Elucidating the role of peripheral monocyte nicotinic acetylcholine receptors and inflammation in cognitive outcomes in older adults

Nicotinic acetylcholine receptors (nAChRs) are important regulators of brain and immune function that play critical roles in the neuropathology and progression of Alzheimer's disease and related dementias (ADRD). However, quantifying nAChRs in the brain remains elusive, and little is known about peripheral measures of nAChR in older adults or their relationship to cognition. Here, we examined associations between nAChR expression and immunoregulatory function in peripheral blood monocytes and cognitive performance among 167 older adults (age 72.3 ± 7.6 years; 71% female). Penalized linear and logistic regression were used to identify nAChR-related features in classical, intermediate, and nonclassical monocytes, as well as immunophenotypes, clinical and sociodemographic factors, associated with cognitive status (Montreal Cognitive Assessment; MoCA). Intermediate monocytes had the highest expression of alpha-7 nAChRs and greater ex vivo inflammatory responses (83.7% TNF-ɑ⁺ cells) relative to classical (68.4%, d = 1.98, P < 0.001) or nonclassical monocytes (58.9%, d = 3.20, P < 0.001). Participants with mild cognitive impairment (MCI: N = 76) had higher soluble CD14 levels (1777 ± 377 pg/uL) and greater anticholinergic medication burden (ACB; mean = 1.76) than normocognitive participants (NC: N = 91; 1638 ± 352 pg/uL sCD14, t₁₅₅ = 2.78, P = 0.006; mean ACB: 1.05, t₁₄₃ = 3.13, P = 0.002). Multivariate regression models indicated that stronger nAChR-mediated immunoregulation in intermediate monocytes was associated with higher MoCA scores (beta = 0.13) and 14% lower odds of MCI, as well as lower ACB (beta = - 2.10; 95% CI - 4.14, - 0.61). This study demonstrates that peripheral monocytes exhibit subset-specific differences in nAChR phenotypes in older adults and provides preliminary evidence for their association with cognitive function and a potential mediating role between ACB and cognitive impairment.