title: APOE2 eases cognitive decline during Aging: Clinical and preclinical evaluations.
abstract: OBJECTIVE
  Apolipoprotein E (apoE), a major cholesterol carrier in the brain, is associated with a strong risk for Alzheimer disease. Compared to the risky APOE4 gene allele, the effects of the protective APOE2 gene allele are vastly understudied, and thus need to be further clarified.
  
  
  METHODS
  We reviewed National Alzheimer's Coordinating Center clinical records and performed preclinical experiments using human apoE-targeted replacement (apoE-TR) mice, which do not show amyloid pathology.
  
  
  RESULTS
  Clinically, the APOE2 allele was associated with less cognitive decline during aging. This effect was also seen in subjects with little amyloid pathology, or after adjusting for Alzheimer disease-related pathologies. In animal studies, aged apoE2-TR mice also exhibited preserved memory function in water maze tests. Regardless, apoE2-TR mice showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress compared to apoE3-TR or apoE4-TR mice. Interestingly, apoE concentrations in the cortex, hippocampus, plasma, and cerebrospinal fluid (CSF) were positively correlated with memory performance across apoE isoforms, where apoE2-TR mice had higher apoE levels. Moreover, apoE2-TR mice exhibited the lowest levels of cholesterol in the cortex, despite higher levels in CSF and plasma. These cholesterol levels were associated with apoE levels and memory performance across apoE isoforms.
  
  
  CONCLUSIONS
  APOE2 is associated with less cognitive decline during aging. This can occur independently of age-related synaptic/neuroinflammatory changes and amyloid accumulation. Higher levels of apoE and associated cholesterol metabolism in APOE2 carriers might contribute to this protective effect. Ann Neurol 2016;79:758-774.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Longyu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Duane
authors.initials: D
authors.lastname: Linthicum
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Motoko
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.
authors.forename: Laura
authors.initials: L
authors.lastname: Price
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, Orlando, FL.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Frisch-Daiello
authors.affiliation: Sanford-Burnham Prebys Medical Discovery Institute, Orlando, FL.
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu