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.

Genome-Wide Epistatic Network Analyses of Semantic Fluency in Older Adults.

Semantic fluency impairment has been attributed to a wide range of neurocognitive and psychiatric conditions, especially in the older population. Moderate heritability estimates on semantic fluency were obtained from both twin and family-based studies suggesting genetic contributions to the observed variation across individuals. Currently, effort in identifying the genetic variants underlying the heritability estimates for this complex trait remains scarce. Using the semantic fluency scale and genome-wide SNP genotype data from the Long Life Family Study (LLFS), we performed a genome-wide association study (GWAS) and epistasis network analysis on semantic fluency in 2289 individuals aged over 60 years from the American LLFS cohorts and replicated the findings in 1129 individuals aged over 50 years from the Danish LLFS cohort. In the GWAS, two SNPs with genome-wide significance (rs3749683, p = 2.52 × 10-8; rs880179, p = 4.83 × 10-8) mapped to the CMYAS gene on chromosome 5 were detected. The epistasis network analysis identified five modules as significant (4.16 × 10-5 < p < 7.35 × 10-3), of which two were replicated (p < 3.10 × 10-3). These two modules revealed significant enrichment of tissue-specific gene expression in brain tissues and high enrichment of GWAS catalog traits, e.g., obesity-related traits, blood pressure, chronotype, sleep duration, and brain structure, that have been reported to associate with verbal performance in epidemiological studies. Our results suggest high tissue specificity of genetic regulation of gene expression in brain tissues with epistatic SNP networks functioning jointly in modifying individual verbal ability and cognitive performance.

A Genome-Wide Association Study of 2304 Extreme Longevity Cases Identifies Novel Longevity Variants.

We performed a genome-wide association study (GWAS) of human extreme longevity (EL), defined as surviving past the 99th survival percentile, by aggregating data from four centenarian studies. The combined data included 2304 EL cases and 5879 controls. The analysis identified a locus in CDKN2B-AS1 (rs6475609, p = 7.13 × 10-8) that almost reached genome-wide significance and four additional loci that were suggestively significant. Among these, a novel rare variant (rs145265196) on chromosome 11 had much higher longevity allele frequencies in cases of Ashkenazi Jewish and Southern Italian ancestry compared to cases of other European ancestries. We also correlated EL-associated SNPs with serum proteins to link our findings to potential biological mechanisms that may be related to EL and are under genetic regulation. The findings from the proteomic analyses suggested that longevity-promoting alleles of significant genetic variants either provided EL cases with more youthful molecular profiles compared to controls or provided some form of protection from other illnesses, such as Alzheimer's disease, and disease progressions.

Functional aging in health and heart failure: the COmPLETE Study.

BACKGROUND: Cardiovascular (CV) diseases including heart failure are the leading causes of morbidity, with age being the primary risk factor. The combination of age-related organic functional impairment and reduced physical fitness can drastically impact an individual's healthspan. One's lifespan can potentially be prolonged by the preservation or improvement of physical fitness. However, it remains unclear as to which biomarkers are most suitable for distinguishing between healthy aging and the impaired organ function associated with heart failure. Therefore, a comprehensive assessment of the components of physical fitness and CV function will be performed to identify the most important factors contributing to aging in relation to both health and disease. METHODS: This cross-sectional investigation will consist of two parts: COmPLETE-Health (C-Health) and COmPLETE-Heart (C-Heart). C-Health will examine the aging trajectories of physical fitness components and CV properties in a healthy population sample aged between 20 and 100 years (n = 490). Separately, C-Heart will assess the same markers in patients at different stages of chronic heart failure (n = 80). The primary outcome to determine the difference between C-Health and C-Heart will be cardiorespiratory fitness as measured by cardiopulmonary exercise testing on a bicycle ergometer. Secondary outcomes will include walking speed, balance, isometric strength, peak power, and handgrip strength. Physical activity as a behavioural component will be assessed objectively via accelerometry. Further, CV assessments will include pulse wave velocity; retinal, arterial, and venous diameters; brachial and retinal arterial endothelial function; carotid intima-media thickness; and systolic and diastolic function. The health distances for C-Health and C-Heart will be calculated using the methodology based on statistical (Mahalanobis) distance applied to measurements of quantitative biomarkers. DISCUSSION: This research seeks to identify physical fitness and CV biomarkers that best resemble underlying CV risk with age. Further, it will examine which physical fitness markers are impaired most in heart failure. The presented integrative approach could define new recommendations for diagnostic guidance in aging. Ultimately, this study is expected to offer a better understanding of which functional characteristics should be specifically targeted in primary and secondary prevention to achieve an optimal healthspan.

Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10-9), CHD by 35% (p = 8.9×10-6), HF by 55% (p = 9.7×10-5), stroke by 25% (p = 4.0×10-2), and ND by 100% (p = 1.3×10-3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10-21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.

A genetic stochastic process model for genome-wide joint analysis of biomarker dynamics and disease susceptibility with longitudinal data.

Unraveling the underlying biological mechanisms or pathways behind the effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS (where GWAS is genome-wide association study) era. To further explore the relationship between genetic variations, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally measured biomarkers and risks of diseases. This model is characterized by more profound biological interpretation and takes into account the dynamics of biomarkers during follow-up when investigating the hazards of a disease. We illustrate the rationale and evaluate the performance of the proposed model through two GWAS. One is to detect single nucleotide polymorphisms (SNPs) having interaction effects on type 2 diabetes (T2D) with body mass index (BMI) and the other is to detect SNPs affecting the optimal BMI level for protecting from T2D. We identified multiple SNPs that showed interaction effects with BMI on T2D, including a novel SNP rs11757677 in the CDKAL1 gene (P = 5.77 × 10-7 ). We also found a SNP rs1551133 located on 2q14.2 that reversed the effect of BMI on T2D (P = 6.70 × 10-7 ). In conclusion, the proposed GSPM provides a promising and useful tool in GWAS of longitudinal data for interrogating pleiotropic and interaction effects to gain more insights into the relationship between genes, quantitative biomarkers, and risks of complex diseases.

rqt: an R package for gene-level meta-analysis.

MOTIVATION: Despite recent advances of modern GWAS methods, it is still remains an important problem of addressing calculation an effect size and corresponding p-value for the whole gene rather than for single variant. RESULTS: We developed an R package rqt, which offers gene-level GWAS meta-analysis. The package can be easily included into bioinformatics pipeline or used stand-alone. We applied this tool to the analysis of Alzheimer's disease data from three datasets CHS, FHS and LOADFS. Test results from meta-analysis of three Alzheimer studies show its applicability for association testing. AVAILABILITY AND IMPLEMENTATION: The package rqt is freely available under the following link: https://github.com/izhbannikov/rqt. CONTACT: ilya.zhbannikov@duke.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

stpm: an R package for stochastic process model.

BACKGROUND: The Stochastic Process Model (SPM) represents a general framework for modeling the joint evolution of repeatedly measured variables and time-to-event outcomes observed in longitudinal studies, i.e., SPM relates the stochastic dynamics of variables (e.g., physiological or biological measures) with the probabilities of end points (e.g., death or system failure). SPM is applicable for analyses of longitudinal data in many research areas; however, there are no publicly available software tools that implement this methodology. RESULTS: We developed an R package stpm for the SPM-methodology. The package estimates several versions of SPM currently available in the literature including discrete- and continuous-time multidimensional models and a one-dimensional model with time-dependent parameters. Also, the package provides tools for simulation and projection of individual trajectories and hazard functions. CONCLUSION: In this paper, we present the first software implementation of the SPM-methodology by providing an R package stpm, which was verified through extensive simulation and validation studies. Future work includes further improvements of the model. Clinical and academic researchers will benefit from using the presented model and software. The R package stpm is available as open source software from the following links: https://cran.r-project.org/package=stpm (stable version) or https://github.com/izhbannikov/spm (developer version).

Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study.

The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (ß = -7.1, p = 6.6 × 10-44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR] = 0.60, p = 3.1 × 10-6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR = 0.70, p = 2.1 × 10-2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.

Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants.

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.

Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.

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.

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.

Associations of infections and vaccines with Alzheimer's disease point to a role of compromised immunity rather than specific pathogen in AD.

INTRODUCTION: Diverse pathogens (viral, bacterial, fungal) have been associated with Alzheimer's disease (AD) and related traits in various studies. This suggests that compromised immunity, rather than specific microbes, may play a role in AD by increasing an individual's vulnerability to various infections, which could contribute to neurodegeneration. If true, then vaccines that have heterologous effects on immunity, extending beyond protection against the targeted disease, may hold a potential for AD prevention. METHODS: We evaluated the associations of common adult infections (herpes simplex, zoster (shingles), pneumonia, and recurrent mycoses), and vaccinations against shingles and pneumonia, with the risks of AD and other dementias in a pseudorandomized sample of the Health and Retirement Study (HRS). RESULTS: Shingles, pneumonia and mycoses, diagnosed between ages 65 and 75, were all associated with significantly increased risk of AD later in life, by 16 %-42 %. Pneumococcal and shingles vaccines administered between ages 65-75 were both associated with a significantly lower risk of AD, by 15 %-21 %. These effects became less pronounced when AD was combined with other dementias. DISCUSSION: Our findings suggest that both the pneumococcal polysaccharide vaccine and the live attenuated zoster vaccine can offer significant protection against AD. It remains to be determined if non-live shingles vaccine has a similar beneficial effect on AD. This study also found significant associations of various infections with the risk of AD, but not with the risks of other dementias. This indicates that vulnerability to infections may play a more significant role in AD than in other types of dementia, which warrants further investigation.

