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. 2016 Apr 18;71(8):1069–1073. doi: 10.1093/gerona/glw053

Meta-analysis of Telomere Length in Alzheimer’s Disease

Diego A Forero 1,✉, Yeimy González-Giraldo 2, Catalina López-Quintero 3, Luis J Castro-Vega 4, George E Barreto 2,5, George Perry 6
PMCID: PMC4945891  PMID: 27091133

Abstract

Background:

Alzheimer’s disease (AD) is a common and severe neurodegenerative disorder. Human telomeres are fundamental for the maintenance of genomic stability and play prominent roles in both cellular senescence and organismal aging. Regulation of telomere length (TL) is the result of the complex interplay between environmental and genetic factors. Alterations in TL are increasingly being studied as a possible risk factor for AD, and published studies on TL in AD show discrepant results, highlighting the need for a meta-analysis.

Methods:

In the current study, we carried out a meta-analysis of published studies of TL in AD patients and healthy controls. PubMed, Web of Science and Google Scholar databases (from inception to September 2015) were used to identify relevant articles reporting TL in humans with AD, from which we retrieved data such as sample size, experimental methods, and mean TL for cases and controls. A random-effects model was used for meta-analytical procedures.

Results:

The meta-analysis included 13 primary studies and demonstrated a significant difference in TL between 860 AD patients and 2,022 controls, with a standardized mean difference of −0.984 (confidence interval: −1.433 to −0.535; p value: <.001).

Conclusions:

Our results show a consistent evidence of shorter telomeres in AD patients and highlight the importance of the analysis of epigenomic markers associated with neurodegeneration and with the risk for common and severe neurological diseases, such as AD.

Keywords: Dementia, Epigenomics, Telomeres, Alzheimer’s disease, Meta-analysis

Introduction

Alzheimer’s disease (AD) is a common and severe neurodegenerative disorder (1). Genomic studies have identified several causal genes for hereditary subtypes of AD (such as APP, PSEN1, and PSEN2) and susceptibility genes for its multifactorial forms (such as APOE, CLU, and CR1) (1,2). Several theories about the etiology and pathophysiology of AD have been developed, which highlight the importance of mechanisms involved in the response to cell-intrinsic and cell-extrinsic stresses and of alterations in neural plasticity (1,3).

Human telomeres are ribonucleoprotein structures that consist of a repetitive DNA sequence (TTAGGG) and a core of associated proteins called shelterin. The capping function of telomeres at the extremities of chromosomes is fundamental for the maintenance of genomic stability (4). Compelling evidence has shown that telomere shortening leads to cellular senescence and is also present with aging in several organisms. In fact, alterations in telomere length (TL) have been reported as critical factors in age-related diseases, including cancer and neurodegenerative disorders (4). Regulation of TL is the result of the interplay between multiple environmental and genetic factors. For instance, it has been suggested that telomere maintenance mechanisms play an important role in the response and plasticity of postmitotic neurons to oxidative and genomic stress (4,5). TL is increasingly being studied as a possible epigenomic marker associated with several neuropsychiatric disorders, such as AD, Parkinson’s disease, vascular dementia, unipolar depression, bipolar disorder, and schizophrenia, among others (6).

Results from published studies for TL in AD are contradictory (7,8), highlighting the need for a meta-analysis. In the current study, we carried out a meta-analysis of published studies for TL, which compared DNA samples of AD patients with samples from healthy controls.

Methods

We followed the recommendations of the PRISMA statement (9) for reporting of meta-analyses (Supplementary Figure S1). There was no previously published review protocol. We searched for original studies analyzing TL in AD patients and control participants in the PubMed, Web of Science, and Google Scholar databases (from inception to September 2015). We combined disease search terms “Alzheimer’s disease” and “telomere.” In addition, we searched reference lists of relevant review and original papers to identify additional papers not covered by the electronic search of abstracts.

We included articles published in English in peer-reviewed journals that described results from case–control studies analyzing the association of TL with AD in different ethnic populations. Exclusion criteria were as follows: lack of control groups, analysis of other types of dementia, or studies of telomerase activity.

We extracted the following information from each one of the included studies: year, country, sample size, age and gender distributions, criteria used for AD diagnosis, disease severity and duration, cell types used for DNA extraction, methodologies used for the analysis of TL, and TL data (mean and SD) for patient and control groups. In cases of missing data, we contacted the corresponding authors to ask TL data that were not available in the main text of the articles or in the Supplementary Material. Quality assessment of included studies was carried out with a modified version of the Newcastle-Ottawa Quality Assessment Scale, as proposed by Colpo and coworkers (10) for meta-analyses of case–control studies of TL. This scale evaluates three dimensions (selection, comparability, and exposure), for a possible maximum of seven points. Study selection and data extraction and synthesis were performed and checked by two independent investigators.

