The cerebrovascular role of the cholinergic neural system in Alzheimer's disease

The intrinsic cholinergic innervation of the cortical microvessels contains both subcortical pathways and local cortical interneurons mediated by muscarinic and nicotinic acetylcholine receptors. Stimulation of this system leads to vasodilatation. In the extrinsic innervation, choline acts as a selective agonist for the α7-nicoticinic acetylcholine receptor on the sympathetic nerves to cause vasodilatation, and through this mechanism, cholinergic modulation may affect this sympathetic vasodilatation. Alzheimer's disease is characterized by a cerebral cholinergic deficit and cerebral blood flow is diminished. Cholinesterase inhibitors, important drugs in the treatment of Alzheimer's disease, could influence the cerebral blood flow through stimulation of the intrinsic cholinergic cerebrovascular innervation. Indeed, cholinesterase inhibitors improve cerebral blood flow in Alzheimer patients who respond to treatment. Further, cerebrovascular reactivity and neurovascular coupling are impaired in Alzheimer's disease and both can be improved by cholinesterase inhibitors. Conversely, cholinesterase inhibitors inhibit the α7-nicoticinic acetylcholine receptor on extrinsic sympathetic nerves and thus may impair vasodilatation. The net outcome of these opposing effects in clinical practice remains unknown. Moreover, it is uncertain whether the regulation of cerebral blood flow during blood pressure changes (cerebral autoregulation) is impaired in patients with Alzheimer's disease. Technological developments now allow us to dynamically measure blood pressure, cerebral blood flow, and cerebral cortical oxygenation. Using simple maneuvers like single sit–stand and repeated sit–stand maneuvers, the regulation of cerebral perfusion in patients with Alzheimer's disease can easily be measured. Sit–stand maneuvers can be considered as a provocation test for cerebral autoregulation, and provide excellent opportunities to study the cerebrovascular effects of cholinesterase inhibitors.