From developmental divergence to degenerative vulnerability: convergent molecular mechanisms linking autism spectrum disorder and Alzheimer’s disease
6 affiliations
- 1Department of Pharmacology, Toxicology, and Therapeutic Chemistry, University of Barcelona, Barcelona, Spain
- 2Institute of Neurosciences of the University of Barcelona, University of Barcelona, Barcelona, Spain
- 3Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
- 4Departamento de Neurociencias, Instituto de Neurociencias Traslacionales, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
- 5División de Neurociencias Clínica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City, Mexico
- 6Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Mexico City, Mexico
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.
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BibTeX
@article{grinanferre2026from,
title = {{From developmental divergence to degenerative vulnerability: convergent molecular mechanisms linking autism spectrum disorder and Alzheimer’s disease}},
author = {Christian Griñán-Ferré and Fahad Hussain and Aina Bellver-Sanchis and Núria Pérez-Salvador and Yeminia Valle and Daniel Ortuño-Sahagún and Oscar Arias-Carrión},
journal = {Frontiers in Molecular Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnmol.2026.1963972},
url = {https://doi.org/10.3389/fnmol.2026.1963972},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - From developmental divergence to degenerative vulnerability: convergent molecular mechanisms linking autism spectrum disorder and Alzheimer’s disease
AU - Christian Griñán-Ferré
AU - Fahad Hussain
AU - Aina Bellver-Sanchis
AU - Núria Pérez-Salvador
AU - Yeminia Valle
AU - Daniel Ortuño-Sahagún
AU - Oscar Arias-Carrión
PY - 2026
DA - 2026/10/21
JO - Frontiers in Molecular Neuroscience
DO - 10.3389/fnmol.2026.1963972
UR - https://doi.org/10.3389/fnmol.2026.1963972
AB - 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.
SN - 1662-5099
ER -