Androgens Protect against Apolipoprotein E4-Induced Cognitive Deficits

Jacob Raber, Gerold Bongers, Anthony LeFevour, Manuel Buttini, Lennart Mucke

Research output: Contribution to journalArticlepeer-review

164 Scopus citations


Compared with apolipoprotein (apo) E2 and E3, apoE4 increases the risk of Alzheimer's disease (AD), but it remains unknown how apoE4 affects neuronal function. ApoE4 interacts with female gender, further increasing the risk of AD and decreasing treatment response. Female mice are also more susceptible to apoE4-induced impairments of spatial learning and memory than male mice. To assess the role of sex steroids in this process, we studied mice deficient in mouse apoE (Apoe-/-) and expressing human apoE4 or apoE3 in the brain at comparable levels. Even brief periods of androgen treatment improved the memory deficits of female apoE4 mice. Female apoE3 mice had no memory deficits and did not benefit from the treatment. ApoE4 male mice, which performed normally in a water-maze test at baseline, developed prominent deficits in spatial learning and memory after blockade of androgen receptors (ARs), whereas apoE3 male mice did not. Untreated apoE4 mice had significantly lower cytosolic AR levels in the neocortex than wild-type, Apoe-/-, and apoE3 mice. Improved memory in androgen-treated female apoE4 mice was associated with increased cytosolic AR levels. Our findings suggest that apoE4 contributes to cognitive decline by reducing AR levels in the brain, and that stimulating AR-dependent pathways can reverse apoE4-induced cognitive deficits.

Original languageEnglish (US)
Pages (from-to)5204-5209
Number of pages6
JournalJournal of Neuroscience
Issue number12
StatePublished - Jun 15 2002


  • Androgen receptor
  • Dihydrotestosterone
  • Hydroxyflutamide
  • Novel object recognition
  • Spatial learning and memory
  • Testosterone
  • apoE

ASJC Scopus subject areas

  • General Neuroscience


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