For the meta-analysis procedures, we used the freely available Meta-Analyst program (11). It is a cross-platform software that allows the analysis of case–control association studies and other advanced approaches (eg, implementation of random-effects models, sensitivity analysis, and generation of forest plots). Following recommendations in the area, we used random-effects models and calculated the I 2 statistic for heterogeneity (12). Standardized mean differences were used as the main index of effect sizes in these meta-analyses. Subgroup analyses were carried out for age at examination of the samples, for methods used for TL measurement, and for cell types employed for DNA extraction (Supplementary Table S1); a sensitivity analysis was carried out with the leave-one-out method.

Results

Thirteen primary studies were included in the current meta-analysis for AD (7,8,13–21). It was not possible to include two additional studies, which did not provide TL data (22,23) (Supplementary Figure S1). The majority of the studies used the NINCDS-ADRDA criteria for the diagnosis of AD and few reported data for disease duration and severity. A quality assessment of included studies showed that several articles did not report information on selection of participants and their comparability (Supplementary Table S2). No studies were excluded due to the results of the quality assessment. Details of included studies are provided in Table 1 and Supplementary Table S1, and data for 860 AD patients and 2,022 controls were analyzed. Sample sizes for the AD patient groups in the different studies ranged from less than 20 to more than 300. An important fraction of the studies used genomic DNA extracted from leukocytes and quantitative polymerase chain reaction–based methods for analysis of TL.

Table 1.

Details of the Original Studies Included in the Meta-analysis for Telomere Length and Alzheimer’s Disease

Author, Year PMID Country Sample Size % Male Mean Ages Tissue Method TL Patients TL Controls Finding
Tedone, 2015 26402514 Italy 31/20 32/50 81/79 PBMC Flow citometry 2.1±0.5 2.3±0.4 Similar
Kota, 2015 25541866 India 57/55 49/47 65/65 Leukocytes qPCR multiplex 0.6±0.58 1.0±0.6 Shorter
Mathur, 2014 24121960 Canada 41/41 46/46 76/74 Buccal cells 3D QFISH 6.227±0.743 7.590±0.165 Shorter
Guan, 2012 21912072 Japan 40/59 48/51 70/70 Leukocytes TRF 8.09±1.34 8.93±2.24 Similar
Takata, 2012 22016362 Japan 74/35 32/40 79/80 Leukocytes qPCR multiplex 0.754±0.13 0.793±0.13 Similar
Hochstrasser, 2012 22178633 Austria 18/14 22/46 75/72 Monocytes TRF 6.6±0.2 7.3±0.2 Shorter
Movérare-Skrtic, 2012 22210159 Sweden 32/20 47/50 75/75 Leukocytes qPCR monoplex NR NR Similar
Honig, 2012 22825311 United States 314/1,469 26/33 84/77 Leukocytes qPCR monoplex 6.13±0.79 6.43±0.86 Shorter
Zekry, 2010 20709332 Switzerland 80/204 NR NR Lymphocytes Flow citometry NR NR Similar
Lukens, 2009 19896585 United States 29/22 27/50 80/80 Cerebellum qPCR monoplex 0.799±0.21 0.736±0.33 Similar
Thomas, 2008-1 18242664 Australia 54/26 30/42 80/69 Leukocytes qPCR monoplex 77.3±32.4 110.3±28.2 Shorter
Thomas, 2008-2 18242664 Australia 54/26 30/42 80/69 Buccal cells qPCR monoplex 27.4±27.7 40.6±19.2 Shorter
Thomas, 2008-3 18242664 Australia 13/9 38/67 76/74 Brain qPCR monoplex 176.9±44.4 118.7±49.6 Longer
Franco, 2006 19595878 United States 8/7 38/86 75/70 Neurons QFISH 0.259±0.048 0.468±0.013 Shorter
Panossian, 2003 12493553 United States 15/15 100/73 73/70 PBMC TRF 6.22±0.23 7.15±0.37 Shorter
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Note: AD = Alzheimer’s disease; NR = not reported; PBMC = peripheral blood mononuclear cells; QFISH = quantitative fluorescent in situ hybridization; qPCR = quantitative polymerase chain reaction; TL = telomere length; TRF = terminal restriction fragment method. TL data for AD patients and controls were provided as kilobases (mean and SD) for studies based on TRF and as T/S ratios (mean and SD) for studies based on qPCR.

We applied random-effects meta-analyses to the available data and a significant difference in TL between AD patients and controls, with a standardized mean difference of −0.984 (confidence interval: −1.433 to −0.535; p value: <.001; Figure 1). There was evidence of heterogeneity (I 2: 91.8%) and a sensitivity analyses (using a leave-one-out method) showed that no single study was responsible for the pooled result of the meta-analysis (Figure 2). A subgroup analysis showed that studies with younger patients (Supplementary Figure S2) and that employed terminal restriction fragment methods (Supplementary Figure S3) showed preliminary evidence for a possible larger effect on shorter telomeres in AD patients and that the significant association was more evident in studies carried out with DNA from leukocytes (Supplementary Figure S4).

Figure 1.

Figure 1.

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Forest plot for the meta-analysis of telomere length and Alzheimer’s disease (AD). p value: <.001, for a random-effects Model. A standardized mean difference below zero means shorter telomeres in AD patients, in comparison with control subjects.

