People with tuberous sclerosis complex, a genetic disease that chronically overactivates the mTOR pathway from birth, show blood levels of a tau-pathology marker approaching those of Alzheimer's disease
People with tuberous sclerosis complex, a genetic disease that chronically overactivates the mTOR pathway from birth, show blood levels of a tau-pathology marker approaching those of Alzheimer's disease
On September 11, a Duke University team compared plasma p-tau217, a sensitive marker of tau protein damage in Alzheimer's disease, across 63 people with tuberous sclerosis complex, 25 people with Alzheimer's disease, and 116 cognitively healthy individuals. In patients with tuberous sclerosis complex, the marker was significantly higher than in healthy age-matched peers, began rising at a younger age, and was statistically indistinguishable from the Alzheimer's disease group.
Tuberous sclerosis complex is a rare hereditary disease that occurs in roughly 7 to 12 people per 100,000. It is caused by a loss-of-function mutation in either TSC1 or TSC2, genes that normally restrain mTOR, a cellular switch between growth and self-cleaning. Without this restraint, mTOR remains chronically overactivated for the person's entire life: patients develop benign tumors in the brain, kidneys, heart, and skin, and most develop epilepsy.
The Duke team has studied the brain in tuberous sclerosis complex for years. In patients' cerebrospinal fluid they found markers of neuronal damage, and in postmortem brain tissue they found tau protein aggregates resembling those seen in Alzheimer's disease, but without amyloid plaques. The connection traces to mTOR itself: when the pathway is chronically overactivated, the cell cannot switch to autophagy, which leads to synaptic damage and tau accumulation, the same processes involved in neuronal death in Alzheimer's disease. Because there is no amyloid in the brain in tuberous sclerosis complex yet tau pathology is still present, this rare disease becomes a natural model: it reveals the contribution of overactivated mTOR to neurodegeneration separately from amyloid, the principal driver of Alzheimer's disease.
The study moved the test to blood, which is easier to collect than cerebrospinal fluid, and chose p-tau217, the most accurate available marker of early tau pathology: this allowed the first direct comparison between tuberous sclerosis complex and Alzheimer's disease. After adjustment for age and sex, p-tau217 levels in patients remained significantly higher than in healthy individuals (p < 0.0001) and statistically indistinguishable from those in Alzheimer's disease (p=0.071). Part of the difference from healthy controls may reflect the kidneys rather than the brain: kidney impairment, common in this disease, reduces p-tau217 clearance, although the authors describe the effect as modest. An independent check that matched the groups by age and sex confirmed the same result.
mTOR is the same pathway around which the hypothesis of lifespan extension through rapamycin has been built for decades: mTOR suppression slowed aging in worms, yeast, and flies, and in 2009 the effect was first confirmed in ordinary mice. In humans, rapamycin trials aimed at longevity have not yet yielded a significant result. A review of rapamycin's failures points to trial design rather than the underlying biology. Tuberous sclerosis complex offers a rare chance to observe what happens when nature itself keeps this pathway overactivated throughout a person's entire life: one of the outcomes is tau pathology on a scale comparable to Alzheimer's disease.
The authors name as the next step a test of whether rising p-tau217 correlates with memory decline in patients. There is already practical relevance: the company Aeovian is testing a selective mTORC1 inhibitor, AV078, against epilepsy in this disease. If hyperactive mTOR does indeed drive tau pathology, the same drug gains a second therapeutic target beyond seizures: tau pathology resembling early Alzheimer's disease.