Localized amyloid-β oligomers in the lateral entorhinal cortex drives olfactory dysfunction through aberrant neuronal...

Olfactory dysfunction is one of the most common early features of Alzheimer's disease (AD), yet its underlying neural mechanisms remains unclear. The lateral entorhinal cortex (LEC), a central node in the olfactory network, is among the earliest regions affected by AD pathology. However, the direct evidence supporting a causal link between LEC dysfunction and olfactory disorders in early AD is limited. In the present study, we explored whether and how LEC dysfunction contributes to early AD olfactory dysfunction by injecting amyloid-β_1-42 (Aβ_1-42) oligomers into the LEC to induce localized Aβ oligomers accumulation in this region. Our data demonstrate that localized Aβ oligomers in the LEC impaired odor detection and discrimination in mice. In vivo recordings revealed that Aβ oligomers increased baseline firing and odor-evoked activity in LEC neurons, while also enhancing odor-evoked beta oscillations. This hyperactive state corresponded with disrupted population-level odor decoding. Furthermore, deficits in synaptic structure and impaired synaptic transmission likely underlie the observed behavioral dysfunctions. Overall, these findings indicate that LEC dysfunction is linked to olfactory deficits in early AD, providing direct evidence for the involvement of this region in AD-related olfactory impairment.