In animals, Nerve Growth Factor (NGF) stimulates cholinergic neuronal function, improves learning and memory, and prevents cholinergic degeneration caused by injury or aging. NGF may therefore ameliorate cholinergic cell loss and reduce cognitive decline in Alzheimer's disease (AD). Using ex vivo gene delivery primary autologous fibroblasts from eight early-stage Probable AD patients were genetically modified to produce and secrete human NGF. These cells were implanted into the cholinergic Nucleus Basalis to act as biological pumps for the secretion of NGF, using a dose-escalation design. Safety, MRI, PET scans and neuropsychological function were measured over time. Results to date indicate 1) NGF expression in the brain was safe over a period of 18-24 months. 2) On the 30-point MMSE scale, mean pre-treatment annual rate of decline was 6.0 + 1.9 points. Post-operatively, the mean annual rate of decline was 3.5 + 1.8 points, a reduction of 40%. On the Alzheimer's Disease Assessment Scale-Cognitive subcomponent (ADAS-Cog) scale, experimental subjects exhibited a 40% reduction in rate of decline compared to historical controls. 4) Autopsy in one subject demonstrated robust "trophic" (growth) responses of cholinergic neurons to NGF in the AD brain. NGF gene delivery to the AD brain stimulates two distinct markers of cholinergic neuronal function and may reduce cognitive decline. These results support the notion that additional clinical trials are warranted.