Project Summary/Abstract It is well known that human cortical neurons exhibit spontaneous firing in the absence of incoming exogenous and endogenous input. Across a neuronal population, these discharges summate with local dendritic currents and synaptic potentials to produce cortical rhythmic activity, which is often referred to as “spontaneous activity.” Such spontaneous rhythms are ubiquitous throughout the human brain, but their role in modulating cognition is only beginning to be understood. Recently, we used magnetoencephalography (MEG) to show that the strength of spontaneous activity directly affects neural oscillatory activity in the same cortical area, and in-turn modulates real time task performance in controls and person with HIV (PWH). Additionally, we have shown that spontaneous activity in multiple brain regions is accentuated and inextricably linked to oscillatory activity in patients with HIV- related cognitive impairment. In fact, our preliminary data suggests that the level of spontaneous activity in specific brain regions, as well as the dynamic interplay between these spontaneous rhythms and cortical oscillations, may be vital in identifying the degree of cognitive impairment in HIV-infected adults. The goals of the parent project are to quantify the trajectory of age-related elevations in spontaneous cortical activity in a large group of PWH and demographically-matched controls, and evaluate how the strength of such spontaneous activity affects neural oscillations and real time cognitive performance. In 2019-2020, we used an administrative supplement to extend our framework to include beta-amyloid positive patients with amnestic mild cognitive impairment (MCI) and mild-to-moderate Alzheimer’s disease (AD). This work has been broadly successful and resulted in groundbreaking publications in leading journals, with multiple other papers pending revision. With the proposed second administrative supplement, we will extend this work by adding tau-PET imaging to the overall cohort. Specifically, we will identify the role of aberrant spontaneous neuronal activity in AD, MCI, and PWH, and examine the spatial covariance between tau, beta-amyloid, and increased spontaneous neural activity in these patients. In line with our findings to date, spontaneous activity will be uniquely elevated in PWH, especially cognitively impaired PWH, and systematically decreased in patients with AD/MCI relative to cognitively normal controls. Further, amyloid burden will spatially covary with the strength of altered neural oscillations in those with AD/MCI, but not PWH who exhibit amyloid negativity like controls. Finally, we hypothesize that tau deposition will be significantly higher in those with AD/MCI relative to PWH, and that tau deposition will predict cognitive performance in those with AD/MCI but not PWH. Beyond providing a novel conceptual framework based on known neurophysiological principles to the study of AD/MCI, this supplement will provide...