The Protective Effect of Familial Longevity Persists After Age 100: Findings From the Danish National Registers.

BACKGROUND: A recent study suggested that the protective effect of familial longevity becomes negligible for centenarians. However, the authors assessed the dependence on familial longevity in centenarians by comparing centenarians with 1 parent surviving to age 80+ to centenarians whose same-sexed parent did not survive to age 80. Here we test whether the protective effect of familial longevity persists after age 100 using more restrictive definitions of long-lived families. METHODS: Long-lived sibships were identified through 3 nationwide, consecutive studies in Denmark, including families with either at least 2 siblings aged 90+ or a Family Longevity Selection Score (FLoSS) above 7. Long-lived siblings enrolled in these studies and who reached age 100 were included. For each sibling, 5 controls matched on sex and year of birth were randomly selected among centenarians in the Danish population. Survival time from age 100 was described with Kaplan-Meier curves for siblings and controls separately. Survival analyses were performed using stratified Cox proportional hazards models. RESULTS: A total of 340 individuals from long-lived sibships who survived to age 100 and 1 700 controls were included. Among the long-lived siblings and controls, 1 650 (81%) were women. The results showed that long-lived siblings presented better overall survival after age 100 than sporadic long-livers (hazard ratio [HR]  = 0.80, 95% confidence interval [CI]  = 0.71-0.91), with even lower estimate (HR = 0.65, 95% CI = 0.50-0.85) if familial longevity was defined by FLoSS. CONCLUSIONS: The present study, with virtually no loss to follow-up, demonstrated a persistence of protective effect of familial longevity after age 100.

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.

Assessing tilavonemab efficacy in early Alzheimer's disease via longitudinal item response theory modeling.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by declines in cognitive and functional severities. This research utilized the Clinical Dementia Rating (CDR) to assess the influence of tilavonemab on these deteriorations. METHODS: Longitudinal Item Response Theory (IRT) models were employed to analyze CDR domains in early-stage AD patients. Both unidimensional and multidimensional models were contrasted to elucidate the trajectories of cognitive and functional severities. RESULTS: We observed significant temporal increases in both cognitive and functional severities, with the cognitive severity deteriorating at a quicker rate. Tilavonemab did not demonstrate a statistically significant effect on the progression in either severity. Furthermore, a significant positive association was identified between the baselines and progression rates of both severities. DISCUSSION: While tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories. Highlights: Utilized longitudinal Item Response Theory (IRT) models to analyze the Clinical Dementia Rating (CDR) domains in early-stage Alzheimer's disease (AD) patients, comparing unidimensional and multidimensional models.Observed significant temporal increases in both cognitive and functional severities, with cognitive severity deteriorating at a faster rate, while tilavonemab showed no statistically significant effect on either domain's progression.Found a significant positive association between the baseline severities and their progression rates, indicating interconnected progression patterns of cognitive and functional declines in AD.Introduced the application of multidimensional longitudinal IRT models to provide a comprehensive perspective on the trajectories of cognitive and functional severities in early AD, suggesting new avenues for future research including the inclusion of time-dependent random effects and data-driven IRT models.

Overweight as a Causal Factor Contributing to Better Survival at the Oldest Old Ages: A Mendelian Randomization Study.

Overweight, defined by a body mass index (BMI) between 25 and 30, has been associated with enhanced survival among older adults in some studies. However, whether being overweight is causally linked to longevity remains unclear. To investigate this, we conducted a Mendelian randomization (MR) study of lifespan 85+ years, using overweight as an exposure variable and data from the Health and Retirement Study and the Long Life Family Study. An essential aspect of MR involves selecting appropriate single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This is challenging due to the limited number of SNP candidates within biologically relevant genes that can satisfy all necessary assumptions and criteria. To address this challenge, we employed a novel strategy of creating additional IVs by pairing SNPs between candidate genes. This strategy allowed us to expand the pool of IV candidates with new 'composite' SNPs derived from eight candidate obesity genes. Our study found that being overweight between ages 75 and 85, compared to having a normal weight (BMI 18.5-24.9), significantly contributes to improved survival beyond age 85. Results of this MR study thus support a causal relationship between overweight and longevity in older adults.

Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease.

Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.