Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Bruno, Davide; Pomara, Nunzio; Nierenberg, Jay; Ritchie, James C.; Lutz, Michael W.; Zetterberg, Henrik; Blennow, Kaj

doi:10.1016/j.exger.2011.09.008

Cited by 33 publications

(25 citation statements)

References 35 publications

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“…The 523 VL poly T resulted in significantly higher expression than the S poly T. These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription [55]. Recent studies also suggest that the TOMM40 gene rs10524523 ("523") variable length poly T repeat polymorphism is associated to a certain extent with similar AD phenotypes as those reported for APOE, such as brain white matter changes [56,57] or different biomarkers [58][59][60][61]. In addition, the TOMM40 rs2075650 G allele may be a risk factor for the development of depression [62] and sporadic inclusion body myositis [63].…”

Section: Introductionmentioning

confidence: 57%

APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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Section: Introductionmentioning

confidence: 57%

APOE-TOMM40 in the Pharmacogenomics of Dementia

Cacabelos

Goldgaber²,

Àlex³

et al. 2013

J Pharmacogenomics Pharmacoproteomics

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“…Furthermore, Bruno et al showed an increase in CSF cortisol concentration, which suggests hippocampal damage, in individuals who carry two copies of the longer 523 alleles[18]. In another study, they also showed that the CSF levels of neurofilament light proteins, markers of neuronal damage that are elevated in LOAD patients, were significantly higher in subjects with two copies of the longer 523 alleles[19]. Recently, Crenshaw and colleagues thoroughly discussed the observation of variable effects of the 523 VL allele [11].…”

Section: Discussionmentioning

confidence: 99%

The cis‐regulatory effect of an Alzheimer's disease‐associated poly‐T locus on expression of TOMM40 and apolipoprotein E genes

Linnertz

Anderson

Gottschalk

et al. 2014

Alzheimer's & Dementia

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Introduction We investigated the TOMM40-APOE genomic region that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine if a highly polymorphic, intronic polyT within this region (rs10524523, hereafter 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified: short-S, long-L, very long-VL based on the number of T-residues. Methods We evaluated differences in APOE-mRNA and TOMM40-mRNA levels as a function of 523 genotype in two brain regions from APOEε3/3 Caucasian autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. Results The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40-mRNA levels were higher in VL-homozygotes compared to S-homozygotes in temporal and occipital cortexes from Normal and LOAD subjects. Results of a luciferase reporter system were consistent with the human brain mRNA analysis: the 523-VL polyT resulted in significantly higher expression than the S-polyT. While the effect of polyT length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523-polyT. Conclusions These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.

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“…Participants in the first group were recruited via advertisements in local newspapers and flyers, or from the Memory Education and Research Initiative (MERI) program at the Nathan Kline Institute for Psychiatric Research; participants' recruitment was part of a study on late-life MDD (Bruno et al, 2012; Bruno, Nierenberg, Ritchie, Lutz & Pomara, 2012; Pillai et al, 2012; Pomara et al, 2012). All participants provided formal consent prior to testing and received compensation for up to $450.00 for their time and efforts.…”

Section: Methodsmentioning

confidence: 99%

A study on the specificity of the association between hippocampal volume and delayed primacy performance in cognitively intact elderly individuals

et al. 2015

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Delayed recall at the primacy position (first few items on a list) has been shown to predict cognitive decline in cognitively intact elderly participants, with poorer delayed primacy performance associated with more pronounced generalized cognitive decline during follow-up. We have previously suggested that this association is due to delayed primacy performance indexing memory consolidation, which in turn is thought to depend upon hippocampal function. Here, we test the hypothesis that hippocampal size is associated with delayed primacy performance in cognitively intact elderly individuals. Data were analyzed from a group (N=81) of cognitively intact participants, aged 60 or above. Serial position performance was measured with the Buschke selective reminding test (BSRT). Hippocampal size was automatically measured via MRI, and unbiased voxel-based analyses were also conducted to explore further regional specificity of memory performance. We conducted regression analyses of hippocampus volumes on serial position performance; other predictors included age, family history of Alzheimer's disease (AD), APOE ε4 status, education, and total intracranial volume. Our results collectively suggest that there is a preferential association between hippocampal volume and delayed primacy performance. These findings are consistent with the hypothesis that delayed primacy consolidation is associated with hippocampal size, and shed light on the relationship between delayed primacy performance and generalized cognitive decline in cognitively intact individuals, suggesting that delayed primacy consolidation may serve as a sensitive marker of hippocampal health in these individuals.

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Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants

Cited by 33 publications

References 35 publications

APOE-TOMM40 in the Pharmacogenomics of Dementia

APOE-TOMM40 in the Pharmacogenomics of Dementia

The cis‐regulatory effect of an Alzheimer's disease‐associated poly‐T locus on expression of TOMM40 and apolipoprotein E genes

A study on the specificity of the association between hippocampal volume and delayed primacy performance in cognitively intact elderly individuals

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