Effect of Apolipoprotein E on Biomarkers of Amyloid Load and Neuronal Pathology in Alzheimer Disease

Aging and Dementia Imaging Research Laboratory, Department of Radiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Annals of Neurology (Impact Factor: 9.98). 11/2009; 67(3):308-16. DOI: 10.1002/ana.21953
Source: PubMed


To study the effect of apolipoprotein E epsilon4 status on biomarkers of neurodegeneration (atrophy on magnetic resonance imaging [MRI]), neuronal injury (cerebrospinal fluid [CSF] t-tau), and brain Abeta amyloid load (CSF Abeta(1-42)) in cognitively normal subjects (CN), amnestic subjects with mild cognitive impairment (aMCI), and patients with Alzheimer disease (AD).
We included all 399 subjects (109 CN, 192 aMCI, 98 AD) from the Alzheimer's Disease Neuroimaging Initiative study with baseline CSF and MRI scans. Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject.
A clear epsilon4 allele dose effect was seen on CSF Abeta(1-42) levels within each clinical group. In addition, the proportion of the variability in Abeta(1-42) levels explained by APOE epsilon4 dose was significantly greater than the proportion of the variability explained by clinical diagnosis. On the other hand, the proportion of the variability in CSF t-tau and MRI atrophy explained by clinical diagnosis was greater than the proportion of the variability explained by APOE epsilon4 dose; however, this effect was only significant for STAND scores.
Low CSF Abeta(1-42) (surrogate for Abeta amyloid load) is more closely linked to the presence of APOE epsilon4 than to clinical status. In contrast, MRI atrophy (surrogate for neurodegeneration) is closely linked with cognitive impairment, whereas its association with APOE epsilon4 is weaker. The data in this paper support a model of AD in which CSF Abeta(1-42) is the earliest of the 3 biomarkers examined to become abnormal in both APOE carriers and noncarriers.

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    • "Other found increased A 1-40 levels[54]or no correlation with presence of ApoE 4 allele[64,66]. In CSF reduced A 1-42 is strongly associated with ApoE 4[70]and are more closely linked to the presence of the ApoE 4 allele than to clinical status[71]. In our study we have obtained very comparable results that plasma A 1-42 and A 1-42 /A 1-40 ratio do stronger correlate with the presence of ApoE 4 than with the cognitive performance, which has never been reported before. "
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    ABSTRACT: Background: Current treatment in Alzheimer's disease (AD) is initiated at a stage where the brain already has irreversible structural deteriorations. Therefore, the concept of treatment prior to obvious cognitive deficits has become widely accepted, and simple biochemical tests to discriminate normal aging from prodromal or demented stages are now common practice. Objective: The objective of the study was the differentiation of controls, mild cognitive impairment (MCI) and AD patients by novel blood-based assays in combination with neuropsychological tests. Methods: In a cross-sectional study, 143 subjects aged 18 to 85 years were recruited. All participants were classified by a comprehensive neuropsychological assessment. Blood samples were analyzed for several amyloid-β (Aβ) species, pro-inflammatory markers, anti-Aβ autoantibodies, and ApoE allele status, respectively. Results: Plasma Aβ1-42 was significantly decreased in MCI and AD compared to age-matched controls, whereas Aβ1-40 did not differ, but increases with age in healthy controls. The Aβ1-42 to Aβ1-40 ratio was stepwise decreased from age-matched controls via MCI to AD, and shows a clear correlation with memory scores. Reduced Aβ1-42 and Aβ1-42 to Aβ1-40 ratio have strongly correlated with carrying ApoE ɛ4 allele. Autoantibodies against pyroglutamate-modified Aβ, but only a certain subclass, were significantly decreased in AD compared to MCI and age-matched controls, whereas autoantibodies against the unmodified N-terminus of Aβ did not differ. Conclusion: Comprehensive sample preparation and assay standardization enable reliable usage of plasma Aβ for diagnosis of MCI and AD. Anti-pGlu-Aβ autoantibodies correlate with cognition, but not with ApoE, supporting the associated plasma Aβ analysis with additional and independent information.
    No preview · Article · Dec 2015 · Journal of Alzheimer's disease: JAD
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    • "The presence of an ε4 allele confers a significantly higher likelihood of developing AD. APOE genotype is also associated with AD biomarkers, with the presence of an APOE ε4 allele associated with greater amyloid deposition (Drzezga et al., 2009; Morris et al., 2010; Fleisher et al., 2011), a higher degree and faster rate of neurodegeneration (Moffat et al., 2000; Caroli and Frisoni, 2010), alterations in brain function and glucose metabolism (Bookheimer et al., 2000; Bondi et al., 2005; Langbaum et al., 2009), changes in cerebrospinal fluid (CSF) measures of amyloid and tau (Vemuri et al., 2010; Tosun et al., 2011), as well as more impaired cognition (Mayeux et al., 2001; Farlow et al., 2004; Caselli et al., 2011) in patients with L-MCI and AD and cognitively healthy older adults (HC). However, the role of APOE genotype in E-MCI has not been assessed. "
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    ABSTRACT: Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort. Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints. Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed. Conclusions: APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.
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    • "Future studies will be needed to better understand the relationship between AD pathology and matrix affects on Ab1–42 measurements. The APOE genotype is known to affect Ab1–42 concentrations when measured in crude CSF (Prince et al. 2004; Sunderland et al. 2004; Peskind et al. 2006; Andersson et al. 2007; Mosconi et al. 2008; Kauwe et al. 2009; Kester et al. 2009; Vemuri et al. 2010). "
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