The disproportionate evolutionary expansion of the human cerebral cortex with reinforcement of cholinergic innervations warranted a major rise in the functional and metabolic load of the conserved basal forebrain (BF) cholinergic system. Given that acetylcholine (ACh) regulates properties of the microtubule-associated protein (MAP) tau and promotes non-amyloidogenic processing of amyloid precursor protein (APP), growing neocortex predicts higher demands for ACh, while the emerging role of BF cholinergic projections in Aβ clearance infers greater exposure of source neurons and their innervation fields to amyloid pathology. The higher exposure of evolutionary most recent cortical areas to the amyloid pathology of Alzheimer's disease (AD) with synaptic impairments and atrophy, therefore, might involve attenuated homeostatic effects of BF cholinergic projections, in addition to fall-outs of inherent processes of expanding association areas. This unifying model, thus, views amyloid pathology and loss of cholinergic cells as a quid pro quo of the allometric evolution of the human brain, which in combination with increase in life expectancy overwhelm the fine homeostatic balance and trigger the disease process.

Center for Molecular and Behavioral Neuroscience Rutgers the State University of New Jersey Newark NJ USA

Department of Experimental Neurobiology National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic

Department of Experimental Neurobiology National Institute of Mental Health Topolová 748 250 67 Klecany Czech Republic; Department of Psychiatry and Medical Psychology 3rd Faculty of Medicine Charles University Ruská 87 100 00 Prague 10 Czech Republic

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruská 87 100 00 Praha 10 Czech Republic

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