Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Hum Brain Mapp. 2018 Feb;39(2):971-984. doi: 10.1002/hbm.23897. Epub 2017 Nov 21.


Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra-hippocampal white matter structure, in relation to the progression of well-accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid-β 1-42 (Aβ) and total-tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple-sibling familial history of AD. Apolipoprotein (APOE) ɛ4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated-tau (p-tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra-hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.

Keywords: APOE ɛ4; Alzheimer's disease; amyloid-β; cerebrospinal fluid biomarkers; fimbria; fornix; hippocampal subfields; preclinical; structural magnetic resonance imaging; tau.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Apolipoprotein E4 / genetics
  • Biomarkers / cerebrospinal fluid
  • Female
  • Genetic Predisposition to Disease
  • Hippocampus / diagnostic imaging*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neural Pathways / diagnostic imaging
  • Prodromal Symptoms
  • White Matter / diagnostic imaging
  • tau Proteins / cerebrospinal fluid


  • Amyloid beta-Peptides
  • Apolipoprotein E4
  • Biomarkers
  • MAPT protein, human
  • tau Proteins