J Neurol Neurosurg Psychiatry 76:1194-1199 doi:10.1136/jnnp.2004.054445
  • Paper

Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people

  1. D A Bennett1,2,
  2. J A Schneider1,2,
  3. R S Wilson1,2,
  4. J L Bienias3,
  5. E Berry-Kravis2,
  6. S E Arnold4
  1. 1Rush Alzheimer’s Disease Center, USA
  2. 2Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
  3. 3Department of Internal Medicine, Rush Institute for Healthy Aging, USA
  4. 4The Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA, USA
  1. Correspondence to:
 Dr D A Bennett
 Rush Alzheimer’s Disease Center, Armour Academic Center, 600 South Paulina, Suite 1028; Chicago, IL. 60612;
  • Received 19 September 2004
  • Accepted 4 January 2005
  • Revised 18 November 2004


Background: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood.

Objective: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death.

Methods: There were 44 subjects with clinically diagnosed Alzheimer’s disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education.

Results: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load.

Conclusion: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.


  • This study was supported by National Institute on Aging grants R01 AG15819, P30 AG10161.

  • Competing interests: none

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