A new era for Alzheimer’s disease may be upon us

The recent FDA approval of Eli Lilly’s new immunotherapy for slowing the cognitive decline of early Alzheimer’s disease marked another step forward in the effort to develop effective therapies for this notoriously difficult disease.

After twenty years without new drugs for Alzheimer’s disease, the FDA has approved this new drug, donanemaband another called immunotherapy lecanemab in the past few years, offering the first glimmers of hope to the more than six million Americans who live with the disease. (In Europe, where I live, that number is estimated to be close eight million people.)

Both therapies attempt to remove toxic amyloid proteins from the brain via injectable monoclonal antibodies given through regular infusions. Lecanemab is the most intensive and requires infusions every two weeks, while donanemab infusions are required monthly.

Dr. Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), described the latest approval as “a very important moment for the Alzheimer’s field,” but also cautioned that neither therapy is a silver bullet. A clinical trial found that donanemab can slow the rate of cognitive decline by 35 percent for 18 months, with both drugs apparently slowing the progression of the disease rather than stopping it altogether.

“Although this class of drugs is only modestly effective and slows cognitive decline by about 30%, they provide about six months of stability when the patient’s disease does not progress further,” says Fillit. “It gives patients more time to remember their loved ones, which I think makes sense for a uniformly fatal disease like this.”

But at this point, not all regulators are convinced of the benefits of these treatments compared to the risks. At the end of July, European regulators rejected lecanemab, describing its benefits as ‘minor’ while highlighting cases of brain swelling and bleeding within the treatment group. In TRAILBLAZER-ALZ 2 by Eli Lilly process of donanemab, more than a third of the treated group suffered cerebral hemorrhages, while three patients died as a result of the administration of the drug.

Now also with a third antibody-based drug, Remternetug in clinical trialsThere are questions about whether such immunotherapies might be more effective if administered earlier in the disease course, perhaps even before the onset of symptoms.

In the future, testing this hypothesis in trials could be more feasible, as the rise of these drugs has been accompanied by a parallel rise in blood tests that screen for molecular signals that reflect the accumulation of disease-causing proteins in the brain.

Two years ago, the National Institute on Aging launched funded a study which showed that measuring certain amyloid biomarkers in blood plasma can predict the amount of amyloid in the brain, while some have suggested that tau, another toxic protein that forms tangles in the brains of Alzheimer’s patients, may be more closely linked to cognitive decline. A newly published study in the journal JAMA also described that testing for a tau-related biomarker in the blood, ptau-217, could detect whether someone has Alzheimer’s disease with 90% accuracy, better than cognitive assessments and CT scans.

Amyloid-removing immunotherapies are just one of many approaches being explored for Alzheimer’s disease, and other treatment options are likely to emerge.

“These drugs [lecanemab and donanemab] are the building blocks for the next generation of care and provide some respite while researchers work to develop more effective therapies that target the underlying biology of the disease,” says Fillit.

Vaccines and the biology of aging

Fillit describes a general renewed sense of optimism in the field of Alzheimer’s drug development, with “neuro-curious” venture capitalists approaching his organization to learn more about emerging research.

One of the most active areas of research is Alzheimer’s disease vaccines, which attempt to trigger the immune system to produce its own antibodies against a host of disease-causing proteins in the brain.

The biotech company Prothena is currently in development a first-class vaccine that attempts to target both amyloid and tau simultaneously, while AC Immune And Alzinova have their own vaccine candidates in the pipeline. These efforts represent a significant resurgence after the first Alzheimer’s vaccine was discontinued in the early 2000s due to reports of encephalitis.

Kristina Torfgård, who worked on Alzinova’s candidate as the company’s former CEO, says a lot was learned from that early failure. The new second-generation vaccines take a much more nuanced approach.

“It is generally agreed that the peptide beta-amyloid causes Alzheimer’s disease, but both non-toxic and toxic forms of this peptide exist,” she says. “The most toxic form is usually called an oligomer, but if you don’t specifically target this form your vaccine probably won’t work because there will be so many off-target reactions to the inert beta-amyloid.”

In the case of Alzinova, Torfgård says the immunogen in their vaccine candidate appears to generate antibodies against amyloid oligomers. Although current studies focus on Alzheimer’s patients with mild cognitive impairment, it is also possible that such vaccines could eventually be administered at a much earlier stage.

“With success, we could ultimately consider a preventative approach for individuals who do not currently have Alzheimer’s and evaluate the potential to delay or prevent the transition to presymptomatic disease,” said Gene Kinney, president and CEO of Prothena. “Diagnostic progress will continue to be important.”

Although the concept of Alzheimer’s vaccines against amyloid or tau has been on the radar for some time, a recent review article found that 75% of drugs in the pipeline target pathways guided by the biology of aging.

“We now know that aging is the most important risk factor for Alzheimer’s disease, but Alzheimer’s disease is not a normal part of aging,” says Fillit. “With decades of knowledge about how the dysfunctional processes caused by the biology of aging culminate in disease, we have several new pathways, including inflammation, epigenetic and vascular and mitochondrial dysfunction, that researchers want to translate into new drugs.”

The brain uses 20% of the body’s energy supply, and research on aging shows that glucose metabolism breaks down with age. That’s why some drug companies are trying to slow cognitive decline by targeting this metabolic dysfunction. Fillit highlights how Novo Nordisk is currently conducting research whether their GLP-1 drug semaglutide can help maintain glucose metabolism in the brain.

Ultimately, Torfgård and Fillit both predict that, as with other chronic diseases such as cancer and high blood pressure, a cocktail of different treatment options will be needed to address both the symptoms and the various underlying causes of Alzheimer’s disease.

“With a disease this complex, we need different drugs that can be used in combination with each other,” says Fillit. “Advances in biomarkers allow physicians to personalize treatments based on each patient’s individual biomarker profile. Current research in this area may also open the door to disease prevention, as our ultimate goal is to slow the progression of the disease or prevent its onset altogether.”

Thanks to David Cox for additional research and reporting on this article.