Oligodendrocytes in the brain carry out one job that matters for memory: they wrap nerve fibers in myelin, the fatty insulation that keeps signals fast. In cells carrying APOE4, the strongest genetic risk factor for late-onset Alzheimer’s disease, a team from MIT’s Aging Brain Initiative found that the cells stockpile fat in droplets rather than using it to insulate neurons. A chemical that blocks the enzyme GSK3b restored myelination in mice.
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Li-Huei Tsai, who directs the initiative, led the work, and Leyla Akay, a former graduate student in her lab, is first author. The paper lists roughly twenty co-authors, among them Joel Blanchard, Carles Boix, Adele Bubnys and Ji-Xin Cheng. Akay earned her PhD in 2025, and Tsai is the Picower Professor at MIT who holds the senior position on the paper.
A CRISPR screen that pointed at Wnt
The study, reported by MIT News on October 28 and published in Cell Stem Cell, is titled as a genome-wide CRISPR screen that reveals Wnt signaling as a potential therapeutic target for lipid accumulation and impaired myelination in APOE4 oligodendrocytes (DOI 10.1016/j.stem.2026.09.012). The team knocked out each protein-coding gene, one at a time, in cultures of human oligodendrocytes carrying APOE4 and looked for genes whose loss changed how much fat the cells hoarded. Losing genes that promote Wnt activity caused lipid droplets to build up.
A second line of evidence agreed. Comparing APOE4 with the common APOE3 variant in cultured cells and in postmortem human brain samples, the researchers found that genes promoting Wnt signaling were less accessible in the chromatin of APOE4 carriers. Tsai said there was a striking overlap between the chromatin results and the screen results, with both methods pointing to disrupted Wnt signaling.
One puzzle remains unresolved in the MIT account: losing genes that suppress Wnt also caused lipid accumulation, so the relationship is not a simple dial.
Akay described the logic of the approach as an unbiased way to test every possibility, covering candidate lipid enzymes as well as the upstream pathways that switch them on. Tsai called the work a proof of principle for running CRISPR screens to find genetic modifiers of the lipid accumulation tied to APOE4. The raw data are posted on the Open Science Framework, according to MIT.
Beta-catenin, GSK3b and the fat droplets
Wnt signaling is regulated by two opposing proteins, beta-catenin, which promotes it, and GSK3b, which suppresses it. APOE4 oligodendrocytes showed reduced beta-catenin and excess GSK3b compared with APOE3 cells. A chemical called Dif3, which increases GSK3b activity, made APOE3 cultures accumulate lipid droplets, imitating the APOE4 state. In APOE4 cultures the reverse worked: a GSK3b inhibitor named CHIR99021 reduced the droplets.
The inhibitor then went into more complex systems. In organoids combining APOE4 oligodendrocytes with neurons, blocking GSK3b increased myelination and promoted axon growth. In mice carrying APOE4 and a genetic model of Alzheimer’s tau pathology, treatment with CHIR99021 left fewer lipid droplets and more myelin in the hippocampus, a region central to memory, than in untreated animals.
From cholesterol in 2022 to Wnt now
The new result builds on a 2022 paper from the same lab. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes, in Nature, used single-nucleus sequencing of more than 160,000 cells from 32 postmortem brains, plus cell cultures and mice, to show that cholesterol accumulates abnormally in oligodendrocytes as myelination falls. That study found excess cholesterol inside oligodendrocyte cell bodies and too little along axons, with thinner myelin in the corpus callosum. Reporting on it, Neuroscience News noted that a cholesterol-transport drug, cyclodextrin, improved myelination and memory performance in APOE4 mice, while statins did not help in the lab experiments.
Wnt is a different handle on the same problem. The 2022 work pointed at cholesterol handling in APOE4 carriers, where the cells misplaced the lipid inside the cell body, and the 2026 screen identifies a signaling pathway upstream of the fat buildup.
Several limits sit on top of the result. The drug was never tested in people, and MIT describes CHIR99021 as a proof-of-concept strategy rather than a usable therapy. The chromatin data show differences in accessibility without proving cause. The authors plan to study how Wnt loss alters lipid metabolism and how GSK3b relates to tau phosphorylation. Funding came from the National Institutes of Health, the Robert and Renee E. Belfer Family Foundation, the Manthripragada McManama Alzheimer’s Fund, the CAMA Seed Fund, the J. Crayton Pruitt Foundation, Joseph P. DiSabato and Nancy Sakamoto, and the Freedom Together Foundation, and Akay and Tsai have applied for a patent on the screen’s results. The mice used in the new study carried both APOE4 and a model of tau pathology, which makes them a closer match to the human disease than APOE4 alone, though still a mouse. The open question is whether blocking GSK3b can restore myelin in a brain that already has plaques and tangles, and the MIT report does not address it.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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