Nerve Growth Factor (NGF)

Nerve growth factor was the first neurotrophin identified, work by Rita Levi-Montalcini and Stanley Cohen that earned the 1986 Nobel Prize in Physiology or Medicine. The active species is a homodimer of the beta subunit, and it signals through two receptors with opposing consequences: the tyrosine kinase TrkA, which drives survival and differentiation, and the p75 neurotrophin receptor, which can promote apoptosis. Its dependent populations are sympathetic neurons, small-diameter sensory neurons, and the basal forebrain cholinergic neurons lost early in Alzheimer's disease.

Its second role made it a drug target. Released at sites of injury and inflammation, it sensitises nociceptors, so blocking it is analgesic. The monoclonal antibody tanezumab reduced osteoarthritis pain in large trials but was associated with rapidly progressive osteoarthritis and joint replacement, and a United States advisory committee voted against approval in 2021. In the other direction, recombinant human nerve growth factor as an eye drop, cenegermin, is approved for neurotrophic keratitis. Attempts to deliver it to the brain in Alzheimer's disease required neurosurgical gene therapy or encapsulated cell implants and have not shown clinical benefit.

The pattern generalises. A growth factor with a genuine trophic action can be limited not by that action but by a second physiological role elsewhere, and systemic administration here causes pain and hyperalgesia at doses far below anything trophic.

The claim to distrust is that raising nerve growth factor is inherently beneficial or cognition-enhancing. Cosmetic and supplement products assert induction from cell-culture readouts with no delivery argument at all, and the molecule does not cross the blood-brain barrier, which is precisely why the Alzheimer's programmes had to open the skull.