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Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.

Abstract

OBJECTIVE

To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles.

DESIGN

Longitudinal clinicopathologic cohort study.

PARTICIPANTS AND SETTING

Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death.

METHODS

The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition.

MAIN OUTCOME MEASURES

Clinically diagnosed AD and level of global cognitive function proximate to death.

RESULTS

In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function.

CONCLUSION

These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.

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  • Authors+Show Affiliations

    ,

    Rush Alzheimer's Disease Center and the Department of Neurological Sciences Rush University Medical Center, Chicago, Il 60612, USA. dbennett@rush.edu

    , , ,

    Source

    Archives of neurology 61:3 2004 Mar pg 378-84

    MeSH

    Aged
    Aged, 80 and over
    Alzheimer Disease
    Amyloid
    Cognition Disorders
    Cohort Studies
    Female
    Humans
    Immunohistochemistry
    Male
    Neurofibrillary Tangles
    Neuropsychological Tests
    Probability
    Regression Analysis

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    15023815

    Citation

    Bennett, David A., et al. "Neurofibrillary Tangles Mediate the Association of Amyloid Load With Clinical Alzheimer Disease and Level of Cognitive Function." Archives of Neurology, vol. 61, no. 3, 2004, pp. 378-84.
    Bennett DA, Schneider JA, Wilson RS, et al. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Arch Neurol. 2004;61(3):378-84.
    Bennett, D. A., Schneider, J. A., Wilson, R. S., Bienias, J. L., & Arnold, S. E. (2004). Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. Archives of Neurology, 61(3), pp. 378-84.
    Bennett DA, et al. Neurofibrillary Tangles Mediate the Association of Amyloid Load With Clinical Alzheimer Disease and Level of Cognitive Function. Arch Neurol. 2004;61(3):378-84. PubMed PMID: 15023815.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function. AU - Bennett,David A, AU - Schneider,Julie A, AU - Wilson,Robert S, AU - Bienias,Julia L, AU - Arnold,Steven E, PY - 2004/3/17/pubmed PY - 2004/4/15/medline PY - 2004/3/17/entrez SP - 378 EP - 84 JF - Archives of neurology JO - Arch. Neurol. VL - 61 IS - 3 N2 - OBJECTIVE: To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. DESIGN: Longitudinal clinicopathologic cohort study. PARTICIPANTS AND SETTING: Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. METHODS: The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. MAIN OUTCOME MEASURES: Clinically diagnosed AD and level of global cognitive function proximate to death. RESULTS: In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function. CONCLUSION: These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles. SN - 0003-9942 UR - https://www.unboundmedicine.com/medline/citation/15023815/Neurofibrillary_tangles_mediate_the_association_of_amyloid_load_with_clinical_Alzheimer_disease_and_level_of_cognitive_function_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/archneur.61.3.378 DB - PRIME DP - Unbound Medicine ER -