White Matter Connects Autism and Alzheimer’s

Many studies have linked proteins in Alzheimer’s Disease (AD) pathways to the increased production of white matter and increased brain growth correlated with Autism Spectrum Disorder (ASD). It has been hypothesized, but not proven, that the excess white matter in ASD brains explains their differential development and behavior. One specific protein, amyloid precursor protein (APP), secretes a metabolite called sAPPα that can increase myelination of neurons in the brain. Myelin—produced by glial cells in the central nervous system called oligodendrocytes—plays an essential role in neuron communication because it enhances electrical signals. Essentially, myelin serves as a conductor for nerve signals to travel faster. This relates to ASD because there is thought to be altered synaptic transmission (nerve communication) and connectivity in ASD individuals.

White matter in the brain is composed of the myelinated axons of neurons, so an increase in APP metabolites can be associated with the increased white matter of children with ASD. The diagram below effectively summarizes the pathway of elevated levels of sAPPα and its effect on ASD endophenotypes like regression. Regression is when a child in the first few months of life develops normally and then suddenly stops hitting these developmental milestones. Common reports of regression in children with ASD include sudden loss of vocabulary or not responding to their own names.

In patients with Alzheimer’s, a dysregulation in APP processing leads to the production of sAPPβ as opposed to sAPPα. Too much beta-amyloid or its slow clearance can lead to buildup of oligomers that are biomarkers of AD. These are the classic amyloid plaques (misfolded proteins) found in the brains of Alzheimer’s patients. There seems to be an inverse relationship between AD and ASD in terms of the mechanisms behind the amyloidogenic pathway, and this could have numerous novel implications in the understanding, pharmacology, and treatment of both.

Beta-amyloid is not typically seen in rich white matter. Consequently, reduction of MBP—an important protein component of myelin—may lead to increased beta-amyloid and brain atrophy of AD, while increased MBP may lead to brain growth of ASD. This study paves the way for future ASD research by utilizing our current knowledge of treatment for AD. New studies synthesizing amyloid precursor protein and its metabolites, hypermyelination, and white matter and brain growth can act as the foundation for future research on ASD.

References:

Sokol, D. K., Maloney, B., Westmark, C. J., & Lahiri, D. K. (2019). Novel Contribution of Secreted Amyloid-β Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder. Frontiers in Psychiatry, 10, 165.