Does APO epsilon 4 correlate with MRI changes in Alzheimer's disease?

Doody, Rachelle S.; Azher, Shaheda N.; Haykal, Hani A.; Dunn, Joseph; Liao, Tso Yu; Schneider, Lon S.

doi:10.1136/jnnp.69.5.668

Cited by 28 publications

(23 citation statements)

References 52 publications

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“…e32,e33 APOE e44 and WMH. When meta-analyzing 12 studies (n 5 7,494, 6,254 in the general population, 1,240 in high-risk populations, tables e-2 and e-3) 3,11,13,21,28,30,31,[37][38][39] (Sydney-MAS, FHS, unpublished data) in a sample size-weighted meta-analysis, APOE e44 was significantly associated with increasing WMH burden: p z score 5 0.0030.…”

Section: Resultsmentioning

confidence: 99%

“…A meta-analysis restricted to studies using continuous WMH burden and providing standardized mean differences (n 5 8,917, 8,405 in the general population and 512 in high-risk populations) 2,3,11,24,26,30,33,35,36,38,39 (Sydney-MAS, unpublished data) yielded a borderline nominal association of APOE e41 with increasing WMH burden: pooled standardized mean difference 5 0.047 (95% confidence interval 0.0006, 0.094) (p 5 0.05) (p z score 5 0.0631) (figure 1A). When adding studies using continuous WMH but providing regression coefficients (n 5 4,004) 5,40,41 (FHS, unpublished data), in a sample size-weighted z score-based metaanalysis, the association was p z score 5 0.0028.…”

Section: Resultsmentioning

confidence: 99%

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APOE genotype and MRI markers of cerebrovascular disease

et al. 2013

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Objective: We aimed to examine the association of APOE e genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.Methods: We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n 5 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis. Conclusions: APOE e4 and APOE e2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE e4 with an increased burden of CVD could be partly contributing to the relationship between APOE e4 and AD, APOE e2 was associated with MRI markers of CVD in the opposite direction compared to AD. The e4 allele of the APOE gene is a major risk factor for dementia and Alzheimer disease (AD). Results 1-6The association of APOE with cerebrovascular disease (CVD) is more controversial.7 APOE e4 is a risk factor for cerebral amyloid angiopathy (CAA), a major determinant of intracerebral hemorrhage (ICH) in older individuals.1 Recent data from the International Stroke Genetics Consortium suggest an association of APOE e4 with an increased risk of ICH, mostly lobar, 8 and an association of the APOE e2 allele with an increased risk and size of lobar ICH. 8,9 Whether the epsilon polymorphism is also associated with an increased risk of ischemic stroke and MRI markers of CVD is unclear.7 MRI markers of CVD-white matter hyperintensities (WMH), brain infarcts (BI), and cerebral microbleeds (CMB)-are powerful predictors of stroke and dementia.10-13 They are highly prevalent in older community-dwelling persons, [14][15][16] and can be assessed noninvasively and quantitatively in large population-based samples. Dissecting the relationship between APOE and MRI

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

APOE genotype and MRI markers of cerebrovascular disease

et al. 2013

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“…14 -36,48 Eleven compared the numbers of individuals in lower and upper WMH grades between genotype groups ( Figure 1A), 14,16,17,22,23,25,29,30,33 3 compared mean grade ( Figure 1B), 15,21,24 and 4 compared mean volume ( Figure 1C). 20,28,34 Random-effects meta-analyses comparing 4ϩ with 4Ϫ genotypes found no evidence of association between APOE and WMH (graded WMH dichotomous pooled OR, 0.97; 95% CI, 0.78 -1.21; graded WMH continuous pooled standardized mean difference: 0.30, 95% CI, Ϫ0.02-0.62; WMH volume pooled standardized mean difference: 0.15, 95%CI Ϫ0.04 to 0.33).…”

Section: Resultsmentioning

confidence: 99%

Genetic Determinants of White Matter Hyperintensities on Brain Scans

Paternoster

Chen

Sudlow

2009

Stroke

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Background and Purpose-White matter hyperintensities (WMH) are highly heritable and associated with small artery ischemic stroke, so they may be a useful trait for studying the genetics of small vessel disease. Many studies have attempted to find associations between polymorphisms in various candidate genes and WMH. We aimed to evaluate the evidence for these associations by performing a systematic review and series of meta-analyses. Methods-We used a comprehensive search strategy to identify studies of the association between any genetic polymorphism and WMH. For all polymorphisms in genes studied in Ͼ2000 subjects we performed meta-analyses, calculating pooled odds ratios or standardized mean differences. Results-We identified 46 studies of polymorphisms in 19 genes in Ϸ19 000 subjects. Most genes were involved in lipid metabolism, control of vascular tone, or blood pressure regulation. Polymorphisms in the apolipoprotein E, angiotensinconverting enzyme, methylenetetrahydrofolate reductase, and angiotensinogen genes had been studied in Ͼ2000 subjects and were evaluated by meta-analysis. There was no evidence for an association between apolipoprotein E (4ϩ/Ϫ), methylenetetrahydrofolate reductase (677 cytosine/thymine polymorphism [C/T]), or angiotensinogen (Met235Thr) and WMH. For the angiotensin-converting enzyme insertion/deletion polymorphism (I/D) there appeared to be a significant association (OR, 1.95; 95% CI, 1.09 -3.48), but this may be partly attributable to the small study (mainly publication) and other biases. Conclusion-No genetic polymorphism has yet shown convincing evidence for an association with WMH. Much larger studies will be needed to detect and confirm genetic associations with this promising trait in the era of genome-wide association studies.

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“…However, this association has been denied by one community study [27]. Studies evaluating the association between the ε4 apoE genotype and WMC in community samples [28, 29], in patients with Alzheimer’s disease [30, 31]and in a twin cohort [32], are consistently negative with one exception [33]. …”

Section: Wmc and Genetically Transmitted Diseasesmentioning

confidence: 99%

Pathophysiology of Age-Related Cerebral White Matter Changes

2002

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The pathogenesis of age-related cerebral white matter changes (WMC) is still a matter of investigation. Alterations of deep small vessels, such as arteriolosclerosis, are considered to play a central role in the development of WMC. Stenosis or occlusion of small vessels may cause sudden or more chronic ischemia resulting in small areas of necrosis (lacunar infarction) or diffuse alterations consistent with the definition of white matter incomplete infarct. Moreover, the arteriolosclerotic changes may cause loss of autoregulation in the deep white matter and consequent cerebral blood flow fluctuations in response to changes of systemic blood pressure. Both these types of mechanisms may be particularly harmful because the blood supply of the white matter is of the terminal type with scarce anastomoses. Other pathophysiological hypotheses on the origin of WMC have been raised, and they can probably be considered as complementary to the ischemic one. The small vessel alterations could lead to damage of the blood-brain barrier and chronic leakage of fluid and macromolecules in the white matter. The increased interstitial fluid concentration in abnormal white matter may be also a consequence of arterial hypertensive bouts. Genetically determined factors could play an important role in the development of WMC, and at least one disease (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy – CADASIL) characterized by severe leukoencephalopathy exists with a determined genetic origin. It is possible that other genetic factors contribute, by interaction with conventional risk factors, to the development of white matter injury in nonfamilial cases.

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Does APO epsilon 4 correlate with MRI changes in Alzheimer's disease?

Cited by 28 publications

References 52 publications

APOE genotype and MRI markers of cerebrovascular disease

APOE genotype and MRI markers of cerebrovascular disease

Genetic Determinants of White Matter Hyperintensities on Brain Scans

Pathophysiology of Age-Related Cerebral White Matter Changes

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