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Neurobiology of Aging 35 (2014) 935.e11e935.e12

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Neurobiology of Aging

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Negative results

Absence of A673T variant in APP gene indicates an alternative protectivemechanism contributing to longevity in Chinese individuals

Yao-Wen Liu a,c,d, Yong-Han He a,c, Yun-Xia Zhang b, Wang-Wei Cai b,*, Li-Qin Yang a,c, Liang-You Xu e,Qing-Peng Kong a,c,*

a State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, ChinabDepartment of Biochemistry and Molecular Biology, Hainan Medical College, Haikou, ChinacKIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming, ChinadUniversity of the Chinese Academy of Sciences, Beijing, ChinaeDujiangyan Longevity Research Centre, Dujiangyan, China

a r t i c l e i n f o

Article history:Received 23 August 2013Received in revised form 13 September 2013Accepted 16 September 2013Available online 12 October 2013

Keywords:Alzheimer’s diseaseAmyloid precursor proteinA673TLongevityChinese

* Corresponding author at: State Key Laboratory oflution, Kunming Institute of Zoology, Chinese Acad650223, China. Tel./fax: þ86 871 65197967 or DepaMolecular Biology, Hainan Medical College, Haikou66968753; fax:þ86-898 66893170.

E-mail addresses: caiww591020@163.com (W.-W.(Q.-P. Kong).

0197-4580/$ e see front matter � 2014 Elsevier Inc. Ahttp://dx.doi.org/10.1016/j.neurobiolaging.2013.09.023

a b s t r a c t

A673T, a rare variant in the amyloid-b precursor protein gene, shows a protective potential againstAlzheimer’s disease (AD) and age-related cognitive decline in an Icelandic population. Although A673Twas observed independently in a Finnish population, this variant was absent in 8721 Asian subjects. Theconflicting observations suggest that the contribution of A673T may be confined to Europeans andAmericans rather than Asians. Nevertheless, A673T confers a protective function against AD and thusmay be observed only in longevity subjects; thus it is not surprising to see its absence when the generalpopulations or the patient cohorts were considered. To test whether the A673T contributes to the Chi-nese population, 1237 healthy longevity subjects (mean age 96.9 years) and 1404 matched youngercontrols (mean age 44.2 years) were genotyped for the variant. Our study failed to observe this variant ineither the longevity subjects or the controls. Given the previous observation from Asians, our resultssuggest that the A673T variant is not involved in longevity in Chinese individuals; some other pro-tective mechanisms may contribute to a lower incidence of AD in Chinese nonagenerians andcentenarians.

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1. Introduction

Alzheimer’s disease (AD) is an age-dependent disease thatcontributes to approximately 69.9% of the dementia that is preva-lent in persons older than 60 years (Plassman et al., 2007). Nearly35.6 million persons experience dementia, and this number willclimb to 65.7 million by 2030 (WHO, 2012). AD is a disease char-acterized by central nervous system degeneration that producesprogressive memory impairment, cognitive dysfunction, personal-ity changes, and linguistic difficulties, and other neuropsychiatricsymptoms. Previous studies have suggested that mutations inthe amyloid-b precursor protein (APP) exons 16 and 17, encodingthe b-amyloid peptide, contributed to occurrence of the disease(Brouwers et al., 2008). However, a recently observed rare mutation

Genetic Resources and Evo-emy of Sciences, Kunmingrtment of Biochemistry and571199, China. Tel.:þ86-898

Cai), kongqp@mail.kiz.ac.cn

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A673T in APP exon 16 was suggested to significantly reduce thegeneration of harmful b-amyloid, thereby decreasing the occurrenceof AD and cognitive decline in an elderly Icelandic population(Jonsson et al., 2012). Although A673T was confirmed by an inde-pendent study in a Finnish population (Kero et al., 2013), a recentreport showed that this variant was completely absent in 8721 Asiansubjects, raising the possibility that the A673Tmay not be relevant toAsian populations (Seng Ting et al., 2013).

