Tau PET in autosomal dominant Alzheimer's disease: Relationship with cognition, dementia and other biomarkers

Brian A. Gordon, Tyler M. Blazey, Jon Christensen, Aylin Dincer, Shaney Flores, Sarah Keefe, Charles Chen, Yi Su, Eric M. McDade, Guoqiao Wang, Yan Li, Jason Hassenstab, Andrew Aschenbrenner, Russ Hornbeck, Clifford R. Jack, Beau M. Ances, Sarah B. Berman, Jared R. Brosch, Douglas Galasko, Serge GauthierJames J. Lah, Mario Masellis, Christopher H. Van Dyck, Mark A. Mintun, Gregory Klein, Smiljana Ristic, Nigel J. Cairns, Daniel S. Marcus, Chengjie Xiong, David M. Holtzman, Marcus E. Raichle, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Tauopathy is a hallmark pathology of Alzheimer's disease with a strong relationship with cognitive impairment. As such, understanding tau may be a key to clinical interventions. In vivo tauopathy has been measured using cerebrospinal fluid assays, but these do not provide information about where pathology is in the brain. The introduction of PET ligands that bind to paired helical filaments provides the ability to measure the amount and distribution of tau pathology. The heritability of the age of dementia onset tied to the specific mutations found in autosomal dominant Alzheimer's disease families provides an elegant model to study the spread of tau across the course of the disease as well as the cross-modal relationship between tau and other biomarkers. To better understand the pathobiology of Alzheimer's disease we measured levels of tau PET binding in individuals with dominantly inherited Alzheimer's disease using data from the Dominantly Inherited Alzheimer Network (DIAN). We examined cross-sectional measures of amyloid-b, tau, glucose metabolism, and grey matter degeneration in 15 cognitively normal mutation non-carriers, 20 asymptomatic carriers, and 15 symptomatic mutation carriers. Linear models examined the association of pathology with group, estimated years to symptom onset, as well as cross-modal relationships. For comparison, tau PET was acquired on 17 older adults with sporadic, late onset Alzheimer disease. Tau PET binding was starkly elevated in symptomatic DIAN individuals throughout the cortex. The brain areas demonstrating elevated tau PET binding overlapped with those seen in sporadic Alzheimer's disease, but with a greater cortical involvement and greater levels of binding despite similar cognitive impairment. Tau PET binding was elevated in the temporal lobe, but the most prominent loci of pathology were in the precuneus and lateral parietal regions. Symptomatic mutation carriers also demonstrated elevated tau PET binding in the basal ganglia, consistent with prior work with amyloid-b. The degree of tau tracer binding in symptomatic individuals was correlated to other biomarkers, particularly markers of neurodegeneration. In addition to the differences seen with tau, amyloid-b was increased in both asymptomatic and symptomatic groups relative to non-carriers. Glucose metabolism showed decline primarily in the symptomatic group. MRI indicated structural degeneration in both asymptomatic and symptomatic cohorts. We demonstrate that tau PET binding is elevated in symptomatic individuals with dominantly inherited Alzheimer's disease. Tau PET uptake was tied to the onset of cognitive dysfunction, and there was a higher amount, and different regional pattern of binding compared to late onset, nonfamilial Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1063-1076
Number of pages14
JournalBrain
Volume142
Issue number4
DOIs
StatePublished - Jan 1 2019

Keywords

  • Alzheimer's
  • Amyloid
  • FDG
  • Flortaucipir
  • MRI

ASJC Scopus subject areas

  • Clinical Neurology

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    Gordon, B. A., Blazey, T. M., Christensen, J., Dincer, A., Flores, S., Keefe, S., Chen, C., Su, Y., McDade, E. M., Wang, G., Li, Y., Hassenstab, J., Aschenbrenner, A., Hornbeck, R., Jack, C. R., Ances, B. M., Berman, S. B., Brosch, J. R., Galasko, D., ... Benzinger, T. L. S. (2019). Tau PET in autosomal dominant Alzheimer's disease: Relationship with cognition, dementia and other biomarkers. Brain, 142(4), 1063-1076. https://doi.org/10.1093/brain/awz019