The UC-led study, conducted in collaboration with the Karolinska Institute in Sweden, claims that the treatment of Alzheimer’s disease might lie in normalizing the levels of a specific brain protein called amyloid-beta peptide. This protein is needed in its original, soluble form to keep the brain healthy, but sometimes it hardens into “brain stones” or clumps, called amyloid plaques.

The study, which appears in the journal EClinicalMedicine (published by the Lancet), comes on the heels of the FDA’s conditional approval of a new medicine, aducanumab, that treats the amyloid plaques.

“It’s not the plaques that are causing impaired cognition,” says Alberto Espay, the new study’s senior author and professor of neurology at UC. “Amyloid plaques are a consequence, not a cause,” of Alzheimer’s disease, says Espay, who is also a member of the UC Gardner Neuroscience Institute.

Alzheimer’s disease became widely known as “the long goodbye” in the late 20th century due to the disease’s slow deterioration of brain function and memory. It was over 100 years ago, however, that scientist Alois Alzheimer first identified plaques in the brain of patients suffering from the disease.

Since then, Espay says that scientists have focused on treatments to eliminate the plaques. But the UC team, he says, saw it differently: Cognitive impairment could be due to a decline in soluble amyloid-beta peptide instead of the corresponding accumulation of amyloid plaques. To test their hypothesis, they analyzed the brain scans and spinal fluid from 600 individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative study, who all had amyloid plaques. From there, they compared the amount of plaques and levels of the peptide in the individuals with normal cognition to those with cognitive impairment. They found that, regardless of the amount of plaques in the brain, the individuals with high levels of the peptide were cognitively normal.

They also found that higher levels of soluble amyloid-beta peptide were associated with a larger hippocampus, the area of the brain most important for memory.

According to the authors, as we age most people develop amyloid plaques, but few people develop dementia. In fact, by the age of 85, 60% of people will have these plaques, but only 10% develop dementia, they say.

“The key discovery from our analysis is that Alzheimer’s disease symptoms seem dependent on the depletion of the normal protein, which is in a soluble state, instead of when it aggregates into plaques,” says co-author Kariem Ezzat from the Karolinska Institute.

The most relevant future therapeutic approach for the Alzheimer’s program will be replenishing these brain soluble proteins to their normal levels, says Espay.

The research team is now working to test their findings in animal models. If successful, future treatments may be very different from those tried over the last two decades. Treatment, says Espay, may consist of increasing the soluble version of the protein in a manner that keeps the brain healthy while preventing the protein from hardening into plaques.

Co-authors include: Andrea Sturchio, University of Cincinnati, and Samir EL Andaloussi, Karolinska Institute.

The research was funded by the UC Gardner Neuroscience Institute.

The authors disclose that they have recently cofounded REGAIN Therapeutics, owner of a patent application that covers synthetic soluble non-aggregating peptide analogues as replacement treatment in proteinopathies.

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Materials provided by University of Cincinnati. Original written by Angela Koenig. Note: Content may be edited for style and length.

“CAR-T cell therapy is a type of immunotherapy that involves harnessing the power of a person’s own immune system by engineering their T cells to recognize and destroy cancer cells,” says Yi Lin, M.D., a Mayo Clinic hematologist and lead author of the study.

Dr. Lin says the Food and Drug Administration approved idecabtagene vicleucel, the first CAR-T cell treatment for multiple myeloma, in March. “Today, we are working toward another potential CAR-T cell treatment for multiple myeloma,” says Dr. Lin.

Dr. Lin says the CARTITUDE-1 study is a registration-phase 1B/II clinical trial. The trial tested B cell maturation antigen targeting CAR-T cell therapy, ciltacabtagene autoleucel (cilta-cel), in patients with multiple myeloma who received at least three previous lines of therapy with standard drugs, including proteasome inhibitors, immunomodulatory drugs and CD38 antibodies.

“Cilta-cel is made from patient’s own T cells that have been genetically engineered and administered as a single dose infusion,” says Dr. Lin.

Dr. Lin says the overall response rate to the treatment was 97%, while the complete response rate and progression-free survival rates were 67% and 77%, respectively. The overall survival rate was 89%.

“Updates on this study were also recently presented at the American Society of Clinical Oncology annual meeting, which occurred after our paper was accepted for publication in The Lancet,” says Dr. Lin. “Our ASCO presentation showed a continued deepening response for patients receiving this therapy, with a complete response rate of 80%,” says Dr. Lin. “These are very impressive results for myeloma patients who have already gone through many lines of therapy for their disease.”

Going forward, Dr. Lin says it will be important to better understand the clinical features of patients who have experienced durable remissions on this therapy and the mechanisms behind patients who relapse.

“While comparisons cannot be formally made across two separate single-arm studies of ide-cel and cilta-cel, the impressive high response rate and progression-free survival of patients treated with cilta-cel are very exciting,” says Dr. Lin.

She cautions, however, that the potential translation of this research into a clinical individualized therapy will require solving many logistical details, including ensuring that the transition from manufacturing for research to a commercial product remains reliable.

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Materials provided by Mayo Clinic. Original written by Joe Dangor. Note: Content may be edited for style and length.