APOE4 and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimer's Pathology: New findings from the ADNI.

Introduction: We investigated the interplay between infections and APOE4 on brain glucose hypometabolism, an early preclinical feature of Alzheimer's Disease (AD) pathology. Methods: Multivariate linear regression analysis was performed on 1,509 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The outcomes were the rank-normalized hypometabolic convergence index (HCI) and statistical regions of interest (SROI) for AD and mild cognitive impairment (MCI). Further, the HCI and its change in the presence and absence of APOE4 were evaluated. Results: Infections were associated with greater hypometabolism [0.15, 95% CI: 0.03, 0.27, p=0.01], with a more pronounced effect among APOE4 carriers, indicating an interaction effect. A higher HCI (0.44, p=0.01) was observed in APOE4 carriers with multiple infections, compared to (0.11, p=0.08) for those with a single infection, revealing a dose-response relationship. The corresponding estimates for the association of infections with SROI AD and SROI MCI were -0.01 (p=0.02) and -0.01 (p=0.04) respectively. Conclusion: Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. Materials and methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. Conclusion: This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

Methods for joint modelling of longitudinal omics data and time-to-event outcomes: Applications to lysophosphatidylcholines in connection to aging and mortality in the Long Life Family Study.

Studying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases.

Traffic-related air pollution and APOE4 can synergistically affect hippocampal volume in older women: new findings from UK Biobank.

A growing research body supports the connection between neurodegenerative disorders, including Alzheimer's disease (AD), and traffic-related air pollution (TRAP). However, the underlying mechanisms are not well understood. A deeper investigation of TRAP effects on hippocampal volume (HV), a major biomarker of neurodegeneration, may help clarify these mechanisms. Here, we explored TRAP associations with the HV in older participants of the UK Biobank (UKB), taking into account the presence of APOE e4 allele (APOE4), the strongest genetic risk factor for AD. Exposure to TRAP was approximated by the distance of the participant's main residence to the nearest major road (DNMR). The left/right HV was measured by magnetic resonance imaging (MRI) in cubic millimeters (mm3). Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found significant interactions between DNMR and APOE4 that influenced HV. Specifically, DNMR <50m (equivalent of a chronically high exposure to TRAP), and carrying APOE4 were synergistically associated with a significant (P = 0.01) reduction in the right HV by about 2.5% in women aged 60-75 years (results for men didn't reach a statistical significance). Results of our study suggest that TRAP and APOE4 jointly promote neurodegeneration in women. Living farther from major roads may help reduce the risks of neurodegenerative disorders, including AD, in female APOE4 carriers.

The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.

Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infection, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2. Materials and methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor). Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p<0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p<0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect. Conclusion: This study reported a new causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD.

End of Life Events and Causes of Death in Danish Long-Lived Siblings: Reduced Dementia Risk Compared to Sporadic Long-Livers.

Background: Better physical robustness and resilience of long-lived siblings compared to sporadic long-livers has been demonstrated in several studies. However, it is unknown whether long-lived siblings also end their lives better. Objective: To investigate end-of-life (EoL) events (dementia diagnosis, medication, hospitalizations in the last 5 years of life), causes of death, and location of death in long-lived siblings compared to matched sporadic long-livers from the Danish population. Methods: Long-lived siblings were identified through three nationwide Danish studies in which the inclusion criteria varied, but 99.5% of the families had at least two siblings surviving to age 90 + . Those who died between 2006 and 2018 were included, and randomly matched with sex, year-of-birth and age-at-death controls (i.e., sporadic long-lived controls) from the Danish population. Results: A total of 5,262 long-lived individuals were included (1,754 long-lived siblings, 3,508 controls; 63% women; median age at death 96.1). Long-lived siblings had a significantly lower risk of being diagnosed with dementia in the last years of life (p = 0.027). There was no significant difference regarding the number of prescribed drugs, hospital stays, days in hospital, and location of death. Compared to controls, long-lived siblings presented a lower risk of dying from dementia (p = 0.020) and ill-defined conditions (p = 0.030). Conclusions: In many aspects long-lived siblings end their lives similar to sporadic long-livers, with the important exception of lower dementia risk during the last 5 years of life. These results suggest that long-lived siblings are excellent candidates for identifying environmental and genetic protective factors of dementia.

