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Genome-wide CRISPR screen implicates Wnt signaling in APOE4's myelin damage

MIT researchers used a genome-wide CRISPR screen to tie APOE4's myelin damage to suppressed Wnt signaling in human oligodendrocytes. The result gives drug researchers a named pathway to test, though the evidence so far comes from cultured cells and mice.

The Scientist · Science desk

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What happened

  • The same lab reported in 2022 that APOE4 caused lipid droplets to build up in oligodendrocytes and upset myelination, but the underlying mechanisms were unknown.
  • In the screen, each protein-coding gene was knocked out one by one in human APOE4 oligodendrocytes, and losing genes that promote Wnt activity left lipid droplets accumulating.
  • Chromatin accessibility data comparing APOE4 with APOE3 samples showed that genes promoting Wnt signaling were less accessible in APOE4 carriers.
  • Restoring Wnt signaling in APOE4 oligodendrocytes brought myelination back, in human cell cultures and in mice modeling Alzheimer's disease.

Why it matters

  • What's now possible capability Drug groups working on APOE4 now have a named pathway to test against, with a myelination readout already shown to respond when Wnt signaling is restored.
  • What it limits constraint One human iPSC line homozygous for APOE4 supplied the screen's oligodendrocytes, so the result rests on a single genetic background until other lines are tested.
  • What it sets up precedent Tsai calls the work a proof of principle for screening a central nervous system cell type this way, and we'd expect the same design to be reused on other APOE4-linked defects.

The sequence the team proposes is short. According to the group led by Li-Huei Tsai and Leyla Akay, APOE4 suppresses Wnt signaling in oligodendrocytes [1]. When Wnt signaling is deficient, the cells accumulate droplets of lipids instead of deploying fats to myelinate the neurons' axon branches [2].

A knockout screen changes a gene and watches the outcome, so it speaks to cause. Chromatin accessibility data show which genes are open for expression and which are locked down from transcription [12], so they describe the state APOE4 leaves the cell in. "There was a striking overlap between ATAC-seq and CRISPR screen results," Tsai said. "Both pointed to a dysregulation of the Wnt signaling pathway." [6]

The screen also spares the team from guessing. Akay said droplet accumulation could happen for many reasons [11]. Her description of the method: "This CRISPR screen allowed us an unbiased way to test every single possibility." [10]

The report does not give the size of the myelination recovery, the number of mice, or the number of postmortem samples compared, and it describes no work in people. The authors' own title calls Wnt signaling "a potential therapeutic target" [8]. We think "candidate" is the accurate word for where this stands.

Tsai, who also directs MIT's Aging Brain Initiative, is more forward-looking about what the approach could yield. "I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development," she said. [13]

What to watch

  • Whether the Wnt rescue holds in other APOE4 cell lines and in readouts beyond myelination.
  • A report of any compound or genetic approach that restores Wnt signaling in oligodendrocytes, with effect sizes in mice.
  • Whether the same genome-wide screen is run in other central nervous system cell types carrying APOE4.

Clarity's read

What the record supports and how the coverage leans. The claims behind it follow.

Reality

Evidence58
Adoption
Not scored
Hype gap+25
Incentives35
Confidence62
Why these scores

Claim ledger

Ranked by verification strength, evidence, and original report placement.

  1. [1]

    The researchers, headed by Li-Huei Tsai and Leyla Akay, showed that APOE4 leads to a suppression of Wnt signaling in oligodendrocytes, the cells that provide neurons with fatty myelin insulation.

    Reported Supported Source: Picower Institute for Learning and Memory at MIT, as reported by GENView cited source
  2. [2]

    When Wnt signaling is deficient, oligodendrocytes accumulate droplets of lipids rather than deploying fats to properly myelinate neurons' axon branches.

    Reported Supported Source: Tsai/Akay team, as reported by GENView cited source
  3. [3]

    In the CRISPR knockout screen, which knocked out each protein-coding gene one by one in cultures of human APOE4-carrying oligodendrocytes, lipid droplets accumulated when genes promoting Wnt activity were lacking.

    Reported Supported Source: Tsai/Akay team, as reported by GENView cited source
  4. [4]

    The screen used oligodendrocytes generated from a well-characterized human iPSC line homozygous for the APOE4 allele.

    Reported Supported Source: Team's description of methods, as reported by GENView cited source
  5. [5]

    Chromatin accessibility analysis comparing APOE4-carrying samples with APOE3 samples showed that genes promoting Wnt signaling were less accessible in APOE4 carriers.

    Reported Supported Source: Tsai/Akay team, as reported by GENView cited source
  6. [6]

    "There was a striking overlap between ATAC-seq and CRISPR screen results," Tsai said. "Both pointed to a dysregulation of the Wnt signaling pathway."

    Reported Supported Source: Li-Huei Tsai, co-senior authorView cited source
  7. [7]

    Experiments in both human cell cultures and in mice modeling Alzheimer's disease showed that when Wnt signaling in APOE4-carrying oligodendrocytes was restored, myelination rebounded.

    Reported Supported Source: Tsai/Akay team, as reported by GENView cited source
  8. [8]

    The paper in Cell Stem Cell is titled "Genome-wide CRISPR screen reveals Wnt signaling as a potential therapeutic target for lipid accumulation and impaired myelination in APOE4 oligodendrocytes"; Tsai is co-senior author and Akay is first author.

    Reported Supported Source: GEN, citing the Cell Stem Cell paperView cited source
  9. [9]

    In 2022, Tsai's lab, led by Akay with co-author Joel Blanchard and colleagues, showed that APOE4 caused lipid droplet accumulation in oligodendrocytes and upset myelination; the team wrote that the underlying mechanisms were unknown.

    Reported Supported Source: Tsai lab, as reported by GENView cited source
  10. [10]

    Akay said: "This CRISPR screen allowed us an unbiased way to test every single possibility."

    Reported Supported Source: Leyla Akay, first authorView cited source
  11. [11]

    Akay said the lipid droplet accumulation seen in the 2022 work could happen for many reasons.

    Reported Supported Source: Leyla Akay, first authorView cited source
  12. [12]

    ATAC-seq analysis allowed the investigators to assess which genes were most accessible for expression and which were locked down from transcription.

    Reported Supported Source: GEN's description of the analysisView cited source
  13. [13]

    Tsai, who also directs MIT's Aging Brain Initiative, said: "I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development."

    Reported Insufficient Source: Li-Huei TsaiView cited source
  14. [14]

    Tsai called the work a "proof of principle of doing CRISPR screens for genetic modifiers of APOE4-associated lipid accumulation in a central nervous system cell type."

    Reported Insufficient Source: Li-Huei TsaiView cited source

Sources

2 independent publishers whose own reporting we read for this story.

  1. genengnews.com

    1 article · October 15, 2026

    How Alzheimer’s Risk Gene APOE4 Disrupts Myelination
  2. neurosciencenews.com

    1 article · October 16, 2026

    Boosting Wnt Signaling Reverses APOE4 Alzheimer’s Damage

Topics and entities

Topics

Entities

  • The Picower Institute for Learning and Memory
  • APOE4