CR1 genotype is associated with entorhinal cortex volume in young healthy adults

Bralten, Janita; Franke, Barbara; Arias-Vásquez, Alejandro; Heister, Angelien J.G.A.M.; Brunner, Han G.; Fernández, Guillén; Rijpkema, Mark

doi:10.1016/j.neurobiolaging.2011.05.017

Cited by 37 publications

(33 citation statements)

References 23 publications

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“…If CR1 was related to AD through its capacity to act as a peripheral sink, removing Aβ from the circulation, facilitating further removal of Aβ from the brain, it would be expected that the larger isoforms would be more efficient at this process, and thus would be protective. Since this is not the case, it strengthens arguments for CR1's relationship with AD stemming from effects on neuroinflammation, or perhaps, as suggested by Bralten et al's research, by affecting the structure of the brain much earlier in life, affecting the brain's ability to cope with AD processes when they occur later on (Bralten et al 2011). …”

Section: Ad Genetics -Updatesupporting

confidence: 68%

“…A final intriguing possibility is raised by a study in which Bralten et al reported an association between CR1 genotype and entorhinal cortex volume in young, healthy adults (Bralten et al 2011), using high resolution MRI technology to assess brain structures. In the discovery cohort, there was an association between CR1 genotype at SNP rs6656401 and gray matter volume in both the hippocampus and entorhinal cortex, with carriers of the risky A allele displaying lower gray matter volume in these regions.…”

Section: Cr1 and Brain Structurementioning

confidence: 99%

“…Although the hippocampal finding was not replicated in the second cohort, the entorhinal cortex volume link was replicated, with evidence that the effect may be dose dependent. Exploratory analysis of other brain regions found evidence the link between CR1 genotype and brain structure may extend into areas such as the amygdala, anterior medial temporal lobe and collateral sulcus, although further study will be necessary to confirm these suggestive findings (Bralten et al 2011). …”

Section: Cr1 and Brain Structurementioning

confidence: 99%

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P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Lord

Turton

Braae

et al. 2014

Alzheimer's & Dementia

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In 2009, two large genome wide association studies (GWAS) found associations between common single nucleotide polymorphisms (SNPs) at three loci (CLU, PICALM and CR1) and Alzheimer's disease (AD) risk. The causal variants underlying these associations and how these impact on AD susceptibility remain unclear. Target enrichment and next generation sequencing (NGS) were used to completely resequence the three associated loci in 96 AD patients in an attempt to uncover potentially causative and rare variants that may explain the observed association signals. A pipeline was developed for the handling of pooled NGS data following a comparison of several different combinations of programs. 33 exonic SNPs were found within the three genes, along with over 1000 non-coding variants. To identify the variants most likely to be affecting AD risk, a two pronged approach was adopted. The variants were imputed in a large case-control cohort (2067 cases, 7376 controls) to test for association with AD, and the likely functional consequences of the variants were assessed using in silico resources. Several of the analysed variants showed suggestive or significant association with AD in the imputed data, and/or were predicted to have consequences on the function or regulation of the genes, suggesting avenues for future research in AD genetics. The whole method of pooled, targeted NGS and prioritisation using imputed data for association testing and in silico resources for functional analysis represents a new strategy for tracking down the illusive causation of GWAS signals. PublicationsNext generation sequencing of CLU, PICALM and CR1: pitfalls and potential solutions. Lord J,

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Section: Ad Genetics -Updatesupporting

confidence: 68%

Section: Cr1 and Brain Structurementioning

confidence: 99%

Section: Cr1 and Brain Structurementioning

confidence: 99%

See 1 more Smart Citation

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Lord

Turton

Braae

et al. 2014

Alzheimer's & Dementia

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“…Importantly, in HC and EMCI stage, the relative size of the hippocampus may be driven by factors besides neurodegeneration, such as genetics [34,35], diabetes [36], recurrent major depression [37], coronary artery disease [38], exercise [39], or higher occupational attainment [40]. When hippocampal atrophy occurs independently of β-amyloid accumulation [21,22], it could reflect other underlying pathological processes including tauopathies, ischemia, and sclerosis [23].…”

Section: Discussionmentioning

confidence: 99%

Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer's Disease

Trzepacz

Hochstetler²,

Yu³

et al. 2015

Dement Geriatr Cogn Disord

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Aims: To assess how hippocampal volume (HV) from volumetric magnetic resonance imaging (vMRI) is related to the amyloid status at different stages of Alzheimer's disease (AD) and its relevance to patient care. Methods: We evaluated the ability of HV to predict the florbetapir positron emission tomography (PET) amyloid positive/negative status by group in healthy controls (HC, n = 170) and early/late mild cognitive impairment (EMCI, n = 252; LMCI, n = 136), and AD dementia (n = 75) subjects from the Alzheimer's Disease Neuroimaging Initiative Grand Opportunity (ADNI-GO) and ADNI2. Logistic regression analyses, including elastic net classification modeling with 10-fold cross-validation, were used with age and education as covariates. Results: HV predicted amyloid status only in LMCI using either logistic regression [area under the curve (AUC) = 0.71, p < 0.001] or elastic net classification modeling [positive predictive value (PPV) = 72.7%]. In EMCI, age (AUC = 0.70, p < 0.0001) and age and/or education (PPV = 63.1%), but not HV, predicted amyloid status. Conclusion: Using clinical neuroimaging, HV predicted amyloid status only in LMCI, suggesting that HV is not a biomarker surrogate for amyloid PET in clinical applications across the full diagnostic spectrum.

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“…To address this confound, one approach is to use the endophenotype based on the neuroimaging data. Despite some contradictory [62], PICALM has been found to be significantly associated with hippocampal volume [63,64] and entorhinal cortex thickness (ECT) [61,64], both of which is unequivocally affected by AD-related neurodegeneration. Additionally, PICALM has also been linked to the earlier age at onset (AAO), which is a specific clinical phenotype of AD [65,66].…”

Section: Genetics Of Picalm Gene In Admentioning

confidence: 99%

The Role of PICALM in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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Alzheimer's disease (AD) is a highly heritable disease (with heritability up to 76%) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer's disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.

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CR1 genotype is associated with entorhinal cortex volume in young healthy adults

Cited by 37 publications

References 23 publications

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

P2‐030: Investigating the Role of Clu, Picalm, and Cr1 in Alzheimer's Disease

Relationship of Hippocampal Volume to Amyloid Burden across Diagnostic Stages of Alzheimer's Disease

The Role of PICALM in Alzheimer’s Disease

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