Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis APOE and Alzheimer Disease Meta Analysis Consortium. JAMA

Department of Neurology, Boston University School of Medicine, Mass 02118, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 01/1997; 278(16):1349-56.
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To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations.
Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources.
Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures.
Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex.
The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.

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    • "Inflammation-related changes in the neurovascular unit eventually amplify neurodegeneration by self-sustaining amyloidogenic over-production and decreased brain clearance, even through derangement of astrocytic Aqp4 expression and distribution (Heppner et al., 2015). Without a doubt, the APOE genotype is the best-known factor with a sizable effect on AD in terms of occurrence risk and of onset age (Farrer et al., 1997). It has been shown that ApoE interacts with Aβ along all its clearance pathways (Kanekiyo et al., 2014) and that the presence of the ApoE4 isoform may adversely affect Aβ metabolism. "

    Frontiers in Aging Neuroscience 11/2015; 7:200. DOI:10.3389/fnagi.2015.00200 · 4.00 Impact Factor
    • "To date, only a few studies have assessed hippocampal shape or subfield volumes in cognitively intact individuals at risk of AD, including carriers of the e4 allele of the Apolipoprotein E, healthy controls with amyloid b deposition, and individuals with isolated subjective memory complaint. The e4 allele of the apolipoprotein E (APOE4) is the largest genetic risk factor for sporadic AD (Corder et al., 1993; Farrer et al., 1997; Genin et al., 2011), and its detrimental effect (as compared to the more frequent e3 allele) is dose-dependent: odds ratio for AD are 3.2 for e4/e3 carriers, and 14.9 for e4/e4 carriers (Farrer et al., 1997). Many studies have assessed the effect of APOE polymorphism on gray matter volume but only a few have examined the effects on hippocampal subfields. "
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    ABSTRACT: Hippocampal atrophy, as evidenced using magnetic resonance imaging (MRI), is one of the most validated, easily accessible and widely used biomarkers of Alzheimer's disease (AD). However, its imperfect sensitivity and specificity have highlighted the need to improve the analysis of MRI data. Based on neuropathological data showing a differential vulnerability of hippocampal subfields to AD processes, neuroimaging researchers have tried to capture corresponding morphological changes within the hippocampus. The present review provides an overview of the methodological developments that allow the assessment of hippocampal subfield morphology in vivo, and summarizes the results of studies looking at the effects of AD and normal aging on these structures. Most studies highlighted a focal atrophy of the CA1 subfield in the early (predementia or even preclinical) stages of AD, before atrophy becomes more widespread at the dementia stage, consistent with the pathological literature. Preliminary studies have indicated that looking at this focal atrophy pattern rather than standard whole hippocampus volumetry improves diagnostic accuracy at the Mild Cognitive Impairment (MCI) stage. However, controversies remain regarding changes in hippocampal subfield structure in normal aging and regarding correlations between specific subfield volume and memory abilities, very likely because of the strong methodological variability between studies. Overall, hippocampal subfield analysis has proven to be a promising technique in the study of AD. However, harmonization of segmentation protocols and studies on larger samples are needed to enable accurate comparisons between studies and to confirm the clinical utility of these techniques. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 08/2015; 309. DOI:10.1016/j.neuroscience.2015.08.033 · 3.36 Impact Factor
    • "For comparison with the other assessments, the apolipoprotein E genotype (ApoE) was ranked by the risk to develop Alzheimer's Disease (Farrer et al., 1997) (ranking: 1:ε2-ε3, 2:ε2-ε2, 3:ε2-ε2, 4:ε2-ε4, 5:ε3-ε4, 6:ε4-ε4). "
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    ABSTRACT: Objective: Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to induce synaptic long-term potentiation (LTP)-like plasticity in the intact human brain. The PAS effect is reduced in Alzheimer's dementia (AD) but has not yet been assessed in patients with mild cognitive impairment (MCI). Methods: PAS was assessed in a group of 24 MCI patients and 24 elderly controls. MCI patients were further stratified by their cognitive profile as well as hippocampal atrophy and Apolipoprotein E (ApoE) genotype. Results: There was no difference in PAS effects between MCI patients and healthy controls. MCI patients tended to show a higher response rate and an average PAS effect. PAS effects were not correlated with markers of disease severity or ApoE genotype but were more pronounced in individuals with shorter sleep duration and in MCI subjects with higher ratings of subjective alertness. Conclusions: Contrary to our initial hypothesis, there was no clear difference in PAS between MCI patients and healthy controls. Significance: Our results argue against a continuous reduction of LTP-like plasticity along the spectrum of clinical MCI when stratified by MCI-subtype, APOE genotype or hippocampus atrophy.
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