Nonetheless, the A673T variant protects against AD, it may bepresent and even enriched in the healthy elderly individuals, asevidenced by the observation that A673T is present at a higherproportion in the elderly persons in Iceland (Jonsson et al., 2012)and is present in a 104.8-year-old Finnish woman (Kero et al., 2013).It is thus not surprising to observe its absence when general pop-ulations or patients with AD or Parkinson’s disease (PD) wereconsidered. Consistently, centenarians show the ability to delay orescape age-related diseases such as heart disease, hypertension,and PD (Evert et al., 2003). More importantly, a significantly lowerincidence of these diseases in the offspring of the nonagenariansthan in their partners was observed (Westendorp et al., 2009),reinforcing a substantial role of genetic factor in contributing to

Table 1Genotyping results of A673T in Hainan and Sichuan populations by using DNA directsequencing and HRM

Sample location Sample No. Meanage, y

A673T

Hainan Province,China

Nonagenarians (90e99 y old) 150 98.3 0Centenarians (�100 y old) 404 102.0 0Younger controls (�70 y old) 1,042 41.4 0

Sichuan Province,China

Nonagenarians (90e99 y old) 644 93.2 0Centenarians (�100 y old) 39 101.7 0Younger controls (�70 y old) 362 52.4 0

Key: HRM, high-resolution melting.

Y.-W. Liu et al. / Neurobiology of Aging 35 (2014) 935.e11e935.e12935.e12

longevity (Herskind et al., 1996). Taken together, it is possible thatthe protective variants such as A673T may be enriched or may bepresent only in the longevity samples, which explains the absenceof variant A673T in Asian populations (Seng Ting et al., 2013)notwithstanding the fact that a huge number of subjects have beenrecruited and studied. Further genetic information from Asiansamples, especially centenarians, would help to resolve the con-flicting observations and provide further insight into the role of thevariant A673T in AD.

2. Methods

A total of 2641 Chinese subjects were included in the presentstudy. DNA samples of 1596 subjects including 554 healthylongevity subjects (150 nonagenarians with mean age of 98.3 yearsand 404 centenarians with mean age of 102.0 years) and 1042controls (mean age of 41.4 years) from Hainan Province weresequenced on an ABI3730xl Genetic Analyzer (ABI, USA). To repli-cate the result from Hainan samples, 1045 additional samplesincluding 683 longevity individuals (644 nonagenarians with meanage of 93.2 years and 39 centenarians with a mean age of 101.7years) and 362 controls (mean age of 52.4 years) from SichuanProvince were examined using a high-resolution melting (HRM)on a lightcycler 480 High Resolution Melting Master (Roche,Switzerland). For replication of the HRM results, sequencing of exon16 in 5% of the HRM samplewas also carried out using an ABI3730xlGenetic Analyzer.

3. Results and discussion

In this study, by genotyping a total of 2641 Chinese subjects,comprising 1237 longevity individuals (794 nonagenarians and 443centenarians) and 1404 younger controls, our results revealed thatnone of the 2641 subjects carried the alanine-to-threonine substi-tution at position 673 in APP (A673T) (Table 1). Although the pro-tective potential of A673T against AD makes it plausible that thisvariant may be present or even enriched in the longevity samples,the complete absence of the A673T in our longevity individualssuggests that this variant does not play a protective role in theChinese population, in agreement with a previous report that thisvariant was not observed in Asian populations and patients with ADor PD in Asia (Seng Ting et al., 2013).

Hitherto, A673T mutation has been observed in European andNorth American populations with a relatively low frequency (0.45%in Iceland and 0.014% in North America) (Jonsson et al., 2012;

Exome Variant Server, 2012). Our failure to observe the variant inAPP exon 16, plus the fact that the prevalence of AD in Asia (3.9%)was much lower than that in Europe (6.2%) and America (6.5%)(Prince and Jackson, 2009), suggests that some other protectivemechanism(s) may contribute to longevity in Chinese individuals.Further research on the other AD-associated genes such as ApoE inthe healthy longevity individuals would help to disclose moreplausibly existing protective genetic factors against AD.

Disclosure statement

The authors declare that they have no conflicts of interest inregard to this work.

Acknowledgements

This work was supported by grants from the National BasicResearch Program of China (2013CB530802), Yunnan Province(2011FA024), the Chinese Academy of Sciences, and Natural ScienceFoundation of China (31100909 and 31322029), and the Departmentof Science and Technology of Hainan Province (013GHXM0025 andZDXM20090805).

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