Altered cerebrospinal fluid-based clearance mechanisms in aging autistic adults

Background. Autistic adults demonstrate a 4–6-fold increased risk of unspecified dementia compared with the general population; however, the neurobiological substrates underlying this elevated risk remain unexplored. Alterations in cerebrospinal fluid–based mechanisms involved in brain metabolic waste clearance may represent a shared neuropathological pathway between autism spectrum disorder and dementia. Specifically, developmental deviations in cerebrospinal fluid-related imaging markers have been consistently reported in autistic infants, children, and adolescents, and brain amyloid and other metabolic waste accumulation is a hallmark of Alzheimer’s disease and related dementias. Despite this overlap, cerebrospinal fluid-based regulatory mechanisms have not been systematically examined in ageing autistic adults. Here, we used a multimodal magnetic resonance imaging approach to quantify structural and diffusion-based markers of cerebrospinal fluid regulation in middle-aged and older autistic adults compared with matched controls. Methods. Forty-nine autistic adults aged 30–73 years and 61 age-, sex-, and intelligence quotient–matched controls underwent T1-, T2-, and diffusion-weighted imaging. Measures included white matter perivascular space volume fraction, count fraction, and mean diameter; diffusion-based indices of fluid movement along perivascular pathways; and volumes of the lateral ventricles and choroid plexus. Results. With increasing age, autistic adults exhibited significantly greater increases in white matter perivascular volume fraction within the left inferior parietal lobule compared with controls. Autistic adults also showed significantly reduced diffusion indices and larger bilateral lateral ventricle and choroid plexus volumes relative to controls. Across both groups, increasing age was associated with higher white matter perivascular volume fraction in the right pars triangularis, reduced diffusion indices, and enlargement of the bilateral lateral ventricles and left choroid plexus. Limitations. First, the cross-sectional design limited our ability to quantify intra-individual variability and capture longitudinal trajectories. Second, the sample primarily comprised cognitively unimpaired autistic adults. Third, participants were predominantly of average or above-average intelligence; thus, findings may not generalize to autistic adults with ID. Finally, health factors including sleep disturbance, cardiovascular and metabolic disease, polypharmacy, and lifelong medication exposure, may have influenced these findings. Future large-scale studies should systematically evaluate their potential confounding and moderating effects. Conclusions. These findings demonstrate that ageing autistic adults exhibit convergent alterations in cerebrospinal fluid regulatory mechanisms, reflected in perivascular space morphology, diffusion-based fluid dynamics, and ventricular and choroid plexus enlargement. Together, the results link early developmental deviations to later-life vulnerability and highlight cerebrospinal fluid dysregulation as a potential candidate neurobiological substrate contributing to the increased prevalence of dementia in autistic adults.