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Cumulative incidence plots estimating the incidence of individuals progressing to Alzheimer’s disease (AD) for (a) non-apolipoprotein E ε4-carriers (non-APOE ε4-carriers) and (b) APOE ε4-carriers according to residualized leukocyte telomere length (rLTL) tertiles. The Fine-Gray hazard function was estimated for a representative 65-year-old female with high levels of cholesterol (> 240 mg/dL), and median values of pulse pressure, plasma glucose, erythrocyte sedimentation rate, lymphocyte proportion, and age squared, including time interactions for short telomere length and lymphocyte proportion in non-APOE ε4-carriers
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Background
Leukocyte telomere length (LTL) has been shown to predict Alzheimer’s disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the asso...
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Citations
... We hypothesize that this explains some of the nine novel findings that are unique to our study, five of which were tested but did not yield significant results in Codd et al. (Additional file 2: Table S5). For instance, our results support the Alzheimer's disease risk-increasing effect of shorter LTL, which was proposed to be driven by promotion of cellular senescence [40][41][42][43][44][45]. In line with previous literature [46,47], our results also suggest that longer LTL increases the risk of systemic lupus erythematosus. ...
Background
Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry.
Results
Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan.
Conclusions
Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.
... Takata et al. [20] found that patients who are homozygous for APOE-ε4 have significantly shorter LTL than those with only one or no copies of APOE-ε4, a finding like that of Dhillon et al. [46], who reported telomeres significantly to be shorter in APOE-ε4 carriers than in non-APOE-ε4 carriers. On the other hand, Hackenhaar and co-workers [47] reported an association between short TL and a higher risk of AD in APOE non-ε4 carriers only, while Wikgren et al. [16] found that nondemented APOE-ε4 carriers had longer telomeres but a higher attrition rate than noncarriers. Differing from these studies, we did not detect any significant relationship between LTL and the presence of the APOE-ε4 allele in none of the analyzed cohorts. ...
Simple Summary
Alzheimer’s disease (AD) is one of the most common forms of dementia in the aging population. The shortening of telomeres, which are complex structures at the ends of chromosomes, is considered one of the hallmarks of aging and has been implicated in several neurodegenerative diseases, especially AD, where the results are conflicting. Thus, to help clarify the association of telomere length with AD risk, leukocyte telomere length (LTL), measured as T/S ratio (telomere vs single-copy gene) was assessed in a cohort of 534 subjects, comprising sporadic and familial cases of late-onset AD (LOAD) and cognitively healthy controls. Compared with controls, LOAD cases showed significantly shorter telomeres. The association with disease risk was independent of confounders such as age, sex, Mini-Mental State Examination (MMSE), and Apolipoprotein E ε4 (APOE-ε4) status. Our findings support telomere shortening as a potential biomarker of LOAD risk.
Abstract
Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer’s disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case–control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.
... Interestingly, longer telomeres have a negative effect on disease dynamics and severity (Movérare-Skrtic et al., 2012;Mahoney et al., 2019). Short TL is a good prognostic marker for determining the long-term risk of AD in APOE4negative individuals (Hackenhaar et al., 2021). Moreover, TL is associated with cognitive function in both elderly and middle-aged individuals (Hägg et al., 2017;Gampawar, 2022). ...
