. In Framingham, for example, the decline in incidence was seen only in those who had graduated from high school.

“If a 25 percent risk reduction were to be observed for a drug tested in a prevention clinical trial then we would be talking about a clinically meaningful effect as if it were a ‘cure’,” commented Dr. Lon Schneider, an Alzheimer’s researcher at the University of Southern California at AlzForum.org.

Time did report on the dropping dementia rate from the Framingham study in a short article in the February 10 issue of TIME and quoted one of the scientists: “We need to look at preventive research with as much enthusiasm as we need to look at treatment modalities.”

Maybe someday research like that coming from Framingham, that actually reports results in humans, will make the cover of TIME.

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Comments (13)

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Matt Shaffer

February 25, 2016 at 3:14 pm

How is it possible to so closely follow Alzheimer’s research yet not even mention the incredible results from a small study published September 2014 by Dr. Dale Bredesen of the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA and The Buck Institute for Research on Aging? Hardly fringe organizations. The study was very small but the results were spectacular and nothing has come close to matching its success because nothing else has modified disease progression in dementia.

Dr. Molchan, you yourself indicate the professional consensus that dementia likely results from a number of different systems failures and may not be solved with a monotherapeutic. Why then do we continue to so laser-focus on monotherapeutics as the solution to this exponentially growing problem? Is it not reasonable that a multivariable disease would require a comprehensive therapy to repair and optimize those different, failing systems? I realize that our current testing and approval structure could not possibly produce such a solution. As Dr. Bredesen says, “It would take forever and cost infinity.” So what do we do, then … stubbornly continue down the same frustrating but comfortably familiar path hoping to someday get lucky, while millions and millions more are affected each passing year either primarily or as caregivers, or do we start to think radically differently about how to solve at least this particular complex family of diseases?

I’m not anti-pharmaceutical, and perhaps a ‘silver bullet’ will come from that industry, but I’m struggling with the belief that the COLLECTIVE medical community is truly interested in solving this crisis NOW, when a comprehensive strategy that has been clinically demonstrated as effective for modifying disease progression is barely acknowledged by the medical community, dementia advocacy groups and even mainstream journalism … much less championed on the cover of TIME Magazine. It’s at the very least extremely frustrating and, depending on the motivation for such ignorance and silence, absolutely shameful.

http://www.impactaging.com/papers/v6/n9/full/100690.html

http://www.northbaybusinessjournal.com/northbay/marincounty/4333649-181/novatos-buck-institute-battles-looming#page=0

http://www.northbaybusinessjournal.com/northbay/marincounty/4357682-181/buck-institute-research-targets-multiply#page=0

    Arthur Leibovitz

    February 26, 2016 at 5:22 am

    Dear Matt – ” this exponentially growing problem ” ? – it is a growing problem but not exponentially ..
    Demetia is a syndrom and can be multifactorial – but main research efforts are devoted to Alzheimer’s disease that is, in about 70% of the patients , the main and distinct cause.

    Bonny McClain

    February 29, 2016 at 10:25 am

    Matt Shaffer I am excited to see you reference Dr Bredesen’s research. I have written about his work and enthusiastically share his manuscript each time I speak about Alzheimer’s Disease. The part that never caught fire was that out of ~25 recommendations in the article, patients reporting clinically significant improvement in cognition only adopted 9 behaviors consistently. My father had Alzheimer’s Disease and I like active solutions that don’t include waiting for a worldwide panacea.

    susan_molchan@verizon.net

    February 29, 2016 at 8:13 pm

    Matt Shaffer, the work you cite from Dr. Bredesen is only a case series. If he reports a randomized controlled trial on his work, and describes inclusion/exclusion criteria for patients, we will have an idea of what his proposed treatment may truly be doing.
    Lisa Furlini, this is the first I’d heard of poor reporting in the Framingham study. From what I understand, they used the same criteria for reporting throughout. The rates of dementia I discussed referred to specific, carefully controlled studies that examined this, not rates throughout the population that depended on death certificates, which, as you say, often don’t note dementia as a cause of death.

Linda Furlini

February 29, 2016 at 12:56 pm

The research based on the Framingham Heart Study indicating a decrease in the number of new cases of dementia is very much flawed. Dementia in the late 70’s, the 80’s, the 90’s and later was very poorly reported, if at all. It is a well-known fact that many people with dementia live in the community or in nursing homes without ever receiving a formal diagnosis. The causes of death, even as they are reported today, may not mention that death was attributable to dementia regardless of the time a person may have suffered from this disease. Even a cursory review of the literature reveals (e.g. pubmed) that underreporting is an ongoing significant issue and does explain, at least in part, the lack of appropriate support and resources for people who suffer from dementia and their families. To publish a study about current rates of dementia in the population with no mention of serious underreporting is disingenuous and misleads not only the medical community, but society at large.

