Study Confirms Role of Structural Connectivity in Spread of Alzheimer’s Disease Pathology

In Alzheimer’s, the proteins amyloid-beta and tau begin to accumulate in the brain many years before any clinical signs of the disease are evident. Propagation of these proteins throughout the brain has been linked to cognitive decline in Alzheimer’s, but exactly how they spread has long been a mystery.

In a study reported in the journal Nature Neuroscience on February 5, the MGH Martinos Center’s Heidi Jacobs and colleagues have shed new light on the question. The researchers looked at 256 older individuals enrolled in the Harvard Aging Brain Study and found evidence that tau propagates through structural connections in the brain. Importantly, this spread seems to be driven by amyloid pathology. The findings thus confirmed the interrelated contributions of of amyloid, tau and specific structural connections to memory decline in preclinical Alzheimer’s.

Animal models of Alzheimer’s have suggested the importance of connectivity in the spread of the proteins. Jacobs and colleagues were able to establish this in vivo in humans using the recently developed positron emission tomography (PET) tracer flortaucipir (FTP) in conjunction with established diffusion tensor imaging (DTI) methods and amyloid PET imaging.

The study has wide-ranging implications for Alzheimer’s and other disorders. “These findings are important for current disease models,” said Jacobs, first author of the Nature Neuroscience paper, “to better understand the mechanisms underlying the interaction between amyloid and tau pathology and how these pathologies drive neurodegeneration and cognitive decline. Furthermore, these findings are important for designs of future clinical trials, suggesting that it will be important that drugs target amyloid pathology early in the disease process, before tau pathology has spread outside the medial temporal lobe. This means that trials should also consider monitoring tau pathology.”

Authors of the paper also include Trey Hedden, Aaron Schultz, Jorge Sepulcre, Rodrigo Perea and Reisa Sperling of the Martinos Center, and Rebecca Amariglio, Kathryn Papp, Dorene Rentz of the MGH Department of Neurology. The study was led by Keith Johnson of the Gordon Center for Medical Imaging at MGH.