Burden of disease variants in participants of the Long Life Family Study

Case control studies of nonagenarians and centenarians provide evidence that long-lived individuals do not differ in the rate of disease associated variants compared to population controls. These results suggest that an enrichment of novel protective variants, rather than a lack of disease associated variants, determine the genetic predisposition to exceptionally long lives. Using data from the Long Life Family Study (LLFS), we sought to replicate these findings and extend them to include a larger number of disease-specific risk alleles. To accomplish this goal, we built a genetic risk score for each of four age-related disease groups: Alzheimer's disease, cardiovascular disease and stroke, type 2 diabetes, and various cancers and compared the distribution of these scores between older participants of the LLFS, their offspring and their spouses. The analyses showed no significant differences in distribution of the genetic risk scores for cardiovascular disease and stroke, type 2 diabetes, or cancer between the groups, while participants of the LLFS appeared to carry an average 1% fewer risk alleles for Alzheimer's disease compared to spousal controls and, while the difference may not be clinically relevant, it was statistically significant. However, the statistical significance between familial longevity and the Alzheimer's disease genetic risk score was lost when a more stringent linkage disequilibrium threshold was imposed to select independent genetic variants

Episodic memory and executive function in familial longevity

Successful aging, the ability to resist age-associated illnesses and functional disability, is of increasing importance as the population ages. Studies have shown that exceptionally long-lived individuals fit the successful aging paradigm by compressing disability toward the end of life. This study investigated whether there is evidence of successful cognitive aging in a familial longevity cohort, the Long Life Family Study (LLFS). Part 1 describes the feasibility of conducting a 2.5 hour neuropsychological battery emphasizing episodic memory and executive function, cognitive domains that elicit signs of cognitive dysfunction in relation to normal aging and dementia. The rationale for the selected tests is discussed within the context of minimizing effects from sensory impairments in an aged cohort and optimizing qualitative and quantitative data. In Part 2, the testing of 70 proband generation and 100 offspring generation LLFS participants and 140 generation-matched referent participants without familial longevity is described. Comparison of LLFS proband generation participants with their referent cohort revealed no significant differences in test scores. However, the referent cohort also had more years of education (an important exposure which is discussed in Part 3). LLFS offspring generation participants had borderline significant better performance on a test of executive function (Clock Drawing Test) and attention (Digits Forward) compared with referents. These findings suggest that familial longevity is associated with better cognitive function even at relatively young ages. Continuing to follow these cohorts to older ages may reveal differences in rate of change in cognitive function. Part 3 examines the role of indicators of cognitive reserve. In the proband generation education and participation in mid- and late-life cognitively stimulating activities were found to be higher in the referent cohort. This suggests that people without familial longevity may be more reliant on higher cognitive reserve in order to achieve similar cognitive performance to those from long-lived families. Implications of preserved cognitive function in long-lived families and the effect of cognitive reserve in those without familial longevity are discussed in terms of compression of disability and successful cognitive aging

Meta-analysis of genetic variants associated with human exceptional longevity

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population

ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups.

BACKGROUND: Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium - Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups. METHODS: Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress. DISCUSSION: General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of'abnormal' in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments

Greater Perceived Physical Fatigability Is Associated with Lower Cognition: The Long Life Family Study

Greater perceived physical fatigability is associated with physical functional decline, but few studies have examined its relation with cognition. Adults ≥60 (mean±SD age 73.7±10.5, 54.7\ 99.6\ from the Long Life Family Study (n=2355) completed the Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater fatigability) and a neurocognitive examination. Generalized estimating equations were used to account for family structure. Covariates included age, sex, field center, depressive symptoms (Center for Epidemiological Studies-Depression), education, and self-reported health. Each 1-point greater PFS was associated with lower: (1) global cognition (Mini-Mental Status Exam; β=-0.36,p\lt;.0001), (2) verbal fluency (phonemic: β=-0.09,p=.029 and semantic: β=-0.14,p\lt;.0001), (3) memory (Hopkins Verbal Learning Test-Revised: β=-0.06,p=.037), and (4) psychomotor speed (Digit Symbol Substitution Test: β=-0.10,p\lt;.0001), after covariate adjustment. Greater perceived physical fatigability was significantly associated with lower memory and cognitive function in older adults, and may represent a promising new biomarker of biological aging reflecting declining brain reserve, resilience, and neurodegeneration

Estimating the cognitive effects of statins from observational data using the survival-incorporated median: a summary measure for clinical outcomes in the presence of death

