More than 90% of people with Down syndrome (DS) are diagnosed with Alzheimer’s disease (AD) by ages 55–60. However, it remains unknown whether there is a difference in the structure of amyloid-β (Aβ) and tau filaments between AD in DS and AD. Now, a new study has determined whether differences exist between the protein structures by reporting on the structure of Aβ and tau filaments from two brains of people with DS.

“Just like in Alzheimer’s disease, the neuropathological phenotype in those with Down syndrome and Alzheimer’s disease is characterized by the presence of amyloid β (Aβ) and by abnormal accumulation of tau protein,” said Ruben Vidal, PhD, professor of clinical Alzheimer’s research at the Indiana University School of Medicine. “The structures of Aβ and tau filaments in Down syndrome have not been previously investigated, and it is unknown whether they are different from those of Alzheimer’s disease.”

This work is published in Nature Structural and Molecular Biology in the paper, “Cryo-EM structures of amyloid-β and tau filaments in Down syndrome.

The research team used cryo-EM in two individuals with both DS and AD. The study revealed two novel types of Aβ filaments in the vascular compartment with structures different from those previously reported in Alzheimer’s disease.

Researchers found that the protein structures of Aβ and tau filaments in people with both Down syndrome and Alzheimer’s disease have similarities to those found in Alzheimer’s disease. More specifically, the authors write that they found “two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau.”

“This study is the first comparison at the near atomic level of Aβ and tau filaments between individuals with both Down syndrome and Alzheimer’s disease and individuals with only Alzheimer’s disease,” Vidal said. “Importantly, the study found variations in the structure of Aβ, but no substantial variation in the structure of tau filaments between individuals with Alzheimer’s disease and both Down syndrome and Alzheimer’s disease. This supports the notion of common mechanisms operating in people with sporadic Alzheimer’s disease and in people with both Down syndrome and Alzheimer’s disease. This knowledge is crucial for understanding Alzheimer’s disease in people with Down syndrome and assessing whether adults with both conditions could be included in Alzheimer’s disease clinical trials. People with Down syndrome are living longer than ever, but almost all of them are dying of Alzheimer’s disease when they get older.”

Vidal said the study’s findings show it is important to include people with both DS and AD in clinical trials targeting the Aβ or tau filaments. He said there are similarities between the mechanisms at play in amyloid aggregation, but more research is needed to determine whether the differences observed in vascular Aβ deposition are unique to those with DS.

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