Ontogenetic abnormalities in the regulation of the cortical cholinergic input system are hypothesized to mediate early-life cognitive limitations (ECL) that later escalate, based on reciprocal interactions between a dysregulated cholinergic system and age-related neuronal and vascular processes, to mild cognitive impairment (MCI) and, subsequently, for a majority of subjects, senile dementia. This process is speculated to begin with the disruption of trophic factor support of the basal forebrain ascending cholinergic system early in life, leading to dysregulation of cortical cholinergic transmission during the initial decades of life and associated limitations in cognitive capacities. Results from neurochemical and behavioral experiments support the possibility that aging reveals the vulnerability of an abnormally regulated cortical cholinergic input system. The decline of the cholinergic system is further accelerated as a result of interactions with amyloid precursor protein metabolism and processing, and with cerebral microvascular abnormalities. The determination of the developmental variables that render the cortical cholinergic input system vulnerable to age-related processes represents an important step toward the understanding of the role of this neuronal system in the age-related decline in cognitive functions.