Apolipoprotein E ε4 and Age at Onset of Sporadic and Familial Alzheimer Disease in Caribbean Hispanics

Olarte, Lucia S.; Schupf, Nicole; Lee, Joseph H.; Tang, Mingxin; Santana, Vincent; Williamson, Jennifer; Maramreddy, Prashanthi; Tycko, Benjamin; Mayeux, Richard

doi:10.1001/archneur.63.11.1586

Cited by 42 publications

(44 citation statements)

References 32 publications

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“…Specifically, ε4 appears to influence rate of decline primarily in Caucasians rather than Hispanics and African Americans. This pattern of results is largely consistent with the literature examining the risk for developing AD (38) although there is some evidence for ε4 as a factor in Hispanic (42,43) and African American populations as well (44).…”

Section: Discussionsupporting

confidence: 89%

APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease

et al. 2008

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Objective-To determine whether APOE ε4 predicts rate of cognitive change in incident and prevalent AD.Methods-Individuals were recruited from two longitudinal cohort studies -the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and were followed for an average of four years. Three samples of participants diagnosed with Alzheimer's disease, with diverse demographic characteristics and baseline cognitive functioning were studied: 1) 199 (48%) of the incident WHICAP cases; 2) 215 (54%) of the prevalent WHICAP cases; and 3)156 (71%) of the individuals diagnosed with AD in the Predictors Study. Generalized estimating equations (GEE) were used to test whether rate of cognitive change, measured using a composite cognitive score in WHICAP and the Mini-Mental Status Exam in Predictors, varied as a function of ε4 status in each sample.Results-The presence of at least one ε4 allele was associated with faster cognitive decline in the incident population-based AD group (p = .01). Parallel results were produced for the two prevalent dementia samples only when adjusting for disease severity or excluding the most impaired participants from the analysis.Conclusion-APOE ε4 may influence rate of cognitive decline most significantly in the earliest stages of AD.

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Section: Discussionsupporting

confidence: 89%

APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease

et al. 2008

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“…This risk factor is dose dependent such that the likelihood of LOAD increases with the number of 4 alleles, specifically " / " < " 4/ " < " 4/ 4" [24]. The risk imposed by APOE 4 is greater among younger carriers than older carriers [25]. The APOE 4 allele also acts to modify FAD mutations on APP, but it is less effective a modifier to some PSEN1 mutations [26].…”

Section: Familial Ad (Fad) and Other Genetic Factors Behind Admentioning

confidence: 99%

Applying Epigenetics to Alzheimer’s Disease via the Latent Early–life Associated Regulation (LEARn) Model

Maloney

Sambamurti

Zawia

et al. 2012

CAR

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Alzheimer's disease (AD) is a leading cause of aging related dementia and has been extensively studied by several groups around the world. A general consensus, based on neuropathology, genetics and cellular and animal models, is that the 4 kDa amyloid β protein (Aβ) triggers a toxic cascade that induces microtubule-associated protein τ (MAPT) hyperphosphorylation and deposition. Together, these lesions lead to neuronal dysfunction and neurodegeneration, modeled in animals, that ultimately causes dementia. Genetic studies show that a simple duplication of the Aβ precursor (APP) gene, as occurs in Down syndrome (trisomy 21), with a 1.5-fold increase in expression, can cause dementia with the complete AD associated neuropathology. The most fully characterized form of AD is early onset familial AD (FAD). Unfortunately, by far the most common form of AD is late onset AD (LOAD). FAD has well-identified autosomally dominant genetic causes, absent in LOAD. It is reasonable to hypothesize that environmental influences play a much stronger role in etiology of LOAD than of FAD. Since AD pathology in LOAD closely resembles FAD with accumulation of both Aβ and MAPT, it is likely that the environmental factors foster accumulation of these proteins in a manner similar to FAD mutations. Therefore, it is important to identify environmentally driven changes that "phenocopy" FAD in order to find ways to prevent LOAD. Epigenetic changes in expression are complex but stable determinants of many complex traits. Some aspects are regulated by prenatal and early post-natal development, others punctuate specific periods of maturation, and still others occur throughout life, mediating predictable changes that take place during various developmental stages. Environmental agents such as mercury, lead, and pesticides can disrupt the natural epigenetic program and lead to developmental deficits, mental retardation, feminization, and other complex syndromes. In this review we discuss latent early- life associated regulation (LEARn), where apparently temporary changes, induced by environmental agents, become latent and present themselves again at maturity or senescence to increase production of Aβ that may cause AD. The model provides us with a novel direction for identifying potentially harmful agents that may induce neurodegeneration and dementia later in life and provides hope that we may be able to prevent age-related neurodegenerative disease by "detoxifying" our environment.

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“…More recent studies have demonstrated significant ApoE association and age-at-onset effect in Caribbean Hispanics with familial (but not sporadic) LOAD [ 105,106 ], suggesting role of additional genes and other gene x ApoE effects in this population. The discrepancies between the ApoE ε4 frequencies and AD associations between Hispanic populations of different source and geography imply the effects of genetic and possibly environmental heterogeneity in this ethnic group, as well [ 107 ].…”

Section: Load Geneticsmentioning

confidence: 99%

“…Although ApoE genotyping increased specificity (decreased false positive rate) when a clinical diagnosis of AD is made, this association is not absolute, such that there are individuals who lack the ApoE ε4 allele and have pathologically confirmed AD, as well as those with ApoE ε4 and cognitive impairment but non-AD pathology. Thus, ApoE genotyping is not advocated as part of the diagnostic work-up for AD [ 106 ].…”

Section: ) Role Of Apoe For the Diagnosis Of Ad And As A Premorbid Mmentioning

confidence: 99%

Genetics of Alzheimer's Disease: A Centennial Review

2007

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Alzheimer's disease (AD) genetics may be one of the most prolifically published areas in medicine and biology. There are nearly 200 reviews on this topic since 1991, when the first report on an autosomal dominant mutation in the amyloid precursor protein gene (APP) came out. Three earlyonset AD genes with causative mutations (APP, PS1, PS2) and one late-onset AD susceptibility gene (ApoE) exist with ample biological, genetic and epidemiological data and essentially universal acceptance about their roles in AD. Evidence from family and twin studies suggest a significant genetic component underlying AD which is not explained by the known genetic risk factors. The past 10 years in AD genetics research have led to ten independent whole genome linkage and association studies with implications for multiple genomic areas for harboring AD susceptibility genes. To date, there are about 900 papers reporting associations between variations in more than 350 genes spread over 23 autosomes. One hundred years after the first published article on Alzheimer's disease, much is known about the pathophysiology of this disease, however much more remains to be discovered about its etiology. This review summarizes the evidence for the genetic component in AD, identification of the early-onset familial AD genes and ApoE, and the current state of knowledge for additional AD susceptibility loci and alleles. The future directions for genetic research in Alzheimer's disease as a common and complex condition are also discussed.

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Apolipoprotein E ε4 and Age at Onset of Sporadic and Familial Alzheimer Disease in Caribbean Hispanics

Cited by 42 publications

References 32 publications

APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease

APOE ε4 allele predicts faster cognitive decline in mild Alzheimer disease

Applying Epigenetics to Alzheimer’s Disease via the Latent Early–life Associated Regulation (LEARn) Model

Genetics of Alzheimer's Disease: A Centennial Review

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