ApoE genotype accounts for the vast majority of AD risk and AD pathology

Raber, Jacob; Huang, Yadong; Ashford, J. Wesson

doi:10.1016/j.neurobiolaging.2003.12.023

Cited by 522 publications

(397 citation statements)

References 60 publications

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“…Men have higher brain iron levels than women [21], and men also have a younger age at onset of AD [27,28]. In large representative American populations after statistically controlling for the risk associated with the apolipoprotein E (APOE) genotype, men have a peak risk for AD onset that is 5 years younger than in women [29,30]. Thus, the peak probability of AD is reached 5 years earlier for men than women: age 78 and 83 years for APOE e4/e4, age 91 and 96 for APOE eX/eX, and age 92 and 97 for APOE e4/eX, respectively [29].…”

Section: Introductionmentioning

confidence: 99%

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Bartzokis

Mintz

2007

Alzheimer's & Dementia

138

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We hypothesized that myelin breakdown in vulnerable late-myelinating regions releases oligodendrocyte-and myelin-associated iron that promotes amyloid beta (Aβ) oligomerization, its associated toxicity, and the deposition of oligomerized Aβ and iron in neuritic plaques observed in Alzheimer's disease (AD). The model was tested by using published maps of cortical myelination from 1901 and recent in vivo imaging maps of Aβ deposits in humans. The data show that in AD, radiolabeled ligands detect Aβ deposition in a distribution that matches the map of late-myelinating regions. Furthermore, the strikingly lower ability of this imaging ligand to bind Aβ in animal models is consistent with the much lower levels of myelin and associated iron levels in rodents when compared with humans. The hypotheses derived from the "myelin model" are testable with current imaging methods and have important implications for therapeutic interventions that should be expanded to include novel targets such as oligodendrocytes, myelin, and brain iron.

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Section: Introductionmentioning

confidence: 99%

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Bartzokis

Mintz

2007

Alzheimer's & Dementia

138

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“…26 However, the strong relationship between APOE and AD has been repeatedly verified and warrants special attention. 27 From the …”

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confidence: 99%

“…26 However, the strong relationship between APOE and AD has been repeatedly verified and warrants special attention. 27 The rising prevalence of dementia combined with the relatively high frequency of the APOE ⑀4 allele, found in about 23% of the US population, 27 make AD a useful model for exploring genetic risk communication and assessment for common, complex, adult-onset diseases. The Risk EValuation and Education for Alzheimer Disease (REVEAL) study is a series of clinical trials examining the psychosocial and behavioral impact of providing susceptibility testing with APOE genotype disclosure to first-degree relatives (FDRs) of people with AD.…”

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confidence: 99%

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

Christensen

Roberts

Royal

et al. 2008

Genetics in Medicine

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Purpose: To describe how investigators in a multisite randomized clinical trial addressed scientific and ethical issues involved in creating risk models based on genetic testing for African American participants. Methods: The following informed our decision whether to stratify risk assessment by ethnicity: evaluation of epidemiological data, appraisal of benefits and risks of incorporating ethnicity into calculations, and feasibility of creating ethnicityspecific risk curves. Once the decision was made, risk curves were created based on data from a large, diverse study of first-degree relatives of patients with Alzheimer disease. Results: Review of epidemiological data suggested notable differences in risk between African Americans and whites and that Apolipoprotein E genotype predicts risk in both groups. Discussions about the benefits and risks of stratified risk assessments reached consensus that estimates based on data from whites should not preclude enrolling African Americans, but population-specific risk curves should be created if feasible. Risk models specific to ethnicity, gender, and Apolipoprotein E genotype were subsequently developed for the randomized clinical trial that oversampled African Researchers are identifying a growing number of genetic markers that are associated with increased or decreased risk for common, complex diseases. Consequently, the development of genetic risk assessment and risk communication strategies are areas of critical importance, especially given that laypersons often have a difficult time in understanding probabilistic information. 1,2 Protocols for disclosing genetic information have been developed and refined for various forms of cancer, 3-6 but similar efforts have been made only recently for other diseases. 7,8 One area of recent focus is Alzheimer disease (AD).AD is the most common form of dementia among the elderly, affecting an estimated five million individuals in the United States. Well over 10 million Americans are expected to have the condition by 2050 as the population continues to age. 9 Many risk factors are well-characterized, including age and family history, 10 -14 whereas many others are under investigation, including education level, 15,16 head trauma, 17,18 high blood pressure, 19 caloric intake, and high cholesterol. 20,21 Regarding genetic factors, rare mutations on genes coding for amyloid precursor protein, presenilin 1, and presenilin 2 have been identified that are deterministic for early-onset AD. 22 Apolipoprotein E (APOE), in contrast, affects susceptibility to AD and has three major forms. APOE ⑀3, the most common allele, is found in over half the US population. The ⑀4 allele is associated with increased risk for AD whereas the ⑀2 allele has a protective effect. 23,24 The ⑀4 allele is neither necessary nor sufficient for AD though, and individuals with the ⑀2 allele still have risk for AD. APOE variants are also associated with other conditions such as hyperlipoproteinemia and atherosclerosis 25 and may play a role in the development of ma...

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“…Analysis of clinical observations based on the AD map may enable us to understand the mechanism underlying the development of this disease. For example, clinical studies indicate that the risk of developing AD is correlated with an individual's ApoE genotype [36]. Thus, future AD map-based analysis of clinical data may provide insights into the pathological roles of different ApoE genotypes.…”

Section: Currently Reported Comprehensive Pathway Mapsmentioning

confidence: 99%

Systems‐based understanding of pharmacological responses with combinations of multidisciplinary methodologies

Kariya

Honma

Suzuki

2013

Biopharm & Drug Disp

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The importance of systems-based pharmacological approaches to drug discovery and development has increasingly been recognized. This reviews summarizes recent advances in the development of systems pharmacology and introduces the methods used for analysis. To understand the cellular response at the molecular level, pathway maps must be prepared to show how the function of the constituent molecules within cells are linked and integrated to form molecular networks. First, the methods used to prepare these pathway maps, such as databases, knowledge bases and software platforms, are introduced. Then the mathematical theories used to analyse the behavior of molecular networks are summarized. To quantitatively predict cellular responses, simulations are performed that are based on the rate equations for each reaction within the pathway map. If the number of reactions described in the pathway map is small, and if the parameter values for the rate constants are available, it is possible accurately to simulate the behavior of the molecular networks. However, to analyse complex maps, mathematical abstraction is required. Such abstraction methods are important to integrate cellular responses and to understand tissue/organ and in vivo pharmacological/toxicological responses. The scope and limitations of the methods are also discussed.

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ApoE genotype accounts for the vast majority of AD risk and AD pathology

Cited by 522 publications

References 60 publications

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Human brain myelination and amyloid beta deposition in Alzheimer's disease

Incorporating ethnicity into genetic risk assessment for Alzheimer disease: the REVEAL study experience

Systems‐based understanding of pharmacological responses with combinations of multidisciplinary methodologies

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