Chapter 12: Dementia: Causes, Symptomatic Treatments, and the Neurotransmitter Network Acetylcholine

Mild Cognitive Impairment represents an intermediate clinical state between normal aging and dementia, though not all patients with MCI progress to full dementia diagnosis. The four primary dementia etiologies discussed are Alzheimer disease, vascular dementia, Lewy body dementias, and frontotemporal dementia, each involving distinct neuropathological mechanisms. Alzheimer disease, the most prevalent form, involves amyloid-beta plaque accumulation, hyperphosphorylated tau protein aggregates forming neurofibrillary tangles, and progressive neuronal death. The Amyloid Cascade Hypothesis proposes that amyloid-beta accumulation initiates a pathological cascade leading to neurodegeneration, with disease progression conceptualized across three stages: presymptomatic asymptomatic amyloidosis, mild cognitive impairment, and full dementia. Pharmacological management of cognitive decline emphasizes augmentation of cholinergic neurotransmission through acetylcholinesterase inhibitors including donepezil, rivastigmine, and galantamine, each with distinct pharmacological profiles. Galantamine provides dual activity through enzyme inhibition and positive allosteric modulation of nicotinic acetylcholine receptors. Glutamate excitotoxicity is addressed using memantine, a noncompetitive NMDA receptor antagonist that selectively blocks pathological excessive signaling while preserving physiological neurotransmission essential for learning. Behavioral and psychological symptoms are managed through targeting specific dysfunctional neural circuits rather than broad receptor blockade. Psychotic symptoms including hallucinations and delusions respond to pimavanserin, a selective serotonin 5HT2A antagonist that avoids dopamine blockade risks. Agitation, characterized by excessive motor or verbal aggression and theorized to result from loss of cortical inhibitory control over limbic structures, is addressed using multimodal agents like brexpiprazole or the combination of dextromethorphan and bupropion. Depression and apathy in dementia present additional therapeutic challenges due to progressive degeneration of mood-regulating neural circuits. This chapter emphasizes that dementia pharmacotherapy requires understanding both the primary neurodegenerative process and the distinct neural networks underlying behavioral symptoms, informing selection of mechanism-specific agents rather than symptomatic polypharmacy.