Unlike familiar Alzheimer’s Disease (FAD) which is caused by mutations, most common sporadic disease (SAD) arises from a combination of risk factors including inflammation. This study aimed to explore and compare the effects of two pro-inflammatory agents: Western-diet (WD) and Lipopolysaccharide (LPS) of Gram-negative bacteria on initiation of AD molecular markers in the brain in the absence of AD mutations. To this aim, 3 months-old (mo) male C57BL/6J mice were divided into 3 groups: fed with WD, with Standard Diet (SD-CTR) and SD-fed mice injected 3 times with LPS (0.5mg/kg) at 3 mo. Mice were analyzed at 4, 8, 12, 16 mo for cerebral markers of insulin resistance (p-IRS-1 Ser616), tau pathology (p-Tau Thr231) and amyloid pathology (APP levels) in the brain regions where neuropathological progression of AD begins: entorhinal cortex (EC) and hippocampus (HIPP).Obtained results show that EC was particularly vulnerable to WD-induced insulin impairment, with elevated p-IRS-1 levels observed first at 8 months of age, followed by amyloidopathy at 16 month, but without changes in p-Tau levels. Conversely, LPS exposure in EC led to an increase in p-Tau levels in the absence of insulin resistance, suggesting an p-IRS-independent mechanism of action. HIPP didn’t show similar p-Tau or Aβ responses to LPS or WD.These findings show that both pro-inflammatory factors increase SAD risk, but via distinct mechanisms, impacting temporal lobe structures differently: in EC, WD by disrupting brain insulin signaling which triggered amyloidogenesis, while LPS through a pathway affecting p-tau levels independent on insulin signaling.