Alzheimer’s Disease: Role of Size and Location of White Matter Changes in Determining Cognitive Deficits

Bracco, Laura; Piccini, Carolina; Moretti, Marco; Mascalchi, Mario; Sforza, Antonio; Nacmias, Benedetta; Cellini, Elena; Bagnoli, Silvia; Sorbi, Sandro

doi:10.1159/000088562

Cited by 52 publications

(36 citation statements)

References 83 publications

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“…Analyzing studies using dichotomized WMH burden assessment (n 5 5,282, 3,627 in the general population and 1,655 in high-risk populations) 21,23,25,[27][28][29]31,32,34,37 revealed no significant association of APOE e41 with large WMH burden: pooled OR 5 1.07 (0.93, 1.22) (p 5 0.34) (p z score 5 0.39) (figure 1A). Results were similar after adding one study using a 3-class variable for WMH with ordinal logistic regression (n 5 106, p z score 5 0.44).…”

Section: Resultsmentioning

confidence: 99%

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 This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study.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%

APOE genotype and MRI markers of cerebrovascular disease

et al. 2013

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“…Nineteen cross-sectional studies [31, 36,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65] and 2 longitudinal studies [66, 67] were performed in patients with cognitive impairment. Characteristics and results of these studies are presented in table 2.…”

Section: Resultsmentioning

confidence: 99%

White Matter Lesions and Brain Atrophy: More than Shared Risk Factors? A Systematic Review

Appelman¹,

et al. 2009

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Background: White matter lesions (WML) and brain atrophy are often found on MRI in the elderly. Shared vascular risk factors may be an explanation for their concomitance. However, disturbances of white matter integrity could also be involved in the pathogenesis of brain atrophy. Our objective was to systematically review studies that investigated the relation between WML and brain atrophy on MRI, and to investigate whether there is sufficient evidence to indicate that this relation is independent of shared risk factors. Methods: We searched PubMed for studies published in English between 1980 and October 2007, combining search terms for WML and brain atrophy. Articles that studied the relation between WML and brain atrophy were included if they met the following criteria: (1) original study, (2) MRI used for imaging, (3) assessment methods for WML and brain atrophy specified, and (4) a sample size of at least 20 participants. We recorded type and age of the study population, type and assessment of WML and brain atrophy, and variables for which adjustments were made in the analyses. Results: We identified 48 studies that met our inclusion criteria. A significant relation between WML and brain atrophy was found in 37 out of 48 studies. The source of the study population (e.g. clinic or population based) did not affect this relation. However, only 10 studies adjusted for shared risk factors, of which 9 found an association. Conclusions: The majority of studies found an association between WML and brain atrophy, but it is not yet clear if this association is independent of shared risk factors.

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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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Alzheimer’s Disease: Role of Size and Location of White Matter Changes in Determining Cognitive Deficits

Cited by 52 publications

References 83 publications

APOE genotype and MRI markers of cerebrovascular disease

APOE genotype and MRI markers of cerebrovascular disease

White Matter Lesions and Brain Atrophy: More than Shared Risk Factors? A Systematic Review

Genetic Determinants of White Matter Hyperintensities on Brain Scans

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