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

Abstract

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-␤proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-␤ accumulation, apolipoprotein 4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-␤ 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-␤ 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.

FDG-PET hypermetabolism is associated with higher tau-PET in mild cognitive impairment at low amyloid-PET levels

“…One possibility to reconcile the findings is that tau enhances amyloid-related neuronal hyperactivity at lower levels of amyloid, but reduces neuronal function at higher levels of amyloid. This stance would be in agreement with results from previous studies in humans reporting tau-PET but not amyloid-PET to be linked to fMRI-assessed hyperactivation [35] or FDG-PET hypermetabolism [15,16]. Furthermore, we observed FDG-PET hypermetabolism in the group of amyloid-negative/high-tau but not amyloid-positive/ low-tau suggesting that higher levels of tau in the presence of lower levels of amyloid are decisive for FDG-PET hypermetabolism.…”

Distinct disease‐sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients

“…Therefore, a reduced activity in this GABAergic population could promote hyperactivity in the entorhinal cortex and, consequently, hyperexcitability across the hippocampus . Interestingly, the hippocampal hyperactivity has also been associated with the spread of tau pathology before the clinical symptoms of AD .…”

SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model

“…Functional brain imaging studies in humans provide evidence that neuronal network hyperexcitability occurs in vulnerable brain regions early in the disease process and even before cognitive impairment is evident (Putcha et al, 2011;Huijbers et al, 2019). Studies of animal models of AD that exhibit A␤ and/or pTau pathology have consistently demonstrated hyperexcitabil-ity of neuronal circuits in the hippocampus and cerebral cortex (Verret et al, 2012;Martinez-Losa et al, 2018).…”