Hierarchical Inference Dysfunction in Autism and Alzheimer's Disease: A Conceptual Predictive-Coding Framework From...

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are characterized by profound alterations in cortical circuit function, synaptic plasticity, and neuromodulatory regulation, leading to disrupted hierarchical integration of feedforward and feedback signaling. This review synthesizes evidence that these disorders represent opposing patterns of dysfunction within hierarchical cortical systems governing sensory integration and contextual modulation. Within a predictive coding framework, these alterations can be understood as disturbances in precision weighting, a process critically implemented by neuromodulatory systems. In ASD, neurodevelopmental alterations in excitatory-inhibitory balance, parvalbumin-positive interneuron function, laminar microcircuit organization, and neuromodulatory tuning bias cortical networks toward excessive bottom-up signaling and heightened synaptic gain, associated with increased gamma-band activity, local hyperconnectivity, and impaired contextual integration. In contrast, AD is marked by progressive degeneration of deep-layer pyramidal neurons, entorhinal-hippocampal circuits, and long-range feedback projections, together with cholinergic and dopaminergic depletion, disrupting beta- and alpha-mediated top-down coordination, impairing synaptic plasticity, and destabilizing large-scale networks such as the default mode system. Across the lifespan, these processes produce opposite distortions in hierarchical signal flow, namely hyper-reactive sensory processing in ASD and degraded generative control in AD. By integrating findings from laminar anatomy, interneuron vulnerability, oscillatory dynamics, and neuromodulatory systems, this review proposes a mechanistic framework linking microcircuit pathology to network dysfunction and clinical phenotypes. Dopaminergic, cholinergic, and noradrenergic systems emerge as key modulators of precision-related processes, positioning neuromodulation as a plausible pharmacological entry point for probing and potentially recalibrating hierarchical inference.