[P‐213]: Early cholinergic deficit in Alzheimer's disease: Can cholinergic replacement therapy decrease deposition of B‐amyloid?

Background: Although it has been known for decades that cholinergic neurons degenerate in Alzheimer’s disease (AD), there has been debate about whether this occurs early or late in the disease, and its significance in the progression of the disease. It has been generally accepted that deposition of -amyloid contributes to the degenerative process of AD. Objectives: We have studied the interactions between cholinergic degeneration and deposition of -amyloid to determine how these two parameters relate. Methods: We examined cholinergic activity in post-mortem brains taken from non-demented aged controls, controls with minimal to moderate deposition of -amyloid, and patients diagnosed with AD. We also examined the effect of cholinergic denervation on deposition of -amyloid in a rabbit model of selective cholinergic degeneration. Conclusions: We found significant cortical cholinergic deafferentation at an early stage, in non-demented controls with moderate deposition of -amyloid. These patients may represent a pre-clinical stage of AD. Nucleus basalis magnocellularis lesioning of rabbits produced both cortical cholinergic deafferentation and increased deposition of -amyloid. Although the -amyloid deposition is primarily on the vasculature, the model demonstrates that a cholinergic deficit induces brain accumulation of -amyloid. We also found that M1 muscarinic agonists and acetylcholinesterase inhibitors lowered CNS -amyloid concentrations in normal rabbits, confirming in vitro work demonstrating that M1 receptor activation shifts APP processing into the non-amyloidogenic pathway. Furthermore, treatment of cholinergic lesioned rabbits with muscarinic agonists or acetylcholinesterase inhibitors prevented increased -amyloid deposition. Our aggregate data suggest a fusion of the cholinergic and -amyloid hypotheses: the cholinergic deficit initiates -amyloid deposition through decreased M1 receptor activation and increased amyloidogenic cleavage of APP. If this hypothesis is true, then cholinergic therapy should delay or slow the rate of degeneration in AD. Supporting this, it has been reported that treatment with cholinesterase inhibitors slows functional decline in AD and conversion of MCI to AD. We feel that treatment should begin at the preclinical stage, as both cholinergic neuron loss and deposition of -amyloid are already advanced by the time of first diagnosis. Supported by NIH grants R01NS38674, R15AG17046, P30AG19610-01 (Arizona NIA AD Core Center) and the Arizona AD Research Center.