We examine the evolution of the discovery of peripheral cholinergic changes in Alzheimers disease (AD). Further, we demonstrate a significant eccrine sudomotor cholinergic dysfunction after intradermal injection of pilocarpine in AD subjects compared to non-demented-non-neuropathic control subjects. Active sudomotor gland density was quantified following pilocarpine injection and thermal stimulation. Sympathetic skin responses were collected on the opposite side of the body. The active sudomotor gland density was significantly lower and the percentage of tested skin surface without pilocarpine-activated sweat glands was significantly greater in AD patients after pilocarpine stimulation. The degree of sudomotor activity loss was correlated directly with cognitive decline in AD patients. Neither eccrine gland loss nor afferent or preganglionic neuron dysfunction accounted for these differences. Our experiments reveal sudomotor activity is affected at the postganglionic sympathetic neuron level in AD, thereby inducing readily observable clinical manifestations sufficient to distinguish AD patients from non-demented individuals.