Table 1.

Potential Overlapping Mechanisms of Cholinergic Deficiency in AD and Delirium

Mechanism	Finding in AD	Potential Parallels in Delirium
ApoE4 protein	Cholinergic neuron death: βA tightly binds ApoE4, making the latter unavailable for mobilizing phosphatidylcholine in ACh synthesis. ApoE4 exacerbates this by accelerating APP cleaving into βA and impairing βA clearance (55)	Cholinergic neuron apoptosis: Thiamine deficiency can cause neuronal death by mechanisms similar to ApoE, depleting precursors for ACh synthesis (Figure 2, Item 3) (17) Symptomatic link: APOE-ε4 allele associated with longer duration of delirium, poorer recovery (52,60)
ChAT downregulation	ChAT synthesis: Proportionally downregulated with each APOE-ε4 allele; ChAT catalyzes key step of ACh synthesis (56)	Selective ChAT+ neuron reduction: By stressor-induced cytokine release in rat forebrains (Figure 2) (28)
AChE dysregulation	AChE inhibitors: Dysregulated AChE levels cause excess of AChE that can lead to cholinergic deficits. AChE inhibitor drugs are currently first-line treatment, prolonging the effects of ACh by preventing its hydrolysis, inactivation in synaptic clefts	AChE inhibitors: Theoretically therapeutic, donepezil undergoing clinical trials has not demonstrated statistically significant delirium prevention, treatment (58,59)
Cytokine polymorphisms	IL-1α, 6: Polymorphisms in these cytokines linked with decreased ACh synthesis (68,69)	Decreased ACh synthesis: Due to proinflammatory cytokines released during stress (Figure 2) (70)
Cytokine excess	Elevated IL-1, TNF-αlevels: Inhibit IGF-1, which protects against cholinergic neuron apoptosis and deleterious βA binding (64)	IGF-1 inhibition: By proinflammatory cytokines released during stress prevents neuroprotection of injured brain (Figure 2) (27)

Note: AD = Alzheimer’s disease; ApoE = apolipoprotein E; βA = β-amyloid; APP = amyloid precursor protein; Ach = acetylcholine; ChAT = choline acetyltransferase; AChE = acetylcholinesterase; IL-1 = interleukin-1; TNF-α= tumor necrosis factor-α; IGF-1 = insulin-like growth factor-1.