The ability to employ advanced imaging technology to “see” both of the hallmark proteins of Alzheimer’s (amyloid and tau) in the living brain is a significant recent advance in the field. It may prove to be transformational not only in our understanding of the disease and its progression but also in its potential to accelerate drug discovery.

Jorge Sepulcre, MD, PhD, Harvard Medical School

According to Jorge Sepulcre, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, Boston, understanding the “spreading” phenomenon of abnormal tau and amyloid-beta proteins in the brain is critical to knowing what is causing the devastating cell damage and relentless symptoms of people with Alzheimer’s.

Sepulcre and colleagues developed a novel imaging approach to investigate the spreading pathways of tau and amyloid deposits over time, as well as their genetic vulnerabilities, in a longitudinal sample of elderly participants in the Harvard Aging Brain Study. Eighty-eight (88) study participants, average age about 76, were divided into two independent samples: (1) a cross-sectional sample of 69 people; and (2) a 1-2 year follow-up longitudinal sample of 19 subjects.

The researchers found that tau and amyloid appear to accumulate along distinctive pathways in the brain; the same communication pathways, or neural networks, we use for daily brain function. According to their findings, tau – which we know starts in the middle of the brain memory center – spreads forward and out toward the front of the brain. Amyloid, which starts in the back of the brain, spreads further back and outward from the middle. Specifically:
* Medial/inferior temporal lobe areas project pathways of Tau-spreading toward anterior pole, lateral and posteriomedial temporal cortex, and orbitofrontal cortex.
* Posterior cingulate cortex spreads Aβ toward surrounding areas and lateral parietal lobe.

The scientists discovered that 354 genes were significantly associated with the tau spreading pathway, including the MAPT gene, which was previously associated with Alzheimer’s disease risk. They also found 216 genes, including the CLU gene, significantly associated with the amyloid pathway. Additional analysis characterized the tau spreading genetic profile as “axon-related” and the amyloid-spreading genetic profile as “dendrite-related”. APOE, the gene with the highest impact on Alzheimer’s risk, was found to be the most central gene linking tau- and amyloid-spreading pathways.
“Our results reported at AAIC 2017 suggest that tau and amyloid advance through different brain systems over time,” Sepulcre said. “We also discovered certain genetic traits that may confer tau or amyloid vulnerability in the brain.”

“The findings may improve our ability to track responses to potential therapeutic interventions in the future,” Sepulcre added. “In addition, when more effective drug therapies become available, these results may help doctors determine which patients should get which therapies, and the optimum time to take them.”

Jorge Sepulcre, MD, PhD, et al. In Vivo spreading Pathways of Tau and Amyloid Accumulation and Its Genetic Underpinnings. (Funder(s): U.S. National Institutes of Health, Alzheimer’s Association)   July 2017   AAIC 2017 London, United Kingdom

source:  AAIC Press releases

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