Aged dogs with cognitive impairment exhibit degeneration of noradrenergic neurons, which correlates with higher levels of Aβ deposits in the prefrontal cortex (Insua et al., 2010). Likewise, in human AD, locus coeruleus degeneration and loss of cortical noradrenergic neurons occurs already at early stage (Kelly et al., 2017). The activity of the canine cholinergic system also declines with age (Araujo et al., 2005b). Number of basal forebrain cholinergic neurons was significantly reduced in aged cognitively impaired dogs in comparison to aged cognitive unimpaired and young dogs, but unlike for noradrenergic neurons, this reduction of cholinergic neurons did not correlate with the extent of Aβ cortical load (Insua et al., 2012). As in CCD, cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are usually lost in AD (Whitehouse et al., 1981). In human patients, the cholinergic neurons appear most vulnerable to Aβ pathology, followed by glutamatergic and GABAergic neurons (Bell et al., 2006). The synaptic loss correlates with the disease progression and destruction of cholinergic neurons contributes to memory and attention deficits in AD (Terry et al., 1991). These alterations in neurotransmitter systems, with reduced neuronal and synaptic function have also been observed in dogs (Landsberg et al., 2012) and result in clinical symptoms of CCD. The employment of the canine model to examine the effect of the cholinesterase inhibitors in treatment of CCD is described in details under “Treatment and drug development”.