Figure 2.

Figure 2.

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Sensitivity analysis for the meta-analysis of telomere length and Alzheimer’s disease.

Discussion

Although TL has been evaluated as a possible biomarker for AD in several publications, no meta-analysis has been conducted so far to assess the relative importance of such results (6,24). In the current study, we performed a meta-analysis for 13 published studies and found consistent and significant evidence of shorter telomeres in samples from AD patients (p value: <.001). A sensitivity analysis showed that no single study was responsible for those findings and a subgroup analysis showed that the finding of shorter telomeres in AD patients was more evident in studies that were carried out with DNA from leukocytes. This finding from the available cumulative evidence (standardized mean difference of −0.984) is consistent with results from individual studies that reported shorter telomeres in AD patients (7,8,14,17,18,20,21).

Several studies used DNA extracted from leukocytes, taking into account its broad and easy availability for large samples of living patients (25). It will be important to include in future studies DNA extracted from matched pairs of affected and healthy brain tissues. It is possible that the interstudy variability in the TL data shown in Table 1 is given by the use of different approaches for normalization of quantitative polymerase chain reaction results (26). We did not find studies on TL and AD in African, South Eastern Asian, or Latin American countries, populations that have a large burden of neurodegenerative disorders and particular genetic and environmental features (27).

It has been suggested that telomere maintenance mechanisms play an important role in the response and plasticity of postmitotic neurons to oxidative and genomic stress (5,28). It has been shown that the third generation of knockout mice for the telomerase RNA component TERC (G3Terc−/−, which display short telomeres) have reduced neurogenesis in the dentate gyrus, in addition to neuronal loss in hippocampus and frontal cortex and short-term memory dysfunction (29). On other hand, telomere shortening reduced the number of amyloid plaques and reactive microgliosis in APP23 transgenic mice (29). There is also evidence showing that newly generated neurons and mature neurons have low telomerase levels and are more susceptible to the effects of DNA damage (30), that the antidepressant-effect of telomerase overexpression is possibly associated to adult neurogenesis mechanisms (31), and that lithium normalizes telomerase activity (32). As oxidative stress and inflammation are increased in aged individuals, these mechanisms could be related to telomere shortening (6). In AD patients, the shortest telomeres have been associated with high levels of the proinflammatory cytokine tumor necrosis factor-α (8) and there is evidence that markers of oxidative stress are associated with telomere shortening (6). There is evidence showing that microglial cells, rather than postmitotic neurons, undergo replicative senescence. The microglial activation could contribute with the inflammatory microenvironment ultimately promoting disease progression (6).

Finally, emerging evidence suggests that perceived stress and lower physical activity, known risk factors for AD, are associated with shorter telomeres (33,34). King and coworkers (35) identified a significant correlation between leukocyte TL and volume of total brain and specific regions, such as hippocampus. An inverse correlation between leukocyte TL and hippocampal volume was found in nondemented individuals that were APOE 3/3 carriers (but not in APOE 4 carriers), and it was also found that APOE 4 carriers had longer telomeres and a higher attrition rate (36). APOE 4 carriers with longer telomeres were associated with worse performance on episodic memory tasks (37). A number of epigenetic factors, such as modifications of DNA methylation in the promoter region of the catalytic subunit of the telomerase enzyme and several noncoding RNAs, are known to have an effect on telomere dynamics (38) and could be related to shorter telomeres in AD patients.

Limitations of the current study include the retrospective nature of our meta-analysis, the inclusion of study-level data, and being underpowered for the subgroup analyses. The strengths of our study involve the inclusion of all published studies with available data for TL and AD and the use of state of the art biostatistical methods for meta-analyses.

Future studies using high-throughput approaches, such as next-generation sequencing, could identify novel genetic and epigenetic factors (39) that influence TL in AD patients and in its presymptomatic stages (40). It would be important to carry out longitudinal studies for TL and AD in multiethnic populations that control for genetic and environmental variables and that include quantitative markers of disease progression.

Supplementary Material

Please visit the article online at http://gerontologist.oxfordjournals.org/ to view supplementary material.

Funding

D.A.F. is supported by research grants from Colciencias and VCTI-UAN (grants # 20131079 and 20131080). Y.G.-G. is supported by a PhD fellowship from Centro de Estudios Interdisciplinarios Básicos y Aplicados (CEIBA; Rodolfo Llinás Program). C.L.-Q. is supported by the National Institute on Drug Abuse (grant # T32DA021129, PI: J. Anthony). G.E.B. work is supported by Pontificia Universidad Javeriana. G.P. is supported by a National Institutes of Health grant (G12-MD007591).

Supplementary Material

Supplementary Data
supp_71_8_1069__index.html (792B, html)

Acknowledgments

We thank corresponding authors who contributed with additional data from primary studies that were not available in the original articles.

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Associated Data

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Supplementary Materials

Supplementary Data
supp_71_8_1069__index.html (792B, html)
supp_glw053_Supplementary_AD_TL.docx (240.2KB, docx)

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