Telomere Length Shortening and Alzheimer Disease—A Mendelian Randomization Study

Zhan, Yiqiang; Song, Ci; Karlsson, Robert; Tillander, Annika; Reynolds, Chandra A.; Pedersen, Nancy L.; Hägg, Sara

doi:10.1001/jamaneurol.2015.1513

Cited by 102 publications

(76 citation statements)

References 106 publications

(126 reference statements)

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“…The effect size of telomere length predicting disease is likely small, so these differences in study design would easily obscure effects. Confidence that telomeres are important to disease pathogenesis is increasing with recent Mendelian randomization studies demonstrating that genetic variants associated with shorter telomeres are associated with cardiovascular, pulmonary, and Alzheimer's diseases (23,24) and a recent meta-analysis that includes prospective associations between telomere length and cardiovascular disease (7). Considering the continued debate, however, there remains a significant need for more prospective, meta-analytic, and Mendelian randomization studies with nationally representative populations with other diseases and mortality as outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Puterman

Gemmill

Karasek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

143

102

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Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging. cellular aging | telomeres | lifespan adversity | childhood adversity A ging cells play a crucial role in the pathogenesis of noncommunicable diseases, and telomere shortening in cells plays a part of this aging process (1, 2). Telomeres are DNAprotein caps at the ends of chromosomes that protect genetic material from degradation, and their lengths indicate cellular aging (2, 3). Experiments in rodents implicate shortened telomeres and lower activity of telomerase, the enzyme that lengthens telomeres, as causes of mitochondrial and tissue damage associated with disease pathogenesis (4-6).Telomere length is linked cross-sectionally and prospectively with human disease states in many studies. A recent meta-analysis suggests that individuals with observed short leukocyte telomeres are at an ∼80% increased risk of concurrent reports of cardiovascular disease and an ∼40% increased risk of developing cardiovascular disease in the future (7). Other recent meta-analyses support the concurrent associations between short telomeres and diabetes (8) and several cancers (9, 10). Several studies indicate that short telomeres from varied sources, including leukocytes and saliva, are related to early mortality (11-17), including a study with >60,000 adults (18), although null studies also exist (19)(20)(21)(22).Although these studies suggest that telomere length plays a role in disease, they are observational, and studies directly linking genetics...

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Section: Discussionmentioning

confidence: 99%

“…They showed that common sequence variants of seven genes that directly regulate telomere maintenance, summed as a genetic risk score, significantly increase risks for cardiovascular, pulmonary (23), and Alzheimer's diseases (24).…”

mentioning

confidence: 99%

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Puterman

Gemmill

Karasek

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

143

102

View full text Add to dashboard Cite

show abstract

“…(Danese & McEwens, 2012). Telomere length appears to be one of the causal factors, as recent mendelian genetic studies of telomere length have shown direct prediction of earlier onset of certain diseases of aging (Codd et al , 2013; Zhan et al , 2015). …”

Section: Discussionmentioning

confidence: 99%

The relationship between childhood psychosocial stressor level and telomere length: a meta-analysis

Hanssen¹,

Schutte²,

Malouff³

et al. 2017

Health Psych Res

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This meta-analysis examined the association between the level of childhood psychosocial stressors and telomere length, an important health biomarker. The meta-analysis, including 27 samples and 16,238 participants, found a significant association of -0.08 between a higher level of childhood stressors and shorter telomere length at a mean age of 42 across studies. Moderator analyses showed a trend in the direction of effect sizes being significantly larger with shorter times between the stressors and telomere measurement. Moderator analyses showed significantly higher effect sizes for studies that used a categorical method for assessing child stressor level and for assays completed with qPCR rather than with the Southern blot method. There was no significant moderation of effect size by whether study assayed leukocytes or buccal cells, whether the study assessed child stressor level by memory-based recall versus archival records, and whether the study controlled for age, sex, or additional variables. The results, focused on childhood events, add to prior findings that perceived stress and negative emotions are associated with telomere length.

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“…1 An increasing number of studies have shown the importance of telomere length (TL) in ageing, specifically in the development of dementia and cognitive impairment. 2, 3, 4, 5, 6, 7, 8 Using a relatively large group of non-demented older individuals, Yaffe et al 3 demonstrated an association between longer telomeres and higher score in the digit symbol substitution test (DSST)—a measure of processing speed—at baseline. After seven years, the individuals with longer telomeres at baseline performed better in the modified mini-mental state exam (MMSE) but not in DSST.…”

Section: Introductionmentioning

confidence: 99%

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

et al. 2017

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The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10−5), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−0.699; 95% CI: −1.330, −0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

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Telomere Length Shortening and Alzheimer Disease—A Mendelian Randomization Study

Cited by 102 publications

References 106 publications

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

The relationship between childhood psychosocial stressor level and telomere length: a meta-analysis

Short telomere length is associated with impaired cognitive performance in European ancestry cohorts

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