Alzheimer’s disease (AD) is a progressive irreversible neurodegenerative disorder that occurs gradually and results in cognitive impairment, unusual behavior, personality changes, and ultimately death. Intracerebroventricular (ICV) route is the favored route of drug administration as it allows the drug to be directly injected to the appointed site and bypasses the blood-brain barrier. In vitro and ex vivo models are discussed. Cultures of rat cerebral cortical and hippocampal neurons are used to evaluate various intracellular mechanisms involved in synaptic plasticity, neuronal development and learning, and memory. Acetylcholinesterase activity method aims to determine the rate of hydrolysis of acetylthiocholine (ATCh) by acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) in tissues taken from the laboratory rat or dog. In vivo models are described. The development of animal models mimicking the complex pathogenesis and clinical symptoms of AD still represents a challenge for the preclinical investigators. Behavioral paradigms to assess learning and memory are described. Passive avoidance explains the step-down model. This is a classical model for the assessment of cognitive performance after inducing brain lesions. Active avoidance explains step-through model. Active avoidance is induced by a sequence of conditioned and unconditioned stimuli to the animal. Mazes are traditional tools for assessing learning and memory performance in laboratory animals. Nootropic agents are effectively screened using this paradigm in scopolamine-induced dementia. Elevated Plus Maze, Radial Maze, Y Maze, and Figure 8 Maze are based on this phenomenon. Conditioned avoidance response (CAR) is discussed. This test characterizes the influence of the compound on both learning ability and memory (retention of the avoidance behavior after extinction period, that is, the rest period without training and drug treatment). Microdialysis of acetylcholine release is explained. In vivo microdialysis techniques can be used to estimate the cholinergic neuronal activity in the hippocampus of freely moving rats.