Accordingly, although tangles are not generally present in animal models of normal brain aging, we suggest that declining FKBP1b function and resulting Ca2+ dysregulation during normal aging in animals recapitulate brain-aging processes in humans that subtly degrade the cytoskeleton and, in susceptible individuals, eventually result in irreversible neurofibrillary tangles and AD. The gene discussed is FKBP1B; the disease is Alzheimer disease.