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Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques.
JAMA Neurol 2015; 72(10):1124-31JN

Abstract

IMPORTANCE

β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis.

OBJECTIVES

To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD.

DESIGN, SETTING, AND PARTICIPANTS

Data on participants included in this study were obtained from the National Alzheimer Coordinating Center's Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015.

MAIN OUTCOMES AND MEASURES

Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes.

RESULTS

Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4 carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features.

CONCLUSIONS AND RELEVANCE

In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.

Authors+Show Affiliations

National Alzheimer's Coordinating Center, University of Washington, Seattle.National Alzheimer's Coordinating Center, University of Washington, Seattle2Department of Epidemiology, University of Washington, Seattle.Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.Banner Sun Health Research Institute, Sun City, Arizona.Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.Banner Sun Health Research Institute, Sun City, Arizona4Arizona Alzheimer's Consortium, Phoenix, Arizona.Department of Neurology, Mayo Clinic, Scottsdale, Arizona.Department of Pathology, University of Washington, Seattle.Arizona Alzheimer's Consortium, Phoenix, Arizona7Banner Alzheimer's Institute, Phoenix, Arizona8University of Arizona, Phoenix9Arizona State University, Phoenix10Translational Genomics Research Institute, Phoenix, Arizona.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26302353

Citation

Monsell, Sarah E., et al. "Characterizing Apolipoprotein E Ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques." JAMA Neurology, vol. 72, no. 10, 2015, pp. 1124-31.
Monsell SE, Kukull WA, Roher AE, et al. Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques. JAMA Neurol. 2015;72(10):1124-31.
Monsell, S. E., Kukull, W. A., Roher, A. E., Maarouf, C. L., Serrano, G., Beach, T. G., ... Reiman, E. M. (2015). Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques. JAMA Neurology, 72(10), pp. 1124-31. doi:10.1001/jamaneurol.2015.1721.
Monsell SE, et al. Characterizing Apolipoprotein E Ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques. JAMA Neurol. 2015;72(10):1124-31. PubMed PMID: 26302353.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques. AU - Monsell,Sarah E, AU - Kukull,Walter A, AU - Roher,Alex E, AU - Maarouf,Chera L, AU - Serrano,Geidy, AU - Beach,Thomas G, AU - Caselli,Richard J, AU - Montine,Thomas J, AU - Reiman,Eric M, PY - 2015/8/25/entrez PY - 2015/8/25/pubmed PY - 2016/1/31/medline SP - 1124 EP - 31 JF - JAMA neurology JO - JAMA Neurol VL - 72 IS - 10 N2 - IMPORTANCE: β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis. OBJECTIVES: To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD. DESIGN, SETTING, AND PARTICIPANTS: Data on participants included in this study were obtained from the National Alzheimer Coordinating Center's Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015. MAIN OUTCOMES AND MEASURES: Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes. RESULTS: Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4 carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features. CONCLUSIONS AND RELEVANCE: In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/26302353/Characterizing_Apolipoprotein_E_ε4_Carriers_and_Noncarriers_With_the_Clinical_Diagnosis_of_Mild_to_Moderate_Alzheimer_Dementia_and_Minimal_β_Amyloid_Peptide_Plaques_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2015.1721 DB - PRIME DP - Unbound Medicine ER -