Genetic reports abstractNegative resultsAbsence of A673T amyloid-β precursor protein variant in Alzheimer's disease and other neurological diseases
Introduction
The presence of amyloid plaque is a core pathological feature of Alzheimer's disease (AD) (Bateman et al., 2011). Mutations of amyloid-β precursor protein (APP) gene linked with autosomal-dominant Alzheimer's disease (ADAD) are associated with an increase in amyloid-β peptide products. Mutations adjacent to the β-secretase cleavage site increase cleavage by β-secretase, generating increased Aβ40 and Aβ42 from APP (Citron et al., 1992). APP mutations around the γ-secretase cleavage sites can lead to modification of γ-secretase activity, enhancing only the production of Aβ42 (Stenh et al., 2002). Although most of APP mutations are found in young-onset ADAD families, N660Y, a rare variant of APP gene, has also been described in a late-onset AD family (Cruchaga et al., 2012). Recently, Jonsson et al. (2012) identified a variant (A673T) in APP gene which was shown to protect against AD and cognitive decline in the elderly without AD in an Icelander cohort. In vitro studies showed that the variant led to an approximate 40% reduction in the formation of amyloidogenic peptides.
To date, replication studies have not been reported in Asian populations. As there appears to be a lower prevalence of dementia reported in epidemiological studies in Asia, it is possible that protective and risk factors differ across populations. To address this, we screened the APP A673T variant in a large cohort of Asian subjects.
Section snippets
Method
Subjects with AD and vascular dementia from 2 tertiary hospitals were identified and recruited into the study. Population controls and control group with a well-defined neurodegenerative disease (Parkinson's disease [PD]) were also recruited. Diagnosis of probable and possible AD was made by neurologists and specialists in dementia according to the criteria of the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association
Results
A total of 8721 subjects comprising 552 Alzheimer's disease and vascular dementia patients (aged 71.8 ± 9.2 years, 49.1% male, 61% AD), 790 Parkinson's disease patients (aged 68.1 ± 10.0 years, 57.5% male), 539 healthy controls (aged 51.7 ± 11.6 years, 56.6% male), and 6840 population controls (aged 46.5 ± 11.2 years, 73.5% male) were included. Approximately 95% of the subjects were ethnic Chinese, and the rest were of other or mixed Asian ethnicity. Genotyping revealed that none of the 8721
Discussion
Because independent replication is essential for genetic association studies, we have examined a recently reported, protective APP variant in a large cohort of Asian subjects comprising those with clinical dementia, those with PD, and healthy controls. The complete absence of the A673T variant suggests that this is possibly an ethnicity-specific variant. Epidemiological studies have shown that the prevalence of dementia in Asian countries is generally lower compared to that in western
Disclosure statement
The authors declare that they have no conflicts of interest in regard to this work.
Acknowledgements
The authors thank National Medical Research Council and Singapore Millennium Foundation for their support.
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Cited by (24)
Genomics of Alzheimer's disease: Value of high-throughput genomic technologies to dissect its etiology
2016, Molecular and Cellular ProbesCitation Excerpt :This variant decreases β-secretase processing of APP, leading to lower Aβ burden; clinically, it seems to protect elderly without cognitive impairment against cognitive decline and AD. Follow up studies in elderly from the United States suggested that this variant is extremely rare and might be primarily present in Icelandic and Scandinavian populations [49–52]. Several independent studies identified rare disease-associated variants at loci identified by GWAS (Table 1).
The APP A673T frequency differs between Nordic countries
2015, Neurobiology of AgingCitation Excerpt :Later studies, however, reported slightly lower frequencies in Nordic populations but these were not as low as the frequency seen in the Danes in the present work (Kero et al., 2013; Wang et al., 2015). However, more geographically distant population, that is, Northern Americans and Chinese reported even lower frequencies than in the Danes (Bamne et al., 2014; Liu et al., 2014; Ting et al., 2013). In the study by Jonsson et al., an enrichment of the APP 674T allele in elderly was observed and they estimated that the odds for rs63750847-A carriers of reaching age 85 years was 1.47-fold the odds of noncarriers when unadjusted for cohort differences (Jonsson et al., 2012).
Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer's disease
2014, Neurobiology of AgingCitation Excerpt :In fact, this variant was recently detected also in a 104.8-year-old Finnish demented subject who showed little β-amyloid pathology (Kero et al., 2013), further supporting the possibility that this mutation might protect against amyloid-β accumulation. Recent studies conducted in Asians, however, have found no example of this rare variant among Chinese individuals (Liu et al., 2013; Ting et al., 2013). In this study, we genotyped 4318 late-onset AD cases and older control subjects to determine the frequency of this variant among US Whites and its effect on modulating AD risk in this population.
Absence of A673T variant in APP gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals
2014, Neurobiology of AgingCitation Excerpt :More importantly, a significantly lower incidence of these diseases in the offspring of the nonagenarians than in their partners was observed (Westendorp et al., 2009), reinforcing a substantial role of genetic factor in contributing to longevity (Herskind et al., 1996). Taken together, it is possible that the protective variants such as A673T may be enriched or may be present only in the longevity samples, which explains the absence of variant A673T in Asian populations (Seng Ting et al., 2013) notwithstanding the fact that a huge number of subjects have been recruited and studied. Further genetic information from Asian samples, especially centenarians, would help to resolve the conflicting observations and provide further insight into the role of the variant A673T in AD.
Genetics of Alzheimer's disease
2014, Advances in GeneticsCitation Excerpt :This mutation is unique in two ways: it is the first mutation in APP to be associated with late-onset AD and it is the first protective mutation described in APP. Although, the existence of this mutation in LOAD is interesting in term of pathophysiology and identifying therapeutic targets, this result needs confirmation and so far, the variant has been very hard to find outside Iceland, as exemplified by the observation of one very old carrier (age of death 104.8 years old) with little Aβ brain pathology in a Finnish population (Kero et al., 2013) and absence of the variant in two large Asian studies from Singapore (n = 8721; (Ting et al., 2013)) and China (n = 2641; (Liu, He, et al., 2014)). Following similar methodology, the same team identified and replicated a rare variant in the TREM2 gene.