J Korean Med Sci.  2016 Feb;31(2):286-295. 10.3346/jkms.2016.31.2.286.

Independent and Interactive Influences of the APOE Genotype and Beta-Amyloid Burden on Cognitive Function in Mild Cognitive Impairment

• Seo EH
• Kim SH
• Park SH
• Kang SH
• Choo IH
• Alzheimer's Disease Neuroimaging Initiative

• KMID: 2360055
• DOI: http://doi.org/10.3346/jkms.2016.31.2.286

Abstract

This study aimed to investigate the independent and interactive influences of apolipoprotein E (APOE) epsilon4 and beta-amyloid (Abeta) on multiple cognitive domains in a large group of cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were included if clinical and cognitive assessments, amyloid imaging, and APOE genotype were all available from the Alzheimer's Disease Neuroimaging Initiative database (CN = 324, MCI = 502, AD = 182). Individuals with one or two copies of epsilon4 were designated as APOE epsilon4 carriers (epsilon4+); individuals with no epsilon4 were designated as APOE epsilon4 non-carriers (epsilon4-). Based on mean florbetapir standard uptake value ratios, participants were classified as Abeta burden-positive (Abeta+) or Abeta burden-negative (Abeta-). In MCI, APOE epsilon4 effects were predominantly observed on frontal executive function, with epsilon4+ participants exhibiting poorer performances; Abeta positivity had no influence on this effect. Abeta effects were observed on global cognition, memory, and visuospatial ability, with Abeta+ participants exhibiting poorer performances. Measures of frontal executive function were not influenced by Abeta. Interactive effects of APOE epsilon4+ and Abeta were observed on global cognition and verbal recognition memory. Abeta, not APOE epsilon4+, influenced clinical severity and functional status. The influences of APOE epsilon4+ and Abeta on cognitive function were minimal in CN and AD. In conclusion, we provide further evidence of both independent and interactive influences of APOE epsilon4+ and Abeta on cognitive function in MCI, with APOE epsilon4+ and Abeta showing dissociable effects on executive and non-executive functions, respectively.

Keyword

Alzheimer Disease; Mild Cognitive Impairment; APOE epsilon4+; Beta-amyloid Burden; Neuropsychology

MeSH Terms

Aged
Aged, 80 and over
Alzheimer Disease/genetics/pathology
Amyloid beta-Peptides/*metabolism
Aniline Compounds/chemistry
Apolipoprotein E4/*genetics
Brain/radiography
Cognition
Databases, Factual
Demography
Ethylene Glycols/chemistry
Female
Genotype
Humans
Male
Mild Cognitive Impairment/genetics/*pathology
Positron-Emission Tomography
Amyloid beta-Peptides
Aniline Compounds
Apolipoprotein E4
Ethylene Glycols

Figure

• 

  Fig. 1 Effect sizes of APOE ε4 status and Aβ positivity on neuropsychological measures in participants with MCI. Effect sizes were calculated using Cohen’s d. The magnitude of the differences in scores on each neuropsychological measure are presented according to apolipoprotein E (APOE) ε4 status (ε4 non-carriers and ε4 carriers; gray bars) and beta-amyloid positivity (Aβ negative and positive; shaded bars). Lower scores on the ADAS-cog11, ADAS-cog13, TMT A, and TMT B indicate better performances. MMSE, Mini-Mental State Examination; ADAS-cog11, Alzheimer’s Disease Assessment Scale-cognitive subscale, consisting of 11 items; ADAS-cog13, Alzheimer’s Disease Assessment Scale-cognitive subscale, consisting of 13 items; MoCA, Montreal Cognitive Assessment; ADNI_Mem, Alzheimer’s Disease Neuroimaging Initiative composite score for memory; RAVLT_imm, Rey Auditory Verbal Learning Test, immediate recall score; RAVLT_delayed, RAVLT, delayed recall score; RAVLT_recog, RAVLT, recognition score; LM_imm, Logical Memory, immediate recall score; LM_delayed, LM, delayed recall score; ADNI_EF, Alzheimer’s Disease Neuroimaging Initiative composite score for executive functioning; TMT, Trail Making Test; BNT, Boston Naming Test. *False discovery rate (FDR)-corrected P < 0.05.

• 

  Fig. 2 Frontal executive and memory performances of four subgroups of participants with MCI. ε4−, APOE ε4 non-carriers; ε4+, APOE ε4 carriers; Aβ−, beta-amyloid negative; Aβ+, beta-amyloid positive; ADNI_EF, Alzheimer’s Disease Neuroimaging Initiative composite score for executive functioning; ADNI_Mem, Alzheimer’s Disease Neuroimaging Initiative composite score for memory. *P < 0.01; †P < 0.001.

• 

  Fig. 3 Interactive effects of APOE ε4 status and Aβ positivity on cognitive measures in participants with MCI. The upper row displays interactive effects of APOE ε4 status and Aβ positivity on the ADAS-cog13 (A) and RAVLT_recog tests (B). The lower row displays four subgroups according to APOE ε4 and Aβ status on the ADAS-cog13 (A) and RAVLT_recog tests (B). ε4−, APOE ε4 non-carriers, blue circle; ε4+, APOE ε4 carriers, green triangle; Aβ−, beta-amyloid negative; Aβ+, beta-amyloid positive; ADAS-cog13, Alzheimer’s Disease Assessment Scale-cognitive subscale, consisting of 13 items; RAVLT_recog, Rey Auditory Verbal Learning Test, recognition score. *P < 0.01; †P < 0.001.

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