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

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Rush Alzheimer's Disease Center, Armour Academic Center, 600 South Paulina, Suite 1028; Chicago, IL 60612, USA. dbennett@rush.edu

    , , , ,

    Source

    MeSH

    Aged
    Aged, 80 and over
    Alleles
    Alzheimer Disease
    Amyloid
    Apolipoprotein E4
    Apolipoproteins E
    Autopsy
    Case-Control Studies
    Cognition Disorders
    Female
    Humans
    Male
    Regression Analysis

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    16107349

    Citation

    Bennett, D A., et al. "Amyloid Mediates the Association of Apolipoprotein E E4 Allele to Cognitive Function in Older People." Journal of Neurology, Neurosurgery, and Psychiatry, vol. 76, no. 9, 2005, pp. 1194-9.
    Bennett DA, Schneider JA, Wilson RS, et al. Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. J Neurol Neurosurg Psychiatry. 2005;76(9):1194-9.
    Bennett, D. A., Schneider, J. A., Wilson, R. S., Bienias, J. L., Berry-Kravis, E., & Arnold, S. E. (2005). Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. Journal of Neurology, Neurosurgery, and Psychiatry, 76(9), pp. 1194-9.
    Bennett DA, et al. Amyloid Mediates the Association of Apolipoprotein E E4 Allele to Cognitive Function in Older People. J Neurol Neurosurg Psychiatry. 2005;76(9):1194-9. PubMed PMID: 16107349.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people. AU - Bennett,D A, AU - Schneider,J A, AU - Wilson,R S, AU - Bienias,J L, AU - Berry-Kravis,E, AU - Arnold,S E, PY - 2005/8/19/pubmed PY - 2005/9/15/medline PY - 2005/8/19/entrez SP - 1194 EP - 9 JF - Journal of neurology, neurosurgery, and psychiatry JO - J. Neurol. Neurosurg. Psychiatry VL - 76 IS - 9 N2 - 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. SN - 0022-3050 UR - https://www.unboundmedicine.com/medline/citation/16107349/Amyloid_mediates_the_association_of_apolipoprotein_E_e4_allele_to_cognitive_function_in_older_people_ L2 - http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=16107349 DB - PRIME DP - Unbound Medicine ER -