Amyloid-beta deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression

Willem Huijbers*, Elizabeth C. Mormino, Aaron P. Schultz, Sarah Wigman, Andrew M. Ward, Mykol Larvie, Rebecca E. Amariglio, Gad A. Marshall, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

120 Citations (Scopus)


In a 3-year longitudinal study, Huijbers et al. observe increased hippocampal activation, faster rates of hippocampal atrophy, and clinical progression in patients with mild cognitive impairment with elevated levels of amyloid-beta. Amyloid-beta accumulation likely contributes to abnormal neuronal activity on the trajectory towards Alzheimer's disease dementia.Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity-consistent with findings in genetic at-risk populations-and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-beta, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-beta deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-beta status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-beta positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-beta negative patients with mild cognitive impairment. Longitudinally, amyloid-beta positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-beta status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-beta positive patients with mild cognitive impairment are more likely on a path towards Alzheimer's disease dementia than amyloid-beta negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-beta induced excitoxicity.

Original languageEnglish
Pages (from-to)1023-1035
Number of pages13
Publication statusPublished - 1 Apr 2015
Externally publishedYes


  • amyloid deposition
  • MCI
  • hippocampal activation
  • functional MRI
  • clinical progression

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