Significance box Mammalian central nervous system (CNS) non-parenchymal macrophages (border-associated macrophages, BAMs) play distinct roles from parenchymal microglia in supporting neurophysiology during adulthood and aging; they help to prevent the dissemination of infectious agents, or respond to Alzheimer’s disease (AD)-like brain pathology and inflammation. We postulate that the acquisition of an enduring deleterious phenotype by brain BAMs (in response to repeated infections or inflammatory insults) is at the genesis of accelerated cognitive decline in the elderly and in the development of AD. Highlights Border-associated macrophages (BAMs) in the brain are transcriptionally and phenotypically distinct from microglia as shown in mice and humans. BAMs promote brain glymphatic cleansing at steady state, and their homeostatic polarization correlates with proper cognitive function in mice. BAMs play an active role during murine infections by limiting microbial dissemination into the brain. Accordingly, BAMs can be replaced by peripheral monocytes and undergo a long-lasting transcriptional reprogramming which affects their homeostatic signature and could compromise their ability to sustain brain function. With aging, BAMs become major histocompatibility complex type II high (MHC-IIhigh) and cease to degrade the extracellular matrix, contributing to defects in vascular and glymphatic functions in mice. In mice and humans, BAMs, like microglia, express genes that alter the risk for Alzheimer’s disease (AD), including TREM2 and APOE. The depletion of BAMs in a mouse model of AD-like brain amyloidosis led to worsened Aβ accumulation and deposition. By contrast, BAMs respond to increased Aβ pathology by secreting osteopontin that exacerbates microglial activation and synaptic pruning in mice. We propose that BAM dysfunction following serial infections or other inflammatory insults contributes to accelerated brain aging and a higher risk for AD development in mice and humans. Abstract Mammalian brain border-associated macrophages (BAMs) are strategically positioned to support vital properties and processes: for example, the composition of the brain’s perivascular extracellular matrix and cerebrospinal fluid flow via the glymphatic pathway. BAMs also effectively restrict the spread of infectious microbes into the brain. However, while fighting infections, BAMs sustain long-term transcriptomic changes and can be replaced by inflammatory monocytes, potentially leading to a gradual loss of their beneficial homeostatic functions. We hypothesize that by expediting the deterioration of BAMs, multiple infection episodes might be associated with accelerated brain aging and the putative development of neurodegenerative diseases. Our viewpoint is supported by recent studies suggesting that rejuvenating aged BAMs, and counterbalancing their detrimental inflammatory signatures during infections, might hold promise in treating aging-related neurological disorders, including Alzheimer’s disease (AD).