News Out of Stanford
Rethinking Alzheimer’s: Why this common gene variant is bad for your brain
What the Study Found (per the article)
APOE4 is a major Alzheimer’s risk gene, but it has been unclear how it contributes.
People with one copy (heterozygous) have ~2–3× Alzheimer’s risk compared to those with two APOE3 copies.
Those with two APOE4 copies have a significantly higher risk (some estimates ~10×).
The researchers came across two individuals (in a large genetic registry) who carried a non-functional APOE4 allele (i.e. the APOE4 variant didn’t produce a working protein) along with one normal APOE3 allele.
One was ~90 years old at death; the other was ~79 and still living.
Neither showed signs of Alzheimer’s or significant brain plaques or pathological markers (amyloid, etc).
This suggests that having a broken (non-functional) APOE4 may be better than having a functional (but risk-conferring) APOE4 allele — i.e. the functional APOE4 protein may be doing something “toxic” or harmful (rather than simply failing to do a beneficial job).
In other words, APOE4’s risk might derive from active harm (a “gain-of-toxic-function”) rather than only from loss of protective function.
Because of that, the authors argue (and Greicius, the lead researcher, is quoted) that therapeutic strategies should consider suppressing or inhibiting APOE4 activity, rather than trying to “boost” or replace it.
There is caution: completely knocking out all APOE function could harm other organs (e.g. heart) or lipid metabolism.
But partial suppression, or a drug that lowers APOE4’s harmful activity without eliminating all ApoE function, might be a safer route.
The work helps resolve a major question in the Alzheimer’s genetics field: when a variant is harmful, should you enhance its “good parts,” or inhibit its “bad parts”? The evidence here leans toward the latter for APOE4.
https://med.stanford.edu/news/insights/2025/09/rethinking-alzheimers-gene-variant-apoe4.html