Alzheimer’s Advancements: A Roller-coaster Ride of Disappointment and Hope

When it comes to Alzheimer’s, the only thing that is crystal clear is the threat that it poses to the health of our nation and much of the world. As of 2019, 5.8 million Americans are afflicted with Alzheimer’s Disease (AD) and by 2050, this number is expected to rise to nearly 14 million with estimated costs reaching as much as $1.1 trillion per year.1

Symptoms of AD appear to come from one of two types of nerve damage:

  • Plaques are deposits of a protein fragment called beta-amyloid that build up in the spaces between nerve cells.
  • Tangles are twisted fibers of another protein called tau that build up inside cells.

While, there are a variety of diverse theories on the precise roles of plaques and tangles in AD, the root cause of Alzheimer’s symptoms and disease progression is far from understood. Absent an understanding of the cause(s), learning how to reduce critical symptoms is the next best thing. Tragically, for Alzheimer’s and other forms of dementia, there has been no success in treating the cause(s) and very little success treating the symptoms.

Unsuccessful Approaches for Alzheimer’s Treatment

Since 1984, the leading hypothesis has been that Alzheimer’s is caused by the inability to control amyloid and tau proteins. These proteins accumulate to form large, sticky plaques in the brain, which leads to the inability for nerve cells to communicate properly, then to their deaths. While the accumulation of the tau protein is known to be a symptom, the bulk of research has centered on the “amyloid hypothesis.”

After decades of research and billions of dollars spent, it has become clear that the amyloid hypothesis very well may not be the answer. The failure rate of Alzheimer’s drug development is 99 percent and the failure rate of developing disease-modifying therapies for Alzheimer’s is 100 percent.2

The highest-profile discrediting of the amyloid hypothesis occurred just this year. In March 2019, Biogen and its Japanese pharma partner Eisai suspended two phase 3 clinical trials of aducanumab, a drug designed to slow the progression of Alzheimer’s by reducing the accumulation of beta-amyloid. The trials were discontinued after it was concluded that aducanumab was performing on par with the placebo.3

What’s Next?

Of course, scientists persevere. There are currently almost 290 active interventional clinical trials for Alzheimer’s underway in the United States.4 In addition, there are some fascinating new theories that have come to the forefront. The following are just a few of the many developing hypotheses:

Amyloid Hypothesis Reimagined

    • Florida Atlantic University’s Brain Institute is leading a team of neuroscientists to answer a key question: “Is amyloid precursor protein the mastermind behind Alzheimer’s disease or is it just an accomplice?”
    • Much is known about how this protein turns into amyloid plaques; however, little is known about its native function in neurons, and this understanding could be vitally important for reaching a comprehensive understanding. In some instances, the highest genetic risk factor for Alzheimer’s is a protein that facilitates cholesterol transportation and not the amyloid precursor protein.
    • The study led by Florida Atlantic University’s team genetically disrupted the interaction between cholesterol and amyloid precursor protein. The team discovered that this disruption interrupts the trafficking of the amyloid precursor protein and disrupts cholesterol distribution at the neuronal surface. Neurons with this changed distribution of cholesterol showed swollen synapses and other initial signs of neurodegeneration.5 Will preventing this altered distribution prevent the disease and its progression?
    • Inflammation, HIV Drugs and Alzheimer’s Progression
    • Inflammation has long been implicated in Alzheimer’s disease, but now researchers at Brown University suggest it may involve retrotransposons that escape regulation and begin replicating in older cells. In their studies, cells that had replicating L1 retrotransposons triggered interferon production and inflammation which ultimately may lead to Alzheimer’s symptoms.6 Because inflammation induction by retrotransposons is reliant on reverse transcriptase, HIV drugs such as lamivudine are a potential avenue for stopping or slowing the progression of Alzheimer’s.
    • Separately a group at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA suggested that anti-retroviral therapies may hold promise in the treatment of Alzheimer’s by limiting genetic variation in the amyloid precursor protein (APP) gene. Although the exact role of the APP protein is unclear, there are links between mutations in this gene and the risk of early-onset Alzheimer’s disease. The Sanford group found that genetic variation in the APP gene within neuronal cells is dependent on reverse transcriptase, an enzyme targeted by many HIV therapies.7
    • Tau, the Other Alzheimer Protein
    • Tau is known to misfold and form intracellular aggregates and ultimately higher-order neurofibrillary tangles in AD that cause neurodegeneration. In addition, tau aggregates or ‘seeds’ are hypothesized to spread from cell to cell in a prion-like fashion thereby propagating AD pathology and disease progression. Despite tau pathology showing a higher correlation to clinical progression of AD than beta-amyloid pathology, few therapeutic approaches have focused on tau.
    • Several animal studies suggest that antibodies against abnormally phosphorylated or pathologically relevant conformational tau epitopes may clear toxic tau species or block cell-to-cell disease spread providing a means of therapeutic intervention. To date, three tau-based antibody programs have entered clinical trials.8
    • Researchers at UCB have taken the approach of employing an unbiased screening approach to identify epitopes within pathological tau species recognized by antibodies that can neutralize cell-to-cell tau seeding. Two recent publications from the group report the characterization of six anti-tau antibodies to physiological and pathological tau species, including antibodies currently in clinical trials as well as novel anti-tau antibodies, and found dramatic differences in the ability to block tau spreading. The group’s efforts identified a new antibody which recognizes a central epitope on tau and is able to completely neutralize seed isolates from AD patients.9 Furthermore, this antibody proved more efficacious at blocking in vivo pathology caused by AD-derived brain-material  than a known high-affinity antibody that recognizes an N-terminal epitope, and blocked cell-to-cell tau spreading.10 Their data strongly suggest that the choice of tau epitope could be a critical determinant of therapeutic efficacy of tau antibodies.
    • Future clinical trial results and continued research promise to shed light on whether anti-tau antibodies will lead to another round of disappointment.

