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J Neurosci. 2019 Jan 16;39(3):548-556. doi: 10.1523/JNEUROSCI.1397-18.2018. Epub 2018 Nov 27.

Tau Accumulation in Clinically Normal Older Adults Is Associated with Hippocampal Hyperactivity.

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Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114,
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129.
Jheronimus Academy of Data Science, Department of Cognitive Science and Artificial Intelligence, Tilburg University, 5037 AB, Tilburg, the Netherlands.
Harvard Aging Brain Study, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720, and.
Neurology Department, Saint-Luc University Hospital, 1200 Brussels, Belgium.
Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.


Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-β proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-β accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-β and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-β accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment.SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-β and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.


Alzheimer's disease; PiB; excitotoxicity; fMRI; flortaucipir; memory

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