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Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

ABSTRACT: Previous evidence linking diabetes to Alzheimer's disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries.To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults.In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed using immunohistochemistry. The associations of diabetes with Consortium to Establish and Registry for Alzheimer Disease (CERAD) scores for neuritic plaques and Braak-Braak (BB) scores for neurofibrillary tangles were investigated using multivariable ordinal logistic regression. We investigated effect modification of education, race, and APOE on these associations.Among 1,037 subjects (mean age?=?74.4±11.5 y; mean education?=?4.0±3.7 y; 48% male, 61% White), diabetes was present in 279 subjects. Diabetes was not associated with BB (OR?=?1.12, 95% CI?=?0.81-1.54, p?=?0.48) or with CERAD (OR?=?0.97, 95% CI?=?0.68-1.38, p?=?0.86) scores on analyses adjusted for sociodemographic and clinical variables. We observed effect modification by the APOE allele ?4 on the association between diabetes mellitus and BB scores.No evidence of an association between diabetes and AD neuropathology was found in a large sample of Brazilians; however, certain subgroups, such as APOE allele ?4 carriers, had higher odds of accumulation of neurofibrillary tangles.

SUBMITTER: Dos Santos Matioli MNP

PROVIDER: S-EPMC5892204 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

Dos Santos Matioli Maria Niures Pimentel MNP Suemoto Claudia Kimie CK Rodriguez Roberta Diehl RD Farias Daniela Souza DS da Silva Magnólia Moreira MM Leite Renata Elaine Paraizo REP Ferretti-Rebustini Renata Eloah Lucena REL Farfel José Marcelo JM Pasqualucci Carlos Augusto CA Jacob Filho Wilson W Arvanitakis Zoe Z Naslavsky Michel Satya MS Zatz Mayana M Grinberg Lea Tenenholz LT Nitrini Ricardo R

Journal of Alzheimer's disease : JAD 20170101 3

<h4>Background</h4>Previous evidence linking diabetes to Alzheimer's disease (AD) neuropathology is mixed and scant data are available from low- and middle-income countries.<h4>Objective</h4>To investigate the association between diabetes and AD neuropathology in a large autopsy study of older Brazilian adults.<h4>Methods</h4>In this cross-sectional study, diabetes was defined by diagnosis during life or use of antidiabetic medication. A standardized neuropathological examination was performed u ...[more]

PMID: 28984587

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Project description:Background Alzheimer’s disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. Previous studies of DNA modifications in Alzheimer’s disease have been unable to distinguish between DNA methylation and DNA hydroxymethylation. DNA hydroxymethylation has been shown to be enriched in the human brain, although its role in Alzheimer’s disease has not yet been fully explored. Here we utilize oxidative bisulfite conversion, in conjunction with the Illumina Infinium Human Methylation 450K microarray, to identify neuropathology-associated differential DNA methylation and DNA hydroxymethylation in the entorhinal cortex. Results We identified one experiment-wide significant differentially methylated position residing in the WNT5B gene. Next, we investigated pathology-associated regions consisting of multiple adjacent loci. We identified one significant differentially hydroxymethylated region consisting of four probes spanning 104 bases in the FBXL16 gene. We also identified two significant differentially methylated regions: one consisting of two probes in a 93 base-pair region in the ANK1 gene and the other consisting of six probes in a 99 base-pair region in the ARID5B gene. We also highlighted three regions that show alterations in unmodified cytosine: two probes in a 39 base-pair region of ALLC, two probes in a 69 base-pair region in JAG2, in addition to the same six probes in ARID5B that were differentially methylated. Finally we replicated significant ANK1 disease-associated hypermethylation and hypohydroxymethylation patterns across eight CpG sites in an extended 118 base-pair region in an independent cohort using oxidative-bisulfite pyrosequencing. Conclusions Our study represents the first epigenome-wide association study of both DNA methylation and hydroxymethylation in Alzheimer’s disease entorhinal cortex. We demonstrate that previous estimates of DNA hypermethylation in ANK1 in Alzheimer’s disease were underestimates as it is confounded by hypohydroxymethylation.

Project description:BackgroundAlzheimer's disease is a progressive neurodegenerative disorder that is hypothesized to involve epigenetic dysfunction. Previous studies of DNA modifications in Alzheimer's disease have been unable to distinguish between DNA methylation and DNA hydroxymethylation. DNA hydroxymethylation has been shown to be enriched in the human brain, although its role in Alzheimer's disease has not yet been fully explored. Here, we utilize oxidative bisulfite conversion, in conjunction with the Illumina Infinium Human Methylation 450K microarray, to identify neuropathology-associated differential DNA methylation and DNA hydroxymethylation in the entorhinal cortex.ResultsWe identified one experiment-wide significant differentially methylated position residing in the WNT5B gene. Next, we investigated pathology-associated regions consisting of multiple adjacent loci. We identified one significant differentially hydroxymethylated region consisting of four probes spanning 104 bases in the FBXL16 gene. We also identified two significant differentially methylated regions: one consisting of two probes in a 93 base-pair region in the ANK1 gene and the other consisting of six probes in a 99-base pair region in the ARID5B gene. We also highlighted three regions that show alterations in unmodified cytosine: two probes in a 39-base pair region of ALLC, two probes in a 69-base pair region in JAG2, and the same six probes in ARID5B that were differentially methylated. Finally, we replicated significant ANK1 disease-associated hypermethylation and hypohydroxymethylation patterns across eight CpG sites in an extended 118-base pair region in an independent cohort using oxidative-bisulfite pyrosequencing.ConclusionsOur study represents the first epigenome-wide association study of both DNA methylation and hydroxymethylation in Alzheimer's disease entorhinal cortex. We demonstrate that previous estimates of DNA hypermethylation in ANK1 in Alzheimer's disease were underestimates as it is confounded by hypohydroxymethylation.

Dataset Information

Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

Publications

Diabetes is Not Associated with Alzheimer's Disease Neuropathology.

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