Peripheral immune cell imbalance is associated with cortical beta-amyloid deposition and longitudinal cognitive decline

Neuroinflammation is believed to be a key process in Alzheimer's disease (AD) pathogenesis. Recently, the neutrophil-to-lymphocyte (NLR) and lymphocyte-to-monocyte ratios (LMR) have been proposed to be useful peripheral markers of inflammation. However, it is unclear how these inflammatory ratios relate to AD pathology, such as β-amyloid (Aβ) plaques and tau tangles. Using ¹⁸F-florbetapir and ¹⁸F-flortaucipir positron emission tomography (PET), we sought to determine how the NLR and LMR are associated with AD pathology both cross-sectionally and longitudinally. We further evaluated associations between the NLR and LMR and longitudinal cognitive decline. Using data from the Alzheimer's Disease Neuroimaging Initiative, we analyzed blood, PET, and cognitive data from 1544 subjects-405 cognitively normal, 838 with mild cognitive impairment (MCI), and 301 with AD. Associations between the NLR and LMR and Aβ and tau on PET were assessed using ordinary least-squares and mixed-effects regression models, while adjusting for age, sex, years of education, and apolipoprotein E ε2 or ε4 carrier status. Associations between the NLR and LMR and cognitive function, as measured by the AD Assessment Scale-Cognitive Subscale, 13-item version, were also assessed. MCI and AD subjects had higher NLR (p = 0.017, p < 0.001, respectively) and lower LMR (p = 0.013, p = 0.023). The NLR, but not the LMR, was significantly associated with Aβ (p = 0.028), suggesting that higher NLR was associated with greater Aβ deposition in the brain. Neither the NLR nor the LMR was associated with tau deposition (p > 0.05). A higher NLR was associated with greater longitudinal cognitive decline (p < 0.001). A higher ratio of peripheral neutrophils to lymphocytes, possibly reflecting an imbalance in innate versus adaptive immunity, is related to greater Aβ deposition and longitudinal cognitive decline. As the field moves toward blood-based biomarkers of AD, the altered balance of innate versus adaptive immunity could be a useful biomarker of underlying pathology and may also serve as a potential therapeutic target.