Healthy human longevity is a global goal of the world health system. Determining the causes and processes influencing human longevity is the primary fundamental goal facing the scientific community. Currently, the main efforts of the scientific community are aimed at identifying the qualitative characteristics of the genome that determine the trait. At the same time, when evaluating qualitative characteristics, there are many challenges that make it difficult to establish associations. Quantitative traits are burdened with such problems to a lesser extent, but they are largely overlooked in current genomic studies of aging and longevity. Although there is a wide repertoire of quantitative trait analyses based on genomic data, most opportunities are ignored by authors, which, along with the inaccessibility of published data, leads to the loss of this important information. This review focuses on describing quantitative traits important for understanding aging and necessary for analysis in further genomic studies, and recommends the inclusion of the described traits in the analysis. The review considers the relationship between quantitative characteristics of the mitochondrial genome and aging, longevity, and age-related neurodegenerative diseases, such as the frequency of extensive mitochondrial DNA (mtDNA) deletions, mtDNA half-life, the frequency of A>G replacements in the mtDNA heavy chain, the number of mtDNA copies; special attention is paid to the mtDNA methylation sign. A separate section of this review is devoted to the correlation of telomere length parameters with age, as well as the association of telomere length with the amount of mitochondrial DNA. In addition, we consider such a quantitative feature as the rate of accumulation of somatic mutations with aging in relation to the lifespan of living organisms. In general, it may be noted that there are quite serious reasons to suppose that various quantitative characteristics of the genome may be directly or indirectly associated with certain aspects of aging and longevity. At the same time, the available data are clearly insufficient for definitive conclusions and the determination of causal relationships.
... Takata et al. [20] found that patients that are homozygous for APOE-ε4 have significantly shorter LTL than those with only one or no copies of APOE-ε4, a finding like that of Dhillon et al. [36] who reported telomeres significantly shorter in APOE-ε4 carriers compared with non-APOE-ε4 carriers. On the other hand, Hackenhaar and co-workers [37] reported the association between short TL and a higher risk of AD in APOE non-ε4 carriers only, while Wikgren et al. [16] found that nondemented APOE-ε4 carriers had longer telomeres but a higher attrition rate compared to non-carriers. Differing from these studies, we did not detect any significant relationship between LTL and the presence of the APOE-ε4 allele in none of the analysed cohorts. ...
Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are considered markers of premature cellular senescence. This is believed to contribute to age-related diseases, including Alzheimer's disease (AD) and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, which were all from Calabria, a region from south Italy. Following regression analysis, telomeres were found to be significantly shorter in LOAD cases than in controls (p<0.001 for both sporadic and familial cases). Interestingly, LTL were associated to disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the patho-genesis of LOAD.
... Longer TL also was associated with a lower risk of AD/ADRD across APOE genotypes (e3e3, e2, or e4). In contrast, a Sweden study (Hackenhaar et al., 2021) showed the association between short TL (first tertile) and a higher risk of AD in APOE non-e4 carriers only. ...
Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (n = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (n = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90-0.96, p = 3.37 × 10-7 ). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies.
... Many causes are responsible for this shortening of telomere, including reduced telomerase expression, telomere trimming by removal of telomere loop (T-loop), and inflammation which enhance cell proliferation and cause oxidative damage to telomeric DNA and its associated proteins (Eitan et al., 2014). TL is also related to smoking, obesity and air pollution and its shortening has been linked to several neuropsychiatric disorders, such as schizophrenia, Alzheimer's disease (Hackenhaar et al., 2021) and attention-deficit/hyperactivity disorder (Costa Dde et al., 2015). By comparing RTL between autistic patients and control subjects in our study, a significant decrease was revealed suggesting the potential role of telomere length in mediating autistic behaviour. ...
Autism is associated with genomic instability, which is regulated by telomere length (TL) and index of global methylation (LINE-1). This study will determine relative TL (RTL) and LINE-1 methylation percentage for 69 patients and 33 control subjects to evaluate their potential role as biomarkers for autism. The results displayed a significant decrease of both RTL and LINE-1 methylation in autistic cases relative to controls (P < 0.001). Analysis of receiver operating characteristics curve revealed that both of RTL and LINE-1 methylation percentage have the ability to serve as autism biomarkers (area under the curve = 0.817 and 0.889, respectively). The statistical analysis revealed positive correlation between the two biomarkers (correlation coefficient = 0.439 and P < 0.001).
... Both shorter telomeres and increased peripheral levels of inflammation are associated with increased risk for Alzheimer's disease (King et al., 2018;Wood, 2018;Hackenhaar et al., 2021). Whether shorter telomeres are a risk for cancer development might depend on cancer type (Zhu et al., 2016), although damage-induced telomere dysfunction can occur irrespective of telomere length (Victorelli and Passos, 2017;Brand, 2019). ...
