Cholinergically Mediated Augmentation of Cerebral Perfusion in Alzheimer's Disease and Related Cognitive Disorders: The Cholinergic-Vascular Hypothesis

The treatment of Alzheimer's disease (AD) with cholinesterase inhibitors (ChEIs) is based on the cholinergic hypothesis. This hypothesis fails to account for the global nature of the clinical effects of ChEIs, for the replication of these effects in other dementias, and for the strong and unpredictable intraindividual variation in response to treatment. These findings may be better explained by the premise that ChEIs primarily act by augmenting cerebral perfusion: the cholinergic–vascular hypothesis. This article will review the evidence from preclinical and clinical investigations on the vascular role of the cholinergic neural system. The clinical relevance of this hypothesis is discussed with respect to its interactions with the vascular and amyloid hypotheses of AD. Implications for treatment are indicated. Finally, we propose that the role of the cholinergic system in neurovascular regulation and functional hyperemia elucidates how the cholinergic deficit in AD contributes to the clinical and pathological features of this disease.