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      The Synergistic Effects of APOE Genotype and Obesity on Alzheimer’s Disease Risk

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          Abstract

          The APOE gene has three common alleles—E2, E3, and E4, with APOE4 being the strongest genetic risk factor for developing Alzheimer’s Disease (AD). Obesity is a global epidemic and contributes to multiple metabolic problems. Obesity is also a risk factor for cognitive decline. Here, we review the effects of APOE4 and obesity on cognition and AD development, independently and together. We describe studies that have associated APOE4 with cognitive deficits and AD, as well as studies that have associated obesity to cognitive deficits and AD. We then describe studies that have examined the effects of obesity and APOE genotypes together, with a focus on APOE4 and high fat diets. Both human studies and rodent models have contributed to understanding the effects of obesity on the different APOE genotypes, and we outline possible underlying mechanisms associated with these effects. Data across approaches support a model in which APOE4 and obesity combine for greater detrimental effects on metabolism and cognition, in ways that are influenced by both age and sex.

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          Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases.

          Yadong Huang, Robert Mahley (2014)
          Apolipoprotein (apo) E is a multifunctional protein with central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. It has three major isoforms (apoE2, apoE3, and apoE4) with different effects on lipid and neuronal homeostasis. A major function of apoE is to mediate the binding of lipoproteins or lipid complexes in the plasma or interstitial fluids to specific cell-surface receptors. These receptors internalize apoE-containing lipoprotein particles; thus, apoE participates in the distribution/redistribution of lipids among various tissues and cells of the body. In addition, intracellular apoE may modulate various cellular processes physiologically or pathophysiologically, including cytoskeletal assembly and stability, mitochondrial integrity and function, and dendritic morphology and function. Elucidation of the functional domains within this protein and of the three-dimensional structure of the major isoforms of apoE has contributed significantly to our understanding of its physiological and pathophysiological roles at a molecular level. It is likely that apoE, with its multiple cellular origins and multiple structural and biophysical properties, is involved widely in processes of lipid metabolism and neurobiology, possibly encompassing a variety of disorders of neuronal repair, remodeling, and degeneration by interacting with different factors through various pathways. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Central obesity and increased risk of dementia more than three decades later.

            R Whitmer, D Gustafson, E Barrett-Connor … (2008)
            Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later. A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted. A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33-3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58-2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98-3.81) vs those with low SAD ( 30 kg/m(2)) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85-4.55). Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.
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              Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults.

              Gerard D. Schellenberg, Michelle L Baker, Mark A Reger … (2008)
              Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimer's disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.
              Article 0 comments Cited 165 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 24 December 2018
                Publication date Collection: January 2019
                Volume: 20
                Issue: 1
                Electronic Location Identifier: 63
                Affiliations
                Department of Neuroscience, Georgetown University, 3970 Reservoir Rd NW, Washington, DC 20007, USA; nsj10@ 123456georgetown.edu
                Author notes
                [* ]Correspondence: gwr2@ 123456georgetown.edu
                Author information
                https://orcid.org/0000-0001-6276-248X
                Article
                Publisher ID: ijms-20-00063
                DOI: 10.3390/ijms20010063
                PMC ID: 6337558
                PubMed ID: 30586872
                SO-VID: 1daee79c-fd5e-4605-93de-024338f329e0
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 December 2018
                Date accepted : 20 December 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: apolipoprotein e,obesity,alzheimer’s disease,cognition,metabolism
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: apolipoprotein e, obesity, alzheimer’s disease, cognition, metabolism

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