Summary - Administrative Supplements (Parent R00 grant - R00AG062746; funding ends on 1/31/2024) For the Parent R00 grant, I proposed to employ integrated multi-omics methods to characterize age-related olfactory decline in Drosophila (see more details in the Research Strategy). Olfactory sensitivity decline is an early symptom of dementia and has a relatively high prevalence in different types of dementia, almost 100% in Alzheimer’s disease (AD), 90% in Parkinson’s disease and 15% in vascular dementias (1,2). Olfactory dysfunction in Alzheimer’s disease patients has been documented about 40 years ago (3). Several clinical studies have reported that combining olfactory function tests with conventional diagnostic methods can significantly increase the prediction accuracy of Alzheimer’s disease progress (4). Olfactory function test is relatively simple and normally non-invasive, and thus may be employed as a clinical marker for Alzheimer’s disease. However, olfactory dysfunction is frequently overlooked by both physicians and patients. One major reason is that it is difficult to distinguish age-related and Alzheimer’s disease-caused olfactory decline. To overcome this limitation, it is important to understand how aging and AD impact the olfactory system at the cellular and molecular level. Unfortunately, so far there is no study systemically addressing this question. Drosophila olfactory sensitivity significantly declines during aging and Alzheimer’s disease models, as in humans, but the mechanism is still a mystery. Here, I propose an extension of current studies in aging flies to AD fly models (Fig. 1), taking advantage of our accumulated tools and knowledge in the Drosophila olfactory system, as well as the scRNA-seq and cell-surface proteomics technologies we recently developed. We aim to characterize how aging and AD differentially impact olfactory receptor neuron integrity and glia-neuron interaction. Importantly, we will potentially identify olfactory changes that are specific to AD but not in normal aging condition, so that we can design specific olfactory function test to distinguish AD from normal aging. Thus, this supplement on one hand is a natural extension of our studies of the olfactory circuit decline during normal aging, and on the other hand can shed light into molecular mechanisms of glia- neuron interactions, dysfunctions of which have been implicated in AD. 1