Work

From developmental divergence to degenerative vulnerability: convergent molecular mechanisms linking autism spectrum disorder and Alzheimer’s disease

Year: 2026

Type: review

Abstract: Neurodevelopmental disorders (NDDs) and neurodegenerative diseases (NDEs) have long been regarded as temporally and mechanistically distinct: NDDs such as autism spectrum disorder (ASD), Fragile X syndrome, Prader-Willi syndrome, and Phelan-McDermid syndrome arise during critical periods of brain maturation, whereas NDEs such as Alzheimer's disease (AD) manifest later with progressive neuronal loss, protein aggregation, and cognitive decline. Accumulating genetic, molecular, cellular, and epidemiological data now suggests substantial overlaps, indicating that diverse genetic and environmental insults converge on a limited set of shared biological pathways across the lifespan. Large-scale genomic analyses have identified at least 148 genes shared between ASD and AD, but this overlap should be understood as a shared regulatory architecture rather than evidence of a common causal pathway. About half of these genes are linked to the mTOR signaling pathway, which regulates protein synthesis, autophagy, and synaptic homeostasis. Epidemiological studies indicate an increased occurrence of early-onset dementia among adults with ASD, although available studies do not establish that this association is specific to Alzheimer's disease or to idiopathic ASD. Both conditions involve dysregulation of synaptic scaffolding (e.g., SHANK3), epigenetic regulation (including G9a/EHMT2-mediated H3K9 methylation), complement-dependent synaptic pruning, mitochondrial and metabolic homeostasis, neuro-inflammation, and glymphatic clearance. We propose a unifying framework, presented as a testable hypothesis rather than an established mechanism, in which NDDs and NDEs represent distinct temporal manifestations within a shared evolutionary trade-off landscape balancing developmental connectivity, metabolic cost, and long-term proteostatic resilience. Within this landscape, convergent nodes-mTOR-autophagy, G9a/EHMT2-mediated chromatin regulation, complement-mediated pruning, and glymphatic function-may contribute to differences in early circuit formation and have been proposed as potential sources of later vulnerability. The APP-FMRP-mGluR5 axis further illustrates molecular convergence between monogenic NDDs and pathways relevant to AD. This review uses ASD and AD as paradigmatic examples to illustrate how heterochronic disruptions in synaptic maturation and proteostasis may create a lifespan continuum from atypical neurodevelopment to accelerated degeneration, while explicitly noting that this framework remains a testable hypothesis and does not establish a causal progression from ASD to AD. Recognizing these shared nodes opens avenues for transdiagnostic biomarkers, longitudinal risk stratification, and multitarget therapies-including epigenetic modulators, mTOR regulators, and glymphatic enhancers-that may benefit both ends of the continuum.

Source: Frontiers in Molecular Neuroscience

DOI: 10.3389/fnmol.2026.1963972