Linda Furlini

March 1, 2016 at 9:52 am

My earlier comment was incomplete and was sent in error.
I am sorry if my comments were misunderstood and certainly I was not a criticizing the Framingham study. My point is that it is a far stretch to report in a study that the numbers of persons with dementia in the general population have diminished when the number of people affected by it are by and large unknown. The numbers appear to diminish very slightly only for those enrolled in the Framingham study.

    Linda Furlini

    March 1, 2016 at 10:08 am

    One more note about the misleading conclusions of the study. I quote directly from the original NEJM article, ” The Framingham Heart Study does not have brain autopsy data from before 1995.” (p.531) Such lack of documentation is a clear limitation of the study, as dementias, such as Alzheimer’s are only confirmed upon autopsy.

      susan_molchan@verizon.net

      March 2, 2016 at 12:00 pm

      Thanks Linda. The numbers of people with dementia will certainly not diminish, as no matter how many people start to exercise healthy lifestyles, age remains the biggest risk factor and the population is aging. Framingham says that a 70 year old today has a much lower risk of getting dementia than a 70 year old 25 years ago, as one example. As you and I know (I am a caregiver for both parents as well as a former Alzheimer’s researcher), caring for these people needs to be as much or more of a priority than the search for a “cure” that will likely not materialize.
      Dementia is a clinical diagnosis: the loss of the ability to carry out many activities of daily life due to impairments in memory and other higher brain functions. To try and better ascertain the actual cause, as messy as that may be, given most dementias are a mix, one does indeed need an autopsy.

Mark Geiger

March 1, 2016 at 12:26 pm

Bravo! I wrote a letter to the editor of Time after seeing the cover and reading The Alzheimer’s Pill article. Drugs, drugs, and more drugs. Jerry Seinfeld said it best in his stand-up routine segment about OTC pain medication: “We have “extra strength” and “maximum strength” pain killers. Find out how much will kill me, and then back it off a little….that’s the one I want!” I’m surprised after all the AD drug study failures, the Lily study where all 2,600 patients taking the experimental drug got worse being the poster child, that we are still holding out hope for a silver bullet. I even saw a new word used in an article the other day: “drugable.” Indeed, the billions of dollars of marketing is working. As others have already suggested it will be a combination of therapies that will crack this disease. I was also surprised that there was no mention of the University of Rochester study entitled “Sleep Drives Metabolic Clearance…” by Lulu Xie et al, describing the “Glymphatic System” and how this system slows/fails over time resulting in the accumulation of harmful proteins that cause the cascade of events that lead to AD. This is truly and exciting area of research following the likes of Conrad Johanson from Brown University. As an aside, when you put a picture like that on the cover does Time understand the impact to the large number of people working on therapies to treat AD that may not get funding as a result? Funders are not scientists. It’s like calling the winner of an election before everyone has voted. We’ve been down that road before, haven’t we?

Tia Powell, MD

March 2, 2016 at 7:08 am

Dr Molchan’s comments are right on the money. What sells magazines is the report, over and over, that the cure for dementia is right around the corner. The failure of the touted drug never gets quite the same amount of air. I wish Dr Longo well, but there is no evidence that this drug will fare better than the many before that failed to benefit patients in phase 2 trials.

Dr Douglas Watt

March 2, 2016 at 2:30 pm

I’m in strong agreement with the author of this piece, and also with those that have emphasized work on the multi-factorial and, as it were, ‘distributed’ and multidimensional nature of neurodegeneration in AD.

We have had two decades of virtual hegemony by the amyloid hypothesis, and during that same period, hundreds of billions spent on finding a disease modifying drug or drugs, all failing to clear the bar. It is the largest and at the same time most minimally acknowledged bioscientific failure in history. And it says that our understanding of the disease has been hijacked by a monocular focus on a single phenotype of aging – declining autophagy and increasing junk protein – when we have known for at least two decades that 1) AD is clearly linked to aging, as its incidence doubles every 5 years after 60-65; 2) that aging itself is highly multifactorial, and may emerge from the positive feedback and mutual acceleration of many core phenotypes of aging, including declining autophagy, but also increasing disinhibition of inflammation, declining genomic integrity and increasing genetic damage, mitochondrial dysfunction, disordering of apoptosis and cell cycling, cell senescence, etc. All of these factors have been linked to multiple diseases of aging, and to AD also. It’s now long overdue that we start taking all of them, and their interaction (which is almost entirely in the form of positive feedback on one another) much more seriously if we want to stop spinning our wheels in relationship to this disease, which more than any other is posed to break the medical and social safety net banks. The work of Dale Bredesen is informed by very similar thinking, and we have had correspondence sharing our frustration with the myopia of single factor thinking about AD.

    Sue Paul

    March 9, 2016 at 3:31 pm

    Amen Dr. Watt.

Peter Whitehouse

March 3, 2016 at 8:15 am

I agree. My opinion of Time dropped considerably. But even the New York Times has not been critical and objective in its Alzheimer’s coverage from time to time. Journalists are naïve about “disease” and influence by fear and false hope like the rest of us. The real story of Alzheimer’s is awaiting to be told but watch for the soon to appear new film Monster in the Mind.