... While the NIM index is associated with survival in cancer patients and all-cause mortality (Gidron et al., 2018;Jarczok et al., 2021), no studies have looked at its role as predictor of age-related pathology such as Alzheimer's disease. Telomere attrition is an antecedent to cellular senescence (Campisi, 2000(Campisi, , 2013Brand, 2019;Coluzzi et al., 2019) and shorter telomeres has been identified as a risk factor for developing Alzheimer's disease (Hackenhaar et al., 2021). While our findings indicate that the NIM index is associated with telomere length, future studies should determine whether the NIM index can serve as a predictor of cognitive decline. ...
Background
Accumulated senescent cells are proposed to be one of the main drivers of age-related pathology such as dementia and cancer through disruption of tissue structure and function. We recently proposed the Neuro-Immuno-Senescence Integrative Model (NISIM), which relates prefrontally modulated vagal tone and subsequent balance between vagal and sympathetic input to the spleen to inflammatory responses leading to generation of reactive oxygen species and oxidative telomere damage.
Aim
In this study, we assess inflammation as a mediator in the relationship between prefrontally modulated vagal tone and leukocyte telomere length (LTL). We also assess the relationship between a recently proposed index of vagal neuroimmunomodulation (vagal tone/inflammation ratio; NIM index) and telomere length.
Methods
This study uses participant data from a large nationally representative longitudinal study since 1974 with a total of 45,000 Norwegian residents so far. A sub-sample of 131 participants from which ultrashort recordings (30 s) of vagal tone, c reactive protein, and LTL could be obtained were included in the study. Relationships were analyzed with Pearson’s correlations and hierarchical multiple linear regression using either vagal tone and CRP or the NIM index to predict telomere length.
Results
Vagal tone was a significant positive predictor of telomere length but this was not mediated by c reactive protein, even after controlling for confounders. The NIM index was a significant positive predictor of telomere length, also when controlling for confounders. In a follow-up analysis simultaneously comparing telomere length between groups with high and low values of vagal tone, and between groups with high and low NIM index values, telomere length was only significantly different between NIM index groups.
Conclusion
This is the first study suggesting that prefrontally modulated vagal neuroimmunomodulation is associated with telomere length thus supporting the NISIM. Results indicate that the NIM index is a more sensitive indicator of vagal neuroimmunomodulation than vagal tone and CRP in isolation.
... Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [63,64], using a modi ed Cawthon's polymerase chain reaction method [65,66]. ...
... Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [63,64], using a modi ed Cawthon's polymerase chain reaction method [65,66]. Preliminary visual inspection of our data indicated a potential differential RTL attrition between cases and controls. ...
Background
DNA methylation (DNAm) is an epigenetic mechanism reflecting both inherited and environmental influences, and is a promising biomarker of multifactorial aging-related disorders like Alzheimer’s disease (AD). Early prediction of AD is critical, but little is known about the time-course of DNAm biomarkers long before symptom onset.
Methods
The long-term predictive ability of four existing DNAm-based epigenetic age acceleration clocks was tested in a longitudinal case-control sample (50 late-onset AD cases; 51 age- and sex-matched controls) with prospective data up to 16 years prior to clinical onset (mean: 8 years), and a post-onset follow-up. In addition, novel blood-based DNAm biomarkers for AD prediction were generated with epigenome-wide longitudinal linear mixed effects models, as well as sparse partial least squares discriminant analysis applied at time-points 10–16 years pre-onset and 0–7 years post-onset.