Prior infections are associated with smaller hippocampal volume in older women.

Accumulating evidence suggests that infections may play a major role in Alzheimer's disease (AD), however, mechanism is unclear, as multiple pathways may be involved. One possibility is that infections could contribute to neurodegeneration directly by promoting neuronal death. We explored relationships between history of infections and brain hippocampal volume (HV), a major biomarker of neurodegeneration, in a subsample of the UK Biobank (UKB) participants. Infectious disease diagnoses were based on ICD10 codes. The left/right HV was measured by the magnetic resonance imaging (MRI) in cubic millimeters and normalized. Analysis of variance (ANOVA), Welch test, and regression were used to examine statistical significance. We found that HV was significantly lower in women aged 60-75, as well as 65-80, years, with history of infections, compared to same age women without such history. The effect size increased with age faster for the left vs. right HV. Results for males didn't reach statistical significance. Results of our study support a major role of adult infections in neurodegeneration in women. The detrimental effect of infections on HV became stronger with age, in line with declining resilience and increasing brain vulnerability to stressors due to aging. The faster increase in the effect size observed for the left vs. right HV may indicate that female verbal memory degrades faster over time than visual-spatial memory. The observed sex difference may reflect a higher vulnerability of female brain to infection-related factors, which in turn may contribute to a higher risk of AD in women compared to men.

The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults.

BACKGROUND: Functional decline associated with dementia, including in Alzheimer's disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: We retrospectively analyzed records on 1310 participants from the ADNI database for the multivariate analysis. We used longitudinal measures of Mini-Mental State Examination (MMSE) scores in participants, who were cognitively normal, or having AD, or other cognitive deficits to investigate the trajectories of cognitive changes. Multiple linear regression, linear mixed models and latent class analyses were conducted to investigate the association of the SNP rs6859 with MMSE. RESULTS: The regression coefficient per one allele dose of the SNP rs6859 was independently associated with MMSE in both cross-sectional (-2.23, p < 0.01) and linear mixed models (-2.26, p < 0.01) analyses. The latent class model with three distinct subgroups (class 1: stable and gradual decline, class 2: intermediate and late decline, and class 3: lowest and irregular) performed best in the posterior classification, 42.67% (n = 559), 21.45% (n = 281), 35.88% (n = 470) were classified as class 1, class 2, and class 3. In the heterogeneous linear mixed model, the regression coefficient per one allele dose of rs6859 - A risk allele was significantly associated with MMSE class 1 and class 2 memberships and related decline; Class 1 (-2.28, 95% CI: -4.05, -0.50, p < 0.05), Class 2 (-5.56, 95% CI: -9.61, -1.51, p < 0.01) and Class 3 (-0.37, 95% CI: -1.62, 0.87, p = 0.55). CONCLUSIONS: This study found statistical evidence supporting the classification of three latent subclass groups representing complex MMSE trajectories in the ADNI cohort. The SNP rs6859 can be suggested as a candidate genetic predictor of variation in modeling MMSE trajectory, as well as for identifying latent classes with higher baseline MMSE. Functional studies may help further elucidate this relationship.

Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer's disease.

Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration) in the literature. Here, we tested the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We assessed the impact of interactions between SNPs in such genes on AD onset in the Long Life Family Study and sought to replicate the findings in the Health and Retirement Study. We found significant interactions between SNPs in the UNC5C and CNTN6, and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Associations with individual SNPs were not statistically significant. Our findings, thus, support a major role of genetic interactions in the heterogeneity of AD and suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development.

Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.

Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.

Understanding Alzheimer's disease in the context of aging: Findings from applications of stochastic process models to the Health and Retirement Study.

