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While amyloid\u2010\u03b2 (A\u03b2) 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\n                    <jats:sup>18<\/jats:sup>\n                    F\u2010MK6240 tau positron emission tomography (PET) and peripheral inflammation across stages defined by A\u03b2 burden and neuronal injury in\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009132 (64.5\u2009\u00b1\u20093.4\u2009years old, 69.7% female, 10.7\u2009\u00b1\u20094.0\u2009years of education, 34.1% APOE4 carriers) cognitively unimpaired late middle\u2010aged Hispanic adults.\n                    <jats:sup>18<\/jats:sup>\n                    F\u2010MK6240 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 A\u03b2 or tau load but exhibited robust associations with neuronal injury (plasma NfL). Importantly, the hallmark biomarkers of AD proteinopathy (A\u03b2 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, A\u03b2 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.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70222-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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