ABSTRACT Autism spectrum disorder (ASD) is typically described as a disorder of childhood; however, challenges in socioemotional behavior and cognition persist across the lifespan. Nearly 6 million adults in the United States currently live with ASD, with prevalence more than doubling in the last 10 years. Recent studies suggest that adults with ASD are twice as likely to develop dementia, and have an increased prevalence of age-related physical and psychiatric conditions. While brain and behavioral differences are well researched in children with ASD, a major gap in knowledge exists for the adult brain. The brains of individuals with ASD undergo an atypical developmental trajectory, marked by initial excess in volume, neuron density, and connectivity in childhood that is followed by a progressive reduction in cell number, myelin thickness, and synapses into adulthood. We propose that early neuronal excess and local over-connectivity, in concert with systemic neuroimmune dysregulation, may render the ASD brain vulnerable to age-related pathological and pro- inflammatory processes beginning in early adulthood that may ultimately lead to cellular dysfunction and later cognitive decline. Here we aim to determine the cell types affected as individuals with ASD age through adulthood and identify neuroinflammatory markers specific to those cells. We will utilize a unique sample of clinically and genetically characterized human postmortem adult brains, examining regions implicated in the socioemotional and neurobiological impairments of ASD and aging. We hypothesize that aberrant immune activation of pro-inflammatory processes contribute to the altered trajectory of brain development, as well as deleterious neuropathogenic protein aggregations associated with cognitive decline. We will utilize unbiased transcriptomic methods to determine which genes may be differentially expressed in specific cell groups, and assays to determine which proteins, including cytokines, may be disproportionately affected with age in ASD (Aim 1). Informed by these results, we will carry out a systematic examination of the expression of high-priority markers in specific cell types with preserved spatial information in brain tissue sections (Aim 2). Finally, we will examine the effects of neuroinflammation and aging in ASD on the synaptic connections between neurons (Aim 3). These critical, discovery-driven studies will serve as an essential first step to characterize cellular and molecular processes associated with brain aging in ASD, and provide a fundamental platform upon which mechanistic studies and animal models can be built. This project will define the neuropathological features associated with brain aging in ASD and correlate these variables with extensive clinical and genetic information for each subject, in support of precision medicine. Ultimately, we aim to shift the mindset of autism research toward the view of adulthood not as an endpoint, but as part of a trajec...