There is growing literature on applications of biodemographic models, including stochastic process models (SPM), to studying regularities of age dynamics of biological variables in relation to aging and disease development. Alzheimer's disease (AD) is especially good candidate for SPM applications because age is a major risk factor for this heterogeneous complex trait. However, such applications are largely lacking. This paper starts filling this gap and applies SPM to data on onset of AD and longitudinal trajectories of body mass index (BMI) constructed from the Health and Retirement Study surveys and Medicare-linked data. We found that APOE e4 carriers are less robust to deviations of trajectories of BMI from the optimal levels compared to non-carriers. We also observed age-related decline in adaptive response (resilience) related to deviations of BMI from optimal levels as well as APOE- and age-dependence in other components related to variability of BMI around the mean allostatic values and accumulation of allostatic load. SPM applications thus allow revealing novel connections between age, genetic factors and longitudinal trajectories of risk factors in the context of AD and aging creating new opportunities for understanding AD development, forecasting trends in AD incidence and prevalence in populations, and studying disparities in those.

Evaluation of GENESIS, SAIGE, REGENIE and fastGWA-GLMM for genome-wide association studies of binary traits in correlated data.

Performing a genome-wide association study (GWAS) with a binary phenotype using family data is a challenging task. Using linear mixed effects models is typically unsuitable for binary traits, and numerical approximations of the likelihood function may not work well with rare genetic variants with small counts. Additionally, imbalance in the case-control ratios poses challenges as traditional statistical methods such as the Score test or Wald test perform poorly in this setting. In the last couple of years, several methods have been proposed to better approximate the likelihood function of a mixed effects logistic regression model that uses Saddle Point Approximation (SPA). SPA adjustment has recently been implemented in multiple software, including GENESIS, SAIGE, REGENIE and fastGWA-GLMM: four increasingly popular tools to perform GWAS of binary traits. We compare Score and SPA tests using real family data to evaluate computational efficiency and the agreement of the results. Additionally, we compare various ways to adjust for family relatedness, such as sparse and full genetic relationship matrices (GRM) and polygenic effect estimates. We use the New England Centenarian Study imputed genotype data and the Long Life Family Study whole-genome sequencing data and the binary phenotype of human extreme longevity to compare the agreement of the results and tools' computational performance. The evaluation suggests that REGENIE might not be a good choice when analyzing correlated data of a small size. fastGWA-GLMM is the most computationally efficient compared to the other three tools, but it appears to be overly conservative when applied to family-based data. GENESIS, SAIGE and fastGWA-GLMM produced similar, although not identical, results, with SPA adjustment performing better than Score tests. Our evaluation also demonstrates the importance of adjusting by full GRM in highly correlated datasets when using GENESIS or SAIGE.

Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality.

BACKGROUND: Severe COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. METHODS: We developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population. FINDINGS: The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age. INTERPRETATION: Short HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Genome-wide analysis of genetic predisposition to common polygenic cancers.

Lung, breast, prostate, and colorectal cancers are among the most common and fatal malignancies worldwide. They are mainly caused by multifactorial mechanisms and are genetically heterogeneous. We investigated the genetic architecture of these cancers through genome-wide association, pathway-based, and summary-based transcriptome-/methylome-wide association analyses using three independent cohorts. Our genome-wide association analyses identified the associations of 33 single-nucleotide polymorphisms (SNPs) at P < 5E - 06, of which 32 SNPs were not previously reported and did not have proxy variants within their ± 1 Mb flanking regions. Moreover, other polymorphisms mapped to their closest genes were not previously associated with the same cancers at P < 5E - 06. Our pathway enrichment analyses revealed associations of 32 pathways; mainly related to the immune system, DNA replication/transcription, and chromosomal organization; with the studied cancers. Also, 60 probes were associated with these cancers in our transcriptome-wide and methylome-wide analyses. The ± 1 Mb flanking regions of most probes had not attained P < 5E - 06 in genome-wide association studies. The genes corresponding to the significant probes can be considered as potential targets for further functional studies. Two genes (i.e., CDC14A and PMEL) demonstrated stronger evidence of associations with lung cancer as they had significant probes in both transcriptome-wide and methylome-wide association analyses. The novel cancer-associated SNPs and genes identified here would advance our understanding of the genetic heterogeneity of the common cancers.

Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.

The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease. SIGNIFICANCE STATEMENT: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.

Genetics of physiological dysregulation: findings from the long life family study using joint models.

