Alzheimer's Risk Gene APOE4 May Cause Reversible Blood Vessel Damage

Scientists investigating the strongest genetic risk factor for Alzheimer's disease have uncovered how it damages the brain and identified a potential route to reversing those effects.

While it has long been recognised that the brain's blood vessels deteriorate in Alzheimer's patients — especially in those carrying the APOE4 gene — the biological steps behind this process had remained elusive. Researchers at the Icahn School of Medicine at Mount Sinai in New York have now traced the mechanism.

According to their findings, APOE4 prompts pericytes — cells that normally lend stability to small blood vessels — to take on the characteristics of scar-forming cells. These transformed cells thicken the vessel walls and encourage the accumulation of amyloid, the misfolded protein clumps that are the target of current Alzheimer's therapies. The resulting changes can restrict blood flow to the brain and cause damage.

The team also found that blocking a protein called TGF-beta, which plays a role in tissue cell activity and repair, shielded the pericytes and reversed the APOE4-linked deterioration of brain blood vessels in mice. The results appear in two papers published in Cell and Cell Stem Cell.

"Damage to the brain's blood vessels is not simply a late consequence of Alzheimer's disease; it is a biologically active process caused by APOE4 that may be reversible," said Joel Blanchard, a co-author of both papers. He added that the findings point to new therapeutic targets for preserving vascular function and limiting amyloid accumulation.

CAR T-cell therapy shows early promise in multiple myeloma

In a separate development, an investigational CAR T-cell therapy from Gilead Sciences produced deep and durable responses in patients with hard-to-treat or recurrent multiple myeloma during an early-stage trial, researchers reported in The New England Journal of Medicine.

Phase 1 trials are designed primarily to assess safety rather than efficacy, so the encouraging results will need confirmation in larger studies. Even so, all 38 patients who received anitocabtagene autoleucel (anito-cel) responded to the treatment, and nearly 80% achieved a complete response, meaning no detectable cancer remained. More than half showed no sign of disease progression two years later, and 65% were still alive after three years.

Serious immune-related and neurological side effects were uncommon, and no delayed neurological complications were reported. Anito-cel is a BCMA-targeted therapy: a patient's T cells are removed, engineered in a laboratory to seek out and destroy cells expressing BCMA — a protein abundant on the surface of multiple myeloma cells — and then reinfused.

"These were great results for a Phase 1 trial," said study leader Dr. Michael Bishop of UChicago Medicine. "Even at a low dose of anito-cel, we were seeing complete responses in the majority of patients right off the bat, and not a single patient developed severe toxicities." The therapy is now being tested in Phase 2 and Phase 3 trials.

Noninvasive method to study ageing cells

Researchers have also developed a noninvasive way to identify and study senescent cells, which contribute to age-related conditions such as cancer, tissue degeneration and inflammatory diseases. These cells stop dividing and growing but fail to die as old cells normally would, instead undergoing marked changes in shape, metabolism and gene activity.

Earlier methods of studying them destroyed the cells, the researchers noted in a report in Nature Aging. Using Raman microscopy, an analytical technique that reveals the biochemical composition of cells without harming them, combined with analysis of individual cells' genetic activity, the team identified unique "barcodes" of senescent cells. The work was conducted in mouse cells, and the researchers are now adapting it for human tissue.

"You can imagine that one day we may develop an endoscope that can look inside your body and identify cellular senescence," said Jeon Woong Kang of MIT, one of the senior authors. Study leader Peter So of MIT noted that senescence "is not just a pathological condition." While it can contribute to sagging skin and muscle weakness in ageing individuals, cellular senescence also plays critical beneficial roles in embryonic development and tissue regeneration, the researchers said. The study is part of the National Institutes of Health's Cellular Senescence Network.