Results
Epigenetic age acceleration clocks did not differentiate cases from controls at any point during the 20-year follow up time (ps > 0.05). Our new DNA biomarkers, comprising 73, 7, and 27 CpG sites respectively, had excellent in-sample discriminatory and predictive accuracy on average 8 years prior to clinical onset (AUCs = 71.1–98.2% including age, sex, and white blood cell proportions). The longitudinal panel of CpGs replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, compared with the established genetic marker APOE ε4 our panel had a limited effect size (OR = 1.38 per 1 SD panel score increase vs. OR = 13.58 for ε4-allele carriage) and discriminatory accuracy in the external cohort (AUC = 77.2% vs. 87.0% for models with age, sex, and white blood cell proportions). A literature review showed low overlap (n = 4) across 3275 CpGs previously reported to be AD-associated in 8 published studies, and no overlap with our currently identified CpGs.
Conclusions
The results extend prior studies showing a limited predictive and prognostic value of epigenetic age acceleration in AD by considering a longer pre-onset follow-up time, and with appropriate control for age, sex, APOE, and white blood cell proportions. The findings further highlight challenges with replicating discriminatory or predictive CpGs across studies.
... Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [63,64], using a modi ed Cawthon's polymerase chain reaction method [65,66]. ...
... Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [63,64], using a modi ed Cawthon's polymerase chain reaction method [65,66]. Preliminary visual inspection of our data indicated a potential differential RTL attrition between cases and controls. ...
Background: DNA methylation (DNAm) is an epigenetic mechanism reflecting both inherited and environmental influences, and is a promising biomarker of multifactorial aging-related disorders like Alzheimer’s disease (AD). Early prediction of AD is critical, but little is known about the time-course of DNAm biomarkers long before symptom onset.
Methods: The long-term predictive ability of four existing DNAm-based epigenetic age acceleration clocks was tested in a longitudinal case-control sample (50 late-onset AD cases; 51 age- and sex-matched controls) with prospective data up to 16 years prior to clinical onset (mean: 8 years), and a post-onset follow-up. In addition, novel blood-based DNAm biomarkers for AD prediction were generated with epigenome-wide longitudinal linear mixed effects models, as well as sparse partial least squares discriminant analysis applied at time-points 10-16 years pre-onset and 0-7 years post-onset.
Results: Epigenetic age acceleration clocks did not differentiate cases from controls at any point during the 20-year follow up time (ps>0.05). Our new DNA biomarkers, comprising 73, 7, and 27 CpG sites respectively, had excellent in-sample discriminatory and predictive accuracy on average 8 years prior to clinical onset (AUCs=71.1-98.2% including age, sex, and white blood cell proportions). The longitudinal panel of CpGs replicated nominally (p=0.012) in an external cohort (n=146 cases, 324 controls). However, compared with the established genetic marker APOEε4 our panel had a limited effect size (OR=1.38 per 1 SD panel score increase vs. OR=13.58 for ε4-allele carriage) and discriminatory accuracy in the external cohort (AUC=77.2% vs. 87.0% for models with age, sex, and white blood cell proportions). A literature review showed low overlap (n=4) across 3275 CpGs previously reported to be AD-associated in 8 published studies, and no overlap with our currently identified CpGs.
Conclusions: The results extend prior studies showing a limited predictive and prognostic value of epigenetic age acceleration in AD by considering a longer pre-onset follow-up time, and with appropriate control for age, sex, APOE, and white blood cell proportions. The findings further highlight challenges with replicating discriminatory or predictive CpGs across studies.
... Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [52,63], using a modi ed Cawthon's polymerase chain reaction method [64,65]. Preliminary visual inspection of our data indicated a potential differential RTL attrition between cases and controls. ...
Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer’s disease (AD) prediction.
Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers.
Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points.
Results: EAA did not differentiate cases from controls during the follow-up time (p-values>0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-< 0.00001). Our longitudinally-derived panel replicated nominally (p=0.012) in an external cohort (n=146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEε4-carriership (OR=1.38 per 1 SD DNAm score increase vs. OR=13.58 for ε4-allele carriage; AUCs=77.2% vs. 87.0%). Literature review showed low overlap (n=4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.
Conclusions: The limited predictive value of EAA for AD extends prior findings by considering a longer follow-up time, and with appropriate control for age, sex, APOE, and blood-cell proportions. Results also highlight challenges with replicating discriminatory or predictive CpGs across studies.
