APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study

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Abstract

Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir ( ¹⁸F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10 ⁻¹⁴) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10 ⁻⁸) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample ( APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.

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Most cited references 28

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Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

E H Corder, A M Saunders, W J Strittmatter … (1993)

The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.

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The role of apolipoprotein E in Alzheimer's disease.

Jungsu Kim, Jacob Basak, David Holtzman (2009)

The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.

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An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

Theresa R Bomfim, Letícia Forny-Germano, Luciana B. Sathler … (2012)

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9607835

Journal ID (pubmed-jr-id): 20545

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol. Psychiatry

Title: Molecular psychiatry

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date Nihms-submitted: 15 January 2013

Publication date (Electronic): 19 February 2013

Publication date (Print): March 2014

Publication date PMC-release: 01 September 2014

Volume: 19

Issue: 3

Pages: 351-357

Affiliations

[1 ]Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana Alzheimer’s Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA

[2 ]Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

[3 ]Medical Scientist Training Program, Indiana University School of Medicine, Indianapolis, IN, USA

[4 ]Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA

[5 ]Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

[6 ]The Translational Genomics Institute (TGen), Phoenix, AZ, USA

[7 ]Department of Neuroscience, University of California-San Diego, San Diego, CA, USA

[8 ]Department of Neurology, Mayo Clinic Minnesota, Rochester, MN, USA

[9 ]Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

[10 ]Department of Radiology, Mayo Clinic Minnesota, Rochester, MN, USA

[11 ]Department of Radiology, University of Michigan, Ann Arbor, MI, USA

[12 ]Department of Neurology, University of California-Berkeley, Berkeley, CA, USA

[13 ]Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA, USA

[14 ]Department of Veterans Affairs Medical Center, San Francisco, CA, USA

Author notes

[* ]Correspondence to: Dr. Andrew J. Saykin, IU Health Neuroscience Center, Suite 4100, Indiana University School of Medicine, 355 West 16 ^th Street, Indianapolis, IN 46202, USA, asaykin@ 123456iupui.edu , Phone (317)278-6947, Fax (317)274-1067

[Ω]

Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database ( http://www.adni.loni.ucla.edu). As such, the investigators within ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf/.

Article

Manuscript ID: NIHMS435300

DOI: 10.1038/mp.2013.19

PMC ID: 3661739

PubMed ID: 23419831

SO-VID: 3432cd38-668b-451f-ab12-ea15fa12d4bc

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