Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life

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Abstract

Background: Possession of APOE ɛ4 is a strong risk factor for late-onset Alzheimer’s disease and is associated with loss of synaptic proteins in the elderly even in the absence of Alzheimer’s disease.

Objective: We hypothesized that ɛ4 allele possession in non-demented adults aged under-75 would also be associated with alterations in the levels of synaptic proteins.

Methods: We measured synaptophysin, PSD95, drebrin, SNAP-25, and septin 7 by ELISA in hippocampus and superior temporal gyrus from 103 adults aged <75 without dementia. Corresponding gene expression was measured by RT-PCR.

Results: There was no evidence that ɛ4 affected levels of the proteins measured. Instead we found an increase in post-synaptic proteins in the hippocampi of those with an ɛ32 genotype. The evidence was strongest for drebrin ( p = 0.011). There was some evidence of increased synaptic protein gene expression in ɛ4 carriers.

Conclusions: People with an APOE ɛ32 genotype have a reduced risk of Alzheimer’s disease. It may be relevant that they have a higher level of post-synaptic proteins in the hippocampus even in earlier adulthood.

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Most cited references 53

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Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

Lars Bertram, Matthew B. McQueen, Kristina Mullin … (2007)

The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.

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Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation.

Peng Lu, Christine Vogel, Rong. Wang … (2007)

We report a method for large-scale absolute protein expression measurements (APEX) and apply it to estimate the relative contributions of transcriptional- and translational-level gene regulation in the yeast and Escherichia coli proteomes. APEX relies upon correcting each protein's mass spectrometry sampling depth (observed peptide count) by learned probabilities for identifying the peptides. APEX abundances agree with measurements from controls, western blotting, flow cytometry and two-dimensional gels, as well as known correlations with mRNA abundances and codon bias, providing absolute protein concentrations across approximately three to four orders of magnitude. Using APEX, we demonstrate that 73% of the variance in yeast protein abundance (47% in E. coli) is explained by mRNA abundance, with the number of proteins per mRNA log-normally distributed about approximately 5,600 ( approximately 540 in E. coli) protein molecules/mRNA. Therefore, levels of both eukaryotic and prokaryotic proteins are set per mRNA molecule and independently of overall protein concentration, with >70% of yeast gene expression regulation occurring through mRNA-directed mechanisms.

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2015 Alzheimer's disease facts and figures.

(2015)

This report discusses the public health impact of Alzheimer’s disease (AD), including incidence and prevalence, mortality rates, costs of care and the overall effect on caregivers and society. It also examines the challenges encountered by health care providers when disclosing an AD diagnosis to patients and caregivers. An estimated 5.3 million Americans have AD; 5.1 million are age 65 years, and approximately 200,000 are age <65 years and have younger onset AD. By mid-century, the number of people living with AD in the United States is projected to grow by nearly 10 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year, and the estimated prevalence is expected to range from 11 million to 16 million. In 2013, official death certificates recorded 84,767 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 years. Between 2000 and 2013, deaths resulting from heart disease, stroke and prostate cancer decreased 14%, 23% and 11%, respectively, whereas deaths from AD increased 71%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2015, an estimated 700,000 Americans age 65 years will die with AD, and many of them will die from complications caused by AD. In 2014, more than 15 million family members and other unpaid caregivers provided an estimated 17.9 billion hours of care to people with AD and other dementias, a contribution valued at more than $217 billion. Average per-person Medicare payments for services to beneficiaries age 65 years with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2015 for health care, long-term care and hospice services for people age 65 years with dementia are expected to be $226 billion. Among people with a diagnosis of AD or another dementia, fewer than half report having been told of the diagnosis by their health care provider. Though the benefits of a prompt, clear and accurate disclosure of an AD diagnosis are recognized by the medical profession, improvements to the disclosure process are needed. These improvements may require stronger support systems for health care providers and their patients.

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Author and article information

Journal

Journal ID (nlm-ta): J Alzheimers Dis

Journal ID (iso-abbrev): J. Alzheimers Dis

Journal ID (publisher-id): JAD

Title: Journal of Alzheimer's Disease

Publisher: IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )

ISSN (Print): 1387-2877

ISSN (Electronic): 1875-8908

Publication date (Electronic, preprint): 17 July 2017

Publication date (Electronic, pub): 29 July 2017

Publication date (Electronic, collection): 2017

Volume: 59

Issue: 3

Pages: 1123-1137

Affiliations

[a ]School of Social and Community Medicine, University of Bristol , Oakfield House, Clifton, Bristol, UK

[b ]School of Clinical Sciences, University of Bristol , Level 1 Learning and Research Building, Southmead Hospital, Bristol, UK

Author notes

[* ]Correspondence to: Dr. Lindsey Sinclair, Dementia Research Group, Level 1 Learning and Research Building, Southmead Hospital, Bristol BS10 5NB, UK. Tel.: +44 0117 4147807; E-mail: lindsey.sinclair@ 123456bristol.ac.uk .

Article

Publisher ID: JAD170316

DOI: 10.3233/JAD-170316

PMC ID: 5545905

PubMed ID: 28731446

SO-VID: f5fa01e5-f62c-439f-90ab-59790f2256e9

License:

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY 4.0) License.

History

Date accepted : 6 June 2017

Effect of APOE Genotype on Synaptic Proteins in Earlier Adult Life

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Karger: Neurology and Neuroscience

Most cited references 53

Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database.

Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation.

2015 Alzheimer's disease facts and figures.

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