Boccalini_2025_Handb.Clin.Neurol_211_137

The cholinergic system plays a central role in cognition and neural function, and, in Alzheimer disease (AD) and Lewy body disease (LBD), it has profound implications for cognitive impairment and dementia. The cholinergic forebrain pathway, innervating the neocortex and limbic system, is crucial for learning, memory, and other essential aspects of cognition and plays a wider role in promoting neuronal plasticity. Given the neuroplasticity processes characterizing the cholinergic regions, this system may be sensitive to modulatory phenomena such as cognitive reserve (CR). The concept of CR has been introduced to account for the fact that individual clinical presentation might be milder than expected based on neuropathology. This mismatch can be explained by individual brain reserve (BR) buildup on life experiences, lifestyles, and neurobiologic factors that are associated with resilience. Sparse findings exist suggesting that the CR might result in an increased or preserved function of the cholinergic system in AD patients, and compensatory mechanisms in the early stages of LBD. The limited availability of effective treatment for neurodegenerative dementia emphasizes the importance of CR and BR, as they play a major role in delaying or slowing disease onset and progression. This chapter will describe the involvement of the cholinergic system in neurodegenerative diseases and the tools for the in vivo assessment, focusing specifically on the evidence suggesting the possibility of its modulation by CR.