The urgency for developing solutions to prevent, stop the progression of, and one day even reverse Alzheimer’s and other neurodegenerative diseases is quite clear. There is much work to be done to understand the mechanisms of these conditions and to develop effective treatment approaches. An incredibly promising aspect of today’s Alzheimer’s research community is the tremendous diversity of thought being applied to the problem.

To test developing theories and deliver potential treatments to clinics as quickly as possible, flexible development platforms that allow teams to formulate their ideas from concept to commercialization using a single platform is critical. In fact, the UCB team conducting the anti-tau antibody efforts required a cell engineering platform to develop a functional cell seeding assay as well as express anti-tau antibodies for in-depth in vitro and in vivo characterization. Using MaxCyte’s ExPERT platform allowed them to rapidly produce large quantities of high-quality therapeutic antibodies for both in vitro and in vivo development work towards an accelerated path to the clinic.

The work that has been completed to date is nothing short of a roller-coaster ride of hope and crushing disappointment. However, with ever-increasing knowledge, constantly advancing enabling technologies, and the determination of scientists around the world, in the end, hope will prevail.

Read full articles from UCB:

  • Epitope determines efficacy of the therapeutic anti-tau antibodies in a functional assay with human Alzheimer tau. (link)
  • Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. (link)


  1. Alzheimer’s Association Facts and Figures,
  2. “The price of progress: Funding and financing Alzheimer’s disease drug development,” Jeffrey Cummings, Carl Reiber, Parvesh Kumar, Alzheimer’s & Dementia: Translational Research & Clinical Interventions, Volume 4, 2018
  3. “Biogen Halts Studies of Closely Watched Alzheimer’s Drug, a Blow to Hopes for New Treatment,” Adam Feuerstein, Scientific American, March 22, 2019
  5. Reciprocal modulation between amyloid precursor protein and synaptic membrane cholesterol revealed by live cell imaging. (2019) Neurobiology of Disease, 127: 449
  6. L1 drives IFN in senescent cells and promotes age-associated inflammation. (2019) Nature, 566(7742): 73-78.
  7. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. (2018) Nature, 563: 639 – 645.
  8. An overview on the clinical development of tau-based therapeutics. (2018) Int. J. Mol. Sci., 19(4): 1160.
  9. Epitope determines efficacy of the therapeutic anti-tau antibodies in a functional assay with human Alzheimer tau. (2018) Acta Neuropathol., 136:729 – 745.
  10. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. (2019) Brain, Apr 30. [Epub ahead of print]