In the long-running debate over just what causes Alzheimer’s disease, one side looks to have scored a victory with new results with an in-development drug. But there’s enough variation in the data to ensure that the squabbling factions of Alzheimer’s will have plenty to fight about.

At issue is the so-called amyloid hypothesis, a decades-old theory claiming that Alzheimer’s gradual degradation of the brain is caused by the accumulation of sticky plaques. And the new drug is BAN2401, designed by Biogen and Eisai to prevent those amyloid plaques from clustering and attack the clumps that already have.

In data presented last week, one group of patients receiving BAN2401 saw their amyloid levels plummet, a result that was tied to a significant reduction in cognitive decline compared with placebo.

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To the amyloid-inclined, like Dr. Howard Fillit of the Alzheimer’s Drug Discovery Foundation, that marks a clear affirmation of the linkage between plaques and mental fortitude.

“I mean if you asked me five or 10 years ago if we’re going to have a drug that can remove the plaques from the brain, I would have thought this was space technology,” Fillit said. “And there was definitely a signal, in my opinion, on clinical outcomes, which is what we’ve all been looking for.”

But to skeptics, the trial was laden with confounding details that make it impossible to draw conclusions.

“These results are a mess,” wrote Baird biotech analyst Brian Skorney. “Not so much that they indicate an outright failure of the [amyloid] hypothesis, but they don’t really say anything informative at all.”

In the trial, every single tested dose had a significant effect on plaques as measured by a brain scan, and the more BAN2401 patients got, the less amyloid they had after 18 months. But looking at cognition, only the highest tested dose was significantly better than placebo at slowing down mental decline. And some of the patients who received lower doses actually declined faster than those who received no treatment at all.

If amyloid really is the driving factor behind Alzheimer’s, why didn’t each incremental reduction in plaques lead to a corresponding improvement in cognition?

Dr. Al Sandrock, Biogen’s chief scientific officer, said there is likely a threshold of amyloid reduction that must be reached before patients actually benefit. The low doses, despite their effect on plaques, might not have hit that threshold, Sandrock said, thus accounting for their poor performance on cognitive decline.

The divergence in the two curves is what gives Dr. Reisa Sperling, who was overall encouraged by the results, “the most pause.” But Sperling, director Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, noted that some of the study’s arms had small numbers of patients, making it difficult to draw conclusions. She said while there is a biological argument that could underpin the threshold hypothesis, she wanted to see more data from a larger trial with a more traditional design.

Even if Sandrock’s theory holds up, what happened to BAN2401 is not a new phenomenon. This year a drug from Merck, meant to shut off the production of plaques by blocking an enzyme called BACE, was successful in reducing amyloid but fared so dismally on cognitive measures that researchers terminated the trial early. A second BACE drug, from Biogen and Eisai, had similar results in miniature, hitting the mark on plaque reduction in a Phase 2 trial but failing to significantly outperform placebo on cognition.

The underlying issue, according Dr. Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California, is that “the plaques are not the target — those are biomarkers.”

“A target is something that, as a result of hitting it, there will be change downstream in behavior, cognition, and illness course,” Schneider said. “So, yeah we’re knocking down amyloid, but so far we’re not changing behavior much.”

Even BAN2401’s saving grace — that its highest dose appeared to both reduce amyloid and improve patient’s clinical results — has come under scrutiny.

In the BAN2401 trial, about 70 percent of patients getting placebo had a genetic mutation that triples the risk of Alzheimer’s. But in the high-dose BAN2401 group, just 30 percent of patients had the mutation, called APOE4.

That could explain why BAN2401 seemed to outperform a saline injection in the high-dose group, skeptics say, as past trials suggest that APOE4 carriers have more rapidly progressing Alzheimer’s than patients without the mutation.

And it could mean that the drug’s seeming promise is a mirage.

Dr. Paul Aisen, who runs the Alzheimer’s Therapeutic Research Institute at the University of Southern California, said the discrepancy “does create a potential bias.” But in trials where patients are confirmed to have amyloid in their brains at the outset, as was the case with BAN2401, “the impact of [APOE4] on progression is modest,” Aisen wrote in an email. “I don’t think this accounts for the apparent slowing of cognitive decline in the high-dose arm.”

Sperling agreed that she did not think the arms’ different populations skewed the data, in part because the group that received the second highest dose of the drug had a larger share of APOE4 carriers and saw results that were similar — though not as substantial — as the high dose group.

“It’s a similar pattern,” she said. “For me that partially mitigates that concern.”

Biogen and Eisai have promised to dig into the data and parse out the effect APOE4 had on whether patients responded to BAN2401, but those results likely won’t be ready for months.

In the meantime, companies are still queueing up to take cracks at amyloid.

Eli Lilly, which has spent billions on failed Alzheimer’s drugs in recent years, has designed a trial that will test the amyloid hypothesis “in the most definitive way possible,” said Mark Mintun, the company’s vice president of neurodegeneration.

The plan is to take a BACE inhibitor and pair it with an injected treatment that targets amyloid already in the brain. That should address the two major concerns with each approach, Mintun said: BACE inhibitors prevent amyloid but don’t address plaques that already exist, while amyloid-targeting therapies don’t stem the flow of new toxic clumps.

“I equate it to going down to your basement and finding three feet of water and there’s been a slow drip for four weeks,” Mintun said. “You can turn off the spigot, but it won’t feel like you’ve made much progress, so you’ve got to pump it out, too.”

That study is enrolling 375 patients into three groups, planning to study whether the combination can improve cognition compared with placebo over 18 months.