Recently, Mahalanobis distance (DM) was suggested as a statistical measure of physiological dysregulation in aging individuals. We constructed DM variants using sets of biomarkers collected at the two visits of the Long Life Family Study (LLFS) and performed joint analyses of longitudinal observations of DM and follow-up mortality in LLFS using joint models. We found that DM is significantly associated with mortality (hazard ratio per standard deviation: 1.31 [1.16, 1.48] to 2.22 [1.84, 2.67]) after controlling for age and other covariates. GWAS of random intercepts and slopes of DM estimated from joint models found a genome-wide significant SNP (rs12652543, p=7.2×10-9) in the TRIO gene associated with the slope of DM constructed from biomarkers declining in late life. Review of biological effects of genes corresponding to top SNPs from GWAS of DM slopes revealed that these genes are broadly involved in cancer prognosis and axon guidance/synapse function. Although axon growth is mainly observed during early development, the axon guidance genes can function in adults and contribute to maintenance of neural circuits and synaptic plasticity. Our results indicate that decline in axons' ability to maintain complex regulatory networks may potentially play an important role in the increase in physiological dysregulation during aging.

Composite Measure of Physiological Dysregulation as a Predictor of Mortality: The Long Life Family Study.

Biological aging results in changes in an organism that accumulate over age in a complex fashion across different regulatory systems, and their cumulative effect manifests in increased physiological dysregulation (PD) and declining robustness and resilience that increase risks of health disorders and death. Several composite measures involving multiple biomarkers that capture complex effects of aging have been proposed. We applied one such approach, the Mahalanobis distance (DM), to baseline measurements of various biomarkers (inflammation, hematological, diabetes-associated, lipids, endocrine, renal) in 3,279 participants from the Long Life Family Study (LLFS) with complete biomarker data. We used DM to estimate the level of PD by summarizing information about multiple deviations of biomarkers from specified "norms" in the reference population (here, LLFS participants younger than 60 years at baseline). An increase in DM was associated with significantly higher mortality risk (hazard ratio per standard deviation of DM: 1.42; 95% confidence interval: [1.3, 1.54]), even after adjustment for a composite measure summarizing 85 health-related deficits (disabilities, diseases, less severe symptoms), age, and other covariates. Such composite measures significantly improved mortality predictions especially in the subsample of participants from families enriched for exceptional longevity (the areas under the receiver operating characteristic curves are 0.88 vs. 0.85, in models with and without the composite measures, p = 2.9 × 10-5). Sensitivity analyses confirmed that our conclusions are not sensitive to different aspects of computational procedures. Our findings provide the first evidence of association of PD with mortality and its predictive performance in a unique sample selected for exceptional familial longevity.

Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. Objective: To examine whether LTL is associated with the life span of contemporary humans. Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study.

BACKGROUND: The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation. METHODS: We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS's oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p < .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication. RESULTS: At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (-8.2%, 95% confidence interval: -14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p < .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p < .05). CONCLUSIONS: The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.

The impact of disregarding family structure on genome-wide association analysis of complex diseases in cohorts with simple pedigrees.

The generalized linear mixed models (GLMMs) methodology is the standard framework for genome-wide association studies (GWAS) of complex diseases in family-based cohorts. Fitting GLMMs in very large cohorts, however, can be computationally demanding. Also, the modified versions of GLMM using faster algorithms may underperform, for instance when a single nucleotide polymorphism (SNP) is correlated with fixed-effects covariates. We investigated the extent to which disregarding family structure may compromise GWAS in cohorts with simple pedigrees by contrasting logistic regression models (i.e., with no family structure) to three LMMs-based ones. Our analyses showed that the logistic regression models in general resulted in smaller P values compared with the LMMs-based models; however, the differences in P values were mostly minor. Disregarding family structure had little impact on determining disease-associated SNPs at genome-wide level of significance (i.e., P < 5E-08) as the four P values resulted from the tested methods for any SNP were all below or all above 5E-08. Nevertheless, larger discrepancies were detected between logistic regression and LMMs-based models at suggestive level of significance (i.e., of 5E-08 ≤ P < 5E-06). The SNP effects estimated by the logistic regression models were not statistically different from those estimated by GLMMs that implemented Wald's test. However, several SNP effects were significantly different from their counterparts in LMMs analyses. We suggest that fitting GLMMs with Wald's test on a pre-selected subset of SNPs obtained from logistic regression models can ensure the balance between the speed of analyses and the accuracy of parameters.