Peripheral Inflammation Is Associated With Greater Neuronal Injury and Lower Episodic Memory Among Late Middle‐Aged Adults

Elucidating the earliest biological mechanisms underlying Alzheimer's disease (AD) is critical for advancing early detection strategies. While amyloid-β (Aβ) and tau pathologies have been central to preclinical AD research, the roles of peripheral biological processes in disease initiation remain underexplored. We investigated patterns of ¹⁸F-MK6240 tau positron emission tomography (PET) and peripheral inflammation across stages defined by Aβ burden and neuronal injury in n = 132 (64.5 ± 3.4 years old, 69.7% female, 10.7 ± 4.0 years of education, 34.1% APOE4 carriers) cognitively unimpaired late middle-aged Hispanic adults. ¹⁸F-MK6240 tau PET imaging revealed early entorhinal and neocortical tau deposition even in individuals lacking biomarker evidence of neuronal injury as measured by plasma neurofilament light (NfL). Peripheral inflammatory markers were not directly associated with Aβ or tau load but exhibited robust associations with neuronal injury (plasma NfL). Importantly, the hallmark biomarkers of AD proteinopathy (Aβ and tau) did not show a significant association with episodic memory performance, whereas peripheral inflammation and plasma NfL markers demonstrated links to subtle episodic memory impairment. Furthermore, Aβ and tau deposition appeared primarily influenced by genetic predisposition and sex, whereas peripheral inflammation was strongly associated with both neuronal injury (plasma NfL) and comorbidities including higher Body Mass Index (BMI) and Diabetes Mellitus (DM). These findings reveal a complex interplay between central and peripheral mechanisms in the potential earliest phases of AD pathophysiology and argue for the integration of peripheral inflammatory and neurodegeneration markers into models of preclinical AD progression. Recognizing the heterogeneity of early biological changes could refine risk stratification, biomarker development, and preventative strategies targeting inflammation and vascular health in cognitively unimpaired individuals at risk for AD.