DOI: 10.1002/alz.083183 ISSN: 1552-5260

Altered resting state hippocampal connectivity associated with amyloid and tau in older adults without dementia from a population‐based cohort study

Anna T Roberts, Carmen Andreescu, Annie Cohen, Victor L Villemagne, Brian J. Lopresti, Neelesh K. Nadkarni, Davneet S Minhas, Charles M Laymon, Beth E. Snitz, Helmet T. Karim
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Alzheimer’s disease (AD) is characterized by amyloid beta plaques and tau‐containing neurofibrillary tangles with disrupted (high and low) resting state hippocampal connectivity. One potential factor that may underlie these differences is that early stages of disease may contribute to greater connectivity and later stages may contribute to lower connectivity (i.e., quadratic associations between amyloid/tau and connectivity). Early stages may be associated with greater recruitment of intranetwork connectivity to compensate, which fails at later stages. Late stages may be associated with greater recruitment of internetwork connectivity, that fails in advanced cognitive impairment. Understanding these dynamics may help us understand resilience to amyloid and tau in cognitively unimpaired individuals.


We recruited 115 adults >65 years old (67‐96, mean 76years) from a population‐based study into a neuroimaging sub‐study. The study area is a formerly heavy manufacturing industrial small‐town area. Participants (106 (92%) CU with CDR = 0) underwent PET imaging for amyloid (PiB) and tau (AV‐1451) and global SUVR measures were computed after appropriate preprocessing. Participants underwent resting state fMRI and hippocampal connectivity was computed for the left/right and anterior/posterior hippocampus. Regression analyses between connectivity and both linear and quadratic terms for amyloid and tau were adjusted for age, sex, race, and education. We adjusted for multiple comparisons using SnPM with FWE correction with α = 0.05 (p‐value threshold of 0.001).


We found a negative quadratic association between left anterior hippocampus with default mode network (DMN) including the posterior cingulate and supramarginal gyrus, where greater amyloid and lower amyloid was associated with low connectivity. Similar effects were found for the right anterior hippocampus. Right anterior hippocampus to cuneus connectivity shows positive U‐shape with amyloid but negative linear relationship with tau. Greater right anterior hippocampus‐inferior parietal and right posterior hippocampus‐inferior temporal connectivity was associated with greater tau. Left posterior hippocampus to left middle temporal showed negative U‐shape with tau.


Amyloid and tau showed complex inverse U‐shaped associations between heightened intranetwork connectivity and moderate amyloid/tau, but low connectivity with higher severity. Internetwork connectivity was heightened with greater tau. These may reflect altered connectivity due to changes in amyloid and tau in older adults without dementia.

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