THE ARISING · Longevity & Healthspan
Brain Blood Flow Rose After Four Weeks of Rapamycin in a Small APOE4 Pilot
Four weeks of a low daily dose of rapamycin was followed by a rise in brain blood flow of more than 15% across multiple regions in middle-aged adults who carry APOE4, the strongest known genetic risk factor for late-onset Alzheimer's disease. Adults without the variant showed no significant change.
The finding comes from an uncontrolled single-arm pilot trial of 23 cognitively normal adults, published in the Journal of Cerebral Blood Flow & Metabolism. Nine were APOE4 carriers and 14 were non-carriers. Everyone took the drug, and the trial had no placebo group.
APOE4 raises Alzheimer's risk 3- to 7-fold in people with one copy and up to 12-fold in people with two, according to the paper. Carriers can develop problems with the brain's blood vessels decades before amyloid and tau, the proteins that mark Alzheimer's pathology, appear. That makes blood flow an early target.
Rapamycin, also called sirolimus, is an FDA-approved drug that blocks mTOR. This pathway helps control cell growth, metabolism and energy use. Blocking it has extended lifespan in several animal models, the authors note. It is not approved to prevent Alzheimer's disease or to extend healthy lifespan.
The researchers at the University of Missouri enrolled adults aged 45 to 65 who scored above 26 on a standard cognitive screening test. People with diabetes were excluded because rapamycin may impair glucose tolerance. Participants took 1 mg of rapamycin a day for four weeks. MRI scans using arterial spin labeling measured blood flow before and after treatment. Among carriers, eight had one copy of APOE4 and one had two.
Beyond blood flow, the researchers reported changes in metabolic and inflammatory markers. These exploratory analyses were not corrected for multiple comparisons. Non-carriers showed distinct responses. Two participants reported minor side effects; the small, short trial cannot establish long-term safety.
The trial builds on the same group's animal work. Four weeks of rapamycin increased brain blood flow and glucose uptake in young APOE4 mice, and the gains lasted at least six months. In those mice, the drug appeared to act by activating an enzyme that produces nitric oxide, which widens blood vessels.
The next question is whether the blood flow gains last and translate into better brain health or a lower chance of developing Alzheimer's. That will take larger, controlled trials.