Telomere length and cognitive function in community-dwelling elders: Findings from the Health ABC Study

Department of Psychiatry, School of Medicine, University of California, San Francisco, CA 94143, USA.
Neurobiology of aging (Impact Factor: 5.01). 11/2011; 32(11):2055-60. DOI: 10.1016/j.neurobiolaging.2009.12.006
Source: PubMed


Telomere shortening is a marker of cellular aging and has been associated with risk of Alzheimer's disease. Few studies have determined if telomere length is associated with cognitive decline in non-demented elders. We prospectively studied 2734 non-demented elders (mean age: 74 years). We measured cognition with the Modified Mini-Mental State Exam (3MS) and Digit Symbol Substitution Test (DSST) repeatedly over 7 years. Baseline telomere length was measured in blood leukocytes and classified by tertile as "short", "medium", or "long". At baseline, longer telomere length was associated with better DSST score (36.4, 34.9 and 34.4 points for long, medium and short, p<0.01) but not for change in score. However, 7-year 3MS change scores were less among those with longer telomere length (-1.7 points vs. -2.5 and -2.9, p=0.01). Findings were similar after multivariable adjustment for age, gender, race, education, assay batch, and baseline score. There was a borderline statistically significant interaction for telomere length and APOE e4 on 3MS change score (p=0.06). Thus, telomere length may serve as a biomarker for cognitive aging.

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    • "To date, investigations on blood cells have been inconsistent in relationship between TL and AD [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]. In particular, several studies reported that TL is associated with cognitive decline in elders [48] [49] [50] [51] and is shorter in patients with AD [38] [39] [40] [41] [42] [43] [44], but other studies showed TL is not associated with either levels of cognitive performance or age-related cognitive change [52] [53] and cannot be used in elderly as marker to diagnose the early phase of cognitive impairment (mild cognitive impairment), to distinguish between demented and non-demented patients and/or the type of dementia [45] [46] [47]. A growing body of literature shows that inflammation is involved in the neurodegeneration process [54] [55] [56] [57] [58] and can furthermore accelerate telomere shortening [26] [27] [28] [29], which, in turn, may be linked with the pathogenesis of AD [38–44, 59–61]. "
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    ABSTRACT: Background: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes. Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-β (Aβ)-stimulated PBMC. Methods: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay. Results: TL (mean±SD) for HE, ADS, and ADFwas 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aβ-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10). Conclusion: PBMC from ADF may be characterized by an impaired response induced by Aβ and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.
    Journal of Alzheimer's disease: JAD 06/2015; 46(3):761-769. DOI:10.3233/JAD-142808 · 4.15 Impact Factor
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    • "Keywords: twins, birth weight, telomere length, IQ, anxiety/depression Shorter telomere length has been found to be associated with cognitive deficits (Devore et al., 2011; Kingma et al., 2012; Pearce et al., 2012; Valdes et al., 2010; Yaffe et al., 2011) and with stress-related conditions, including low birth weight (Davy et al., 2009), affective psychiatric disorders (Elvsashagen et al., 2011; Hartmann et al., 2010; Hoen et al., 2011; Karabatsiakis et al., 2014; Lung et al., 2007; Simon et al., 2006; Szebeni et al., 2014; Verhoeven et al., 2014; Wikgren et al., 2012; Wolkowitz et al., 2011) and anxiety disorders (Hoen et al., 2013; Jergovic et al., 2014; Kananen et al., 2010; Malan et al., 2011; O'Donovan et al., 2011; Zhang et al., 2014). However, the direction of causation underlying these associations is unclear. "
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    ABSTRACT: Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.
    Twin Research and Human Genetics 03/2015; 18(02):1-12. DOI:10.1017/thg.2015.3 · 2.30 Impact Factor
    • "To our knowledge, this is the first study to examine either of these relationships in MDD. These findings add to a growing body of evidence that aspects of the telomere/ telomerase maintenance system are different in MDD vs. controls (Simon et al., 2006; Lung et al., 2007; Hartmann et al., 2010; Hoen et al., 2011; Elvsashagen et al., 2011; Wolkowitz et al., 2011a, 2012; Wikgren et al., 2012b; Verhoeven et al., 2014), and that PBMC telomerase activity is related to brain variables relevant to MDD (Honig et al., 2006; Martin-Ruiz et al., 2006; Canela et al., 2007; Grodstein et al., 2008; Mather et al., 2010; Valdes et al., 2010; Devore et al., 2011; Yaffe et al., 2011; Der et al., 2012; Wikgren et al., 2012a; Ma et al., 2013; Jacobs et al., 2014). The explanation of these associations, however, is not clear, since the relationship between peripheral cell aging markers and HC telomerase activity (which could potentially increase HC volume, as described below) is not known. "
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    ABSTRACT: Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Psychiatry Research: Neuroimaging 01/2015; 232(1). DOI:10.1016/j.pscychresns.2015.01.007 · 2.42 Impact Factor
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