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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Available from: Clifford R Jack, Oct 04, 2015
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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.
    Frontiers in Aging Neuroscience 04/2013; 5:11. DOI:10.3389/fnagi.2013.00011 · 4.00 Impact Factor
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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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    ABSTRACT: Aβ1-42 measurement in CSF is an important biochemical marker for Alzheimer disease (AD). However, our understanding of why this biomarker is predictive and why it is often difficult to measure in a reproducible fashion is still lacking. To study these questions, the concentration of Aβ1-42 in CSF was compared before and after denaturation with 6M guanidine and reverse-phase HPLC. Measurement of the Aβ1-42 after denaturation and reverse-phase HPLC demonstrated that considerably more Aβ1-42 was present in CSF than revealed when assaying non-denatured CSF. A comparison of Aβ1-42 concentrations before and after HPLC in AD CSF with that in normal controls suggested that matrix interference may affect the differentiation between the diagnostic groups. A similar effect was observed with dilutions of crude CSF. Together, these results suggested that at least part of the mechanism by which low Aβ1-42 concentrations in CSF function as a biomarker of AD is related to matrix components which preferentially hide a portion of the Aβ1-42 from detection in AD CSF. In contrast, we show that the association of the APOEε4 allele with lower Aβ1-42 concentrations in CSF is preserved even after denaturation and HPLC. A similar relationship between the presence of the APOEε4 allele and lower concentrations of Aβ1-40 was also apparent, thereby generating similar ratios of Aβ1-42/ Aβ1-40 across the APOE genotypes. The results from the present study suggested that Aβ1-42 in CSF functions as a biomarker of AD in tandem with other CSF matrix components that are increased in AD CSF. Further studies are needed to identify which matrix factors (e.g. binding of Aβ to proteins) underlie the increased detection of Aβ1-42 concentrations after denaturation and HPLC. The data also suggested that denaturation and HPLC of CSF may be a useful approach for studies using Aβ1-42 as a pharmacodynamic marker or in other paradigms where measurement of total non-covalently bound Aβ1-42 is required.
    Journal of Neurochemistry 01/2012; 120(2):325-33. DOI:10.1111/j.1471-4159.2011.07553.x · 4.28 Impact Factor
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    • "Therefore, it may be that among people without AD risk factors, APOE ε4 does not adversely affect cognition and could perhaps be beneficial to its carriers. Some have gone so far as to suggest that APOE has no influence on cognition beyond increasing risk for AD [69]. These authors suggest that APOE, while putting one at risk for prodromal dementia, does not create a specific cognitive phenotype of its own [69]. "
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    ABSTRACT: Research on apolipoprotein E (APOE) has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD). However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.
    International Journal of Alzheimer's Disease 02/2011; 2011(5):726197. DOI:10.4061/2011/726197
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