The issue of "truncation by death" commonly arises in clinical research: subjects may die before their follow-up assessment, resulting in undefined clinical outcomes. This article addresses truncation by death by analyzing the Long Life Family Study (LLFS), a multicenter observational study involving over 4000 older adults with familial longevity. We are interested in the cognitive effects of statins in LLFS participants, as the impact of statins on cognition remains unclear despite their widespread use. In this application, rather than treating death as a mechanism through which clinical outcomes are missing, we advocate treating death as part of the outcome measure. We focus on the survival-incorporated median, the median of a composite outcome combining death and cognitive scores, to summarize the effect of statins. We propose an estimator for the survival-incorporated median from observational data, applicable in both point-treatment settings and time-varying treatment settings. Simulations demonstrate the survival-incorporated median as a simple and useful summary measure. We apply this method to estimate the effect of statins on the change in cognitive function (measured by the Digit Symbol Substitution Test), incorporating death. Our results indicate no significant difference in cognitive decline between participants with a similar age distribution on and off statins from baseline. Through this application, we aim to not only contribute to this clinical question but also offer insights into analyzing clinical outcomes in the presence of death.Comment: 56 page

Estimating the cognitive effects of statins from observational data using the survival-incorporated median:a summary measure for clinical outcomes in the presence of death

The issue of "truncation by death" commonly arises in clinical research: subjects may die before their follow-up assessment, resulting in undefined clinical outcomes. This article addresses truncation by death by analyzing the Long Life Family Study (LLFS), a multicenter observational study involving over 4000 older adults with familial longevity. We are interested in the cognitive effects of statins in LLFS participants, as the impact of statins on cognition remains unclear despite their widespread use. In this application, rather than treating death as a mechanism through which clinical outcomes are missing, we advocate treating death as part of the outcome measure. We focus on the survival-incorporated median, the median of a composite outcome combining death and cognitive scores, to summarize the effect of statins. We propose an estimator for the survival-incorporated median from observational data, applicable in both point-treatment settings and time-varying treatment settings. Simulations demonstrate the survival-incorporated median as a simple and useful summary measure. We apply this method to estimate the effect of statins on the change in cognitive function (measured by the Digit Symbol Substitution Test), incorporating death. Our results indicate no significant difference in cognitive decline between participants with a similar age distribution on and off statins from baseline. Through this application, we aim to not only contribute to this clinical question but also offer insights into analyzing clinical outcomes in the presence of death

PERCEIVED PHYSICAL FATIGABILITY PREDICTS ALL-CAUSE MORTALITY: THE LONG LIFE FAMILY STUDY

Fatigability, the likelihood of fatigue with lower versus higher levels of exertion, is associated with declines in physical function and disability and related to fitness. Thus, fatigability may be a good predictor of mortality. We examined this relationship in the Long Life Family Study (LLFS), an international family cohort enriched for longevity and their spousal controls. We measured perceived physical fatigability at Visit 2 (2014-2017) using the Pittsburgh Fatigability Scale (PFS, 0-50 with higher score=greater fatigability). We identified deaths by family members notifying field centers, reporting during annual phone follow-up, or finding an obituary when unable to reach. Otherwise, we censored participants at most recent contact date when confirmed alive. Covariates included age, sex, and self-reported physical activity using the Framingham Physical Activity Index. We adjusted all analyses for field center and family structure. Participants alive ≥60 years (range 60-108, mean 73.6±10.5) and completed the PFS (N=2,326) at Visit 2 were predominantly white (99.5%) and female (55.1%). Post-Visit 2, 195 (8.4%) died during mean 2.5±1.0 years of follow-up. Age-adjusted PFS score was 7.7 points greater (p<.0001) for those who died (19.8) compared to alive (12.1). Using Cox Proportional-Hazard modeling, each 5-point greater PFS score was associated with 31% (HR: 1.31, 95% CI 1.18,1.43) higher all-cause mortality rate adjusted for covariates listed above. Further adjustment for comorbidities did not attenuate association. PFS’s perceived physical fatigability score may be a useful self-report clinical tool to predict higher risk of mortality among older adults when objective measures of fitness and function are unavailable

Association between late maternal age and age-related endophenotypes in the Long Life Family Study

Extended maternal age has been suggested as marker of delayed age-associated disabilities. We use the Long Life Family Study (LLFS) offspring generation to investigate the association between extended maternal age at last childbirth and healthy-aging endophenotypes. We hypothesize that women with extended maternal age at last childbirth will exhibit healthier endophenotype profiles compared to younger mothers. The association between maternal age and age-related endophenotypes previously derived in LLFS was assessed using Generalized Estimating Equations to adjust for relatedness. The quartiles of the maternal age at last childbirth were modeled as the independent variables. Univariate analyses tested the association between maternal age at last childbirth and age at clinical assessment, education, field center, Apolipoprotein E (APOE) genotype, depression, stress, smoking and successful pregnancies. Only the variables significantly associated in the univariate analyses were considered in secondary multivariate analyses. Univariate analyses showed that compared to older mothers (age at last birth ≥35), mothers 30 years old or younger at last childbirth are less educated (12 ± 3 years versus 13 ± 3 years) and have a higher frequency of smoking (9% versus 3% for maternal age ≥35). Results showed that older mothers (age at last birth ≥31–34 or ≥ 35) demonstrated significantly better cognitive profiles (p = 0.017 and p = 0.021 respectively) compared with mothers with last childbirth age ≤30. Later maternal age among women from long-life families is associated with a better cognitive profile, supporting the hypothesis that later age at childbirth may be a marker for healthy aging.</p