Andrew Joseph contributed reporting.

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  • If I could summarize my 30 years of basic and clinical research on Alzheimer’s, I would say the following: amyloid is a critical factor in the chain of events causing neurodegeneration. There is a large body of data to support this statement. However, it is a downstream event. The etiology of Alzheimer’s, that is, the triggering event that leads to oligomerization of amyloid and tau, followed by oxidative stress, inflammation, nuegeneration and cell death IS UNKNOWN. None of the risk factors alone is sufficient to cause the disease. There also is an extremely complex interplay with genes and environment playing pivotal rolls in tipping the scale either to the size of high neuroresilience or higher risk for Alzheimer’s disease. One of my favorite hypotheses is the reactivation of an ubiquitous infectious agent (an area in which I have not published much myself). Such an event reflects what universally occurs to our bodies as we age. This phenomenon is very well-known in other systems (reactivation of herpes zoster, higher prevalence of pneumonia meningitis, HPV-related cancers, etcetera). The possibility are viral reactivation underline the etiology of Alzheimer’s disease has been proposed by several investigators over two decades. This is also supported by neuropathological data showing that neurofibrillary tangles (a cellular reaction to oxidative stress) made of identical components as seen in Alzheimer’s disease occur in certain infectious diseases uch as in postencephalitic parkinsonism and sub-acute sclerosing panencephalitis. Immune senescence in conjunction with a number of risk factors including apoe4, trem 2 and other immune related genes as well as the number of lifestyle factors are critical determinants for such infectious agent reactivation to occur.

    • Dr Pappolla I appreciate your dedication to these disease that have in common the presence of protein aggregates. My daughter who has ALS diagnosed in 2007 and given 5 years to live is still with us. Her response to treatment and to serological tests not currently avaiable in commercial laboratories have proven that sALS is caused by a Borrelia infection.
      Other ND have also been identified has havng a bacterial etiology. Dr.s Ala Macdonald and Judith Miklossy have cultured Borrelia from amyloid plaques.
      For further information http://www.winningthefight.org.

  • Can anyone explain why someone with significant dementia attributed to Alzheimers can suddenly become lucid and remember information they haven’t been able to recall (sometimes for years) in the hours/days before death? From what I have read the amyloid plaques, deterioration/disappearance of brain matter and breaks in neural pathways cause the dementia so why can they suddenly remember everything again for a short period?

  • The bacteria kill the cells and leave behind the amyloid plaques which are debris from the dead cell.
    The bacteria [Borrelia] kill the cell by usurping the TCA cycle and extract energy from the cell. The bacteria use glycolysis for energy until they reproduce. then they need the TCA cycle so they enter the cell .The energy depleted cell produces mutated genes before it dies.

  • Amyloid is the waste product. You don’t stop the dogs shitting in your yard by cleaning up the poop. Are these people even scientists?

    Cortexyme has developed several compounds that kill the bacteria (the dogs) that are taking plaque dumps in your brain yard.

    • Bacteria aren’t producing amyloid, they’re being produced by an unproductive cleavage of a protein – amyloid precursor protein. This is happening in neurons, not in some invasive cell.

  • Has it been verified that the plaque didn’t result in new/alternate pathways for the info which may not have been productive, unable to connect with contextual info? If alternate pathways were conflicting with the old rejuvenated pathways, would it be a traffic jam? Or am I completely misinterpreting what I’m reading?

  • Please notify me of any trials new trials or any more results or any more information we could possibly give on the subject
    Thank you
    Charles Hom
    I have amyloid angiopathy

  • The Amyloid plaques and the protein aggregates in other neurodegenerative diseases are most likely the debris from dead cells. Borrelia and and other bacteria have been cultured from these protein aggregates have been cultured from these plaques. See the research of Alan MacDonald and Judith Miklossy
    https://alzheimerborreliosis.net/research/
    https://www.j-alz.com/editors-blog/posts/alzheimers-disease-and-spirochetosis-causal-relationship
    My daughter has ALS and has cultured positive for Borrelia and responded to appropriate antibiotics treatment

  • It is great to see potential in the Biogen product and this critical assessment of the “amyloid hypothesis.” Several years ago, we analyzed the growth and maturation of research on amyloid, and concluded that clinical trials were being conducted when this body of research was not yet mature; less mature than the research on any targets for drugs discovered through targeted screening in this decade. (Beierlein et al. Patterns of Innovation in Alzheimer’s Disease Drug Development: A Strategic Assessment Based on Technological Maturity. Clinical Therapeutics, 2015).
    We concluded: “This analysis suggests that AD drug discovery has followed a predictable pattern of innovation in which technological maturity is an important determinant of success in development. Quantitative analysis indicates that the lag in emergence of new products, and the much-heralded clinical failures of recent years, should be viewed in the context of the ongoing maturation of AD-related technologies. Although these technologies were not sufficiently mature to generate successful products a decade ago, they may be now. “

    • It’s sad that the “amyloid hypothesis” has held back actual progress for more than two decades. Thankfully, there are companies like Cortexyme who aren’t blindly dumping billions into someone else’s unfounded, unsubstantiated, and frankly, proven-wrong theory.

      The reason why we’ve dumped over $200billion into AD research in the past quarter century and come up with absolutely nothing… some idiots decided to dump all that money into an invalid theory, and it continues today. Bill Gates just dumped an ungodly amount more into amyloid research. It’s just such a sad waste of money, simply because Stanley Prusiner wrote a paper that got way too much biblical treatment.

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