Untangling the Amyloid-Tau Connection to Inform New Drug Development

Pictured: Doctor holding a brain scan with an elde

Pictured: Doctor holding a brain scan with an elde

peakSTOCK/Getty Images/iStockphoto

Recent data from the Phase III study of donanemab emphasize a correlation between amyloid and tau. Experts say a greater understanding of this link could further Alzheimer’s drug development.

Pictured: Elderly woman in a hospital bed and hands holding a brain MRI/ iStock, peakSTOCK

For the first time, Alzheimer’s patients in the U.S. have a treatment that has shown the ability to modify the disease in some patients. But experts have called Leqembi—developed by Eisai and Biogen—a “modest win” and a “first step” in the fight against Alzheimer’s disease. The next step could lie in untangling the correlation between amyloid and tau proteins—and defining what it means for drug development.

The predominant theory is that Alzheimer’s is caused by the accumulation of two proteins—amyloid-beta and tau—in the brain. The anti-amyloid hypothesis received regulatory validation in June 2021 when the FDA approved Aduhelm (aducanemab) based on clinical data showing that the drug’s reduction of amyloid-beta plaques was reasonably likely to predict clinical benefit. A more solid endorsement arrived last week with the traditional approval of Leqembi (lecanemab).

Leqembi and Aduhelm—along with and Eli Lilly‘s donanemab, which the company is expected to submit for regulatory approval soon—are anti-amyloid antibodies. All of these therapies have secondary effects on tau, Al Sandrock, former Biogen executive and current CEO of Voyager Therapeutics, told BioSpace. “This indicates that tau is downstream of amyloid [and] also fits the hypothesis that amyloid triggers the spread of tau pathology in the brain.”

Al Sandrock

Al Sandrock

“I think of amyloid as the trigger and tau as the bullet,” Sandrock continued. “There is a tipping point in which increasing amounts of amyloid cause tau to spread, and that spread of tau is what causes the neurodegeneration.”

Alvaro Pascual-Leone, professor in neurology at Harvard Medical School and medical director at the Wolk Center for Memory Health, Hebrew SeniorLife, elaborated on this, saying that amyloid—and the inflammatory cascade it causes—appears to be the driver for the tau process. He called it a “complicated relationship that is still to be fully sorted out.”

The Amyloid-Tau Connection

Sandrock pointed to a study of 1,200 people with early-onset, autosomal dominant Alzheimer’s disease with the PSEN1-E280A mutation as support for the hypothesis that tau, rather than amyloid, causes cognitive decline. Individuals with this mutation typically start showing symptoms of the disease in their 40s. The paper, published in May 2023 in Nature Medicine, discussed the case of one man who managed to stave off symptoms until age 67, despite a high level of amyloid plaques. The patient was found to carry one copy of RELN-COLBOS, a gain-of-function variant that has protected against the formation of tau tangles in mouse models, and he harbored relatively few tau tangles.

The same month, Eli Lilly presented results from donanemab’s Phase III TRAILBLAZER-ALZ 2 study, where participants were stratified by brain levels of tau, quantified by positron emission tomography (PET) imaging. Data from the trial found that Lilly’s drug was more effective in the primary analysis population, which comprised people with an intermediate level of tau, than in a combined group of participants with high and intermediate tau levels. Among those with intermediate tau levels, donanemab elicited a 35% slowing of decline on the integrated Alzheimer’s Disease Rating Scale (iADRS), compared to just 22% in the combined group.

Alvaro Pascual-Leone

Alvaro Pascual-Leone

“Presumably, that means that those with more severe disease are less likely to show the benefit,” Pascual-Leone said. “The train has left the station.”

Constantine (Kostas) Lyketsos, a professor and Alzheimer’s researcher at the Johns Hopkins University School of Medicine, said further data from TRAILBLAZER-ALZ 3 will be critical to determine the effects of baseline tau on therapeutic outcomes.

“Lilly has shown high-level data [but] few details,” he told BioSpace. “If the initial hint we have is correct, there are going be people who have a fair bit of amyloid but only a certain amount of tau that will benefit from donanemab. That’s a subgroup that we need to understand.”

Implications for Drug Development

How the correlation between amyloid and tau could inform Alzheimer’s drug development depends on the extent to which tau reduction improves symptoms, Lyketsos said, adding that this is currently unknown. “The best-case scenario says that all you need to do to improve symptoms through tau reduction is to reduce amyloid,” he said. “I think we know enough at this point to know that this is an incomplete response because none of [the anti-amyloid drugs] really change the long-term trajectory [of the disease].”

Lyketsos said the space needs to move away from thinking of Alzheimer’s as a unitary entity and start defining precision medicine approaches for relevant subtypes.

Constantine (Kostas) Lyketsos

Constantine (Kostas) Lyketsos

Keith Weller

Sandrock echoed this sentiment, saying the Phase III development of anti-tau therapies will be aided by understanding the clinical efficacy of anti-amyloid treatments by stage and subtype. “I suspect we will see complete-responders, partial-responders and non-responders to anti-amyloid treatment,” he said. “If [patients] aren’t responding to anti-amyloid [treatment] at all, then anti-tau monotherapy may be appropriate in some cohorts. And for patients who are partial responders to anti-amyloid treatment, we may want to consider combining anti-tau with anti-amyloid.”

Eisai is developing E2814, an anti-tau antibody that is intended to prevent the spread of tau seeds within the brain. E2814 is being tested in a Phase II/III trial that uses lecanemab as the base therapy in order to understand the benefit of this combination. Lecanemab is given to trial participants with an Alzheimer’s disease-causing mutation, who are then randomized after six months to receive either E2814 or placebo.

Eisai will present new data on this drug at the Alzheimer’s Association International Conference (AAIC) next week in Amsterdam, Michael Irizarry, deputy chief clinical officer and senior vice president of clinical research, Alzheimer’s disease and brain health, said in a press release Wednesday.

Meanwhile, Johnson & Johnson is testing its own anti-tau antibody, JNJ-63733657, in a mid-stage trial of patients with early Alzheimer’s. And Bristol Myers Squibb recently paid Prothena $55 million for exclusive worldwide commercial rights to PRX005, an anti-tau antibody that specifically binds to the R1, R2 and R3 repeats within the MTBR of tau and targets both 3R and 4R tau isoforms.

With the caveat that he doesn’t believe the success of Leqembi and other anti-amyloid drugs prove the amyloid hypothesis, Pascual-Leone said the effects described in Leqembi’s Phase III Clarity AD trial are “super exciting.”

“If I had to put money between one or the other, amyloid versus tau, I would have said tau,” he said, “but the combination certainly makes even more sense because of the connection between the two.”

Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.