Dataset Information

Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities.

ABSTRACT: Background:We previously demonstrated familial aggregation of memory performance within the Long Life Family Study (LLFS), suggesting that exceptional cognition (EC) may contribute to their exceptional longevity. Here, we investigated whether LLFS families with EC may also exhibit more favorable profiles of other age-related biomarkers. Methods:Nondemented offspring of the LLFS probands scoring 1.5 SD above the mean in a cognitive phenotype were classified as participants with EC. Families were categorized into EC (n = 28) and non-EC families (n = 433) based on having at least two EC offspring. Adjusted general estimating equations were used to investigate whether EC families had a better longevity and age-related biomarker profiles than non-EC families. Results:EC families exhibited higher scores on familial longevity than non-EC families (average Family Longevity Selection Score of 12 ± 7 vs 9 ± 8, p = 2.5 × 10-14). EC families showed a better a metabolic profile (? = -0.63, SE = 0.23, p = .006) than non-EC families. The healthier metabolic profile is related to obesity in an age-dependent fashion. The prevalence of obesity in EC families is significantly lower compared with non-EC families (38% vs 51%, p = .015) among family members less than 80 years of age; however, among EC family members 80 years of age and older, the prevalence of obesity is higher (40% vs 38%, p = .011). EC families also showed better physical/pulmonary function than non-EC families (? = 0.51, SE = 0.25, p = .042). Conclusions:Long-live families with EC are characterized by a healthier metabolic profile which is related to the prevalence of obesity in the older family members. Our results suggest that familial exceptional longevity may be achieved through heterogeneous yet correlated pathways.

SUBMITTER: Barral S

PROVIDER: S-EPMC5861897 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities.

Barral Sandra S Singh Jatinder J Fagan Erin E Cosentino Stephanie S Andersen-Toomey Stacy L SL Wojczynski Mary K MK Feitosa Mary M Kammerer Candace M CM Schupf Nicole N

The journals of gerontology. Series A, Biological sciences and medical sciences 20171101 12

<h4>Background</h4>We previously demonstrated familial aggregation of memory performance within the Long Life Family Study (LLFS), suggesting that exceptional cognition (EC) may contribute to their exceptional longevity. Here, we investigated whether LLFS families with EC may also exhibit more favorable profiles of other age-related biomarkers.<h4>Methods</h4>Nondemented offspring of the LLFS probands scoring 1.5 SD above the mean in a cognitive phenotype were classified as participants with EC. ...[more]

PMID: 28329324

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Project description:IMPORTANCE:Family studies of centenarians and long-lived persons have found substantial familial aggregation of survival to extreme ages; however, the extent to which such familial longevity is characterized by cognitively intact survival is not established. OBJECTIVE:To determine whether families with exceptional longevity are protected against cognitive impairment consistent with Alzheimer disease. DESIGN:Cross-sectional analysis. SETTING:Multisite study in New York, Massachusetts, Pennsylvania, and Denmark. PARTICIPANTS:A total of 1870 individuals (1510 family members and 360 spouse controls) recruited through the Long Life Family Study. MAIN OUTCOME AND MEASURE:Prevalence of cognitive impairment based on a diagnostic algorithm validated using the National Alzheimer's Coordinating Center data set. RESULTS:The cognitive algorithm classified 546 individuals (38.5%) as having cognitive impairment consistent with Alzheimer disease. Long Life Family Study probands had a slightly but not statistically significant reduced risk of cognitive impairment compared with spouse controls (121 of 232 for probands vs 45 of 103 for spouse controls; odds ratio?=?0.7; 95% CI, 0.4-1.4), whereas Long Life Family Study sons and daughters had a clearly reduced risk of cognitive impairment (11 of 213 for sons and daughters vs 28 of 216 for spouse controls; odds ratio?=?0.4; 95% CI, 0.2-0.9). Restriction to nieces and nephews in the offspring generation attenuated this effect (37 of 328 for nieces and nephews vs 28 of 216 for spouse controls; odds ratio?=?0.8; 95% CI, 0.4-1.4). CONCLUSIONS AND RELEVANCE:Rates of cognitive impairment characteristic of Alzheimer disease were relatively high. In the proband generation, rates were comparable across family members and spouse controls, whereas sons and daughters of probands had significantly lower rates than spouse controls. Results suggest a delayed onset of cognitive impairment in families with exceptional longevity, but assessment of age-specific incidence rates is required to confirm this hypothesis.

Project description:BACKGROUND:Individuals differ in how they remember the past: some richly re-experience specific details of past episodes, whereas others recall only the gist of past events. Little research has examined how such trait mnemonics, or lifelong individual differences in memory capacities, relate to cognitive aging. We specifically examined trait episodic autobiographical memory (AM, the tendency to richly re-experience episodic details of past events) in relation to complaints of everyday cognitive functioning, which are known to increase with age. Although one might predict that individuals reporting higher trait-level episodic AM would be resistant to age-related decline in everyday function, we made the opposite prediction. That is, we predicted that those with lower trait-level episodic AM would be better equipped with compensatory strategies, practiced throughout the lifespan, to cope with age-related memory decline. Those with higher trait-level episodic AM would have enhanced sensitivity to age-related cognitive changes due to their tendency to rely on their perceived above-average memory function. METHODS:We tested these predictions in 959 older adults aged 50-93 using online subjective and objective measures of memory and cognitive function. Our key measures of interest were the Survey of Autobiographical Memory, a measure of autobiographical memory abilities; and the Cognitive Failures Questionnaire, a measure of everyday cognitive function. RESULTS:In keeping with our prediction, we found that complaints of day-to-day memory slips and errors (normally elevated with age) remained stable or even decreased with age among those reporting lower trait-level episodic AM, whereas those reporting higher trait-level episodic AM reported the expected age-related increase in such errors. This finding was specific to episodic AM and not observed for other autobiographical memory capacities (e.g., semantic, spatial). It was further unaccounted for by response bias or objectively assessed cognitive abilities. CONCLUSIONS:Congenitally low trait-level episodic AM may paradoxically confer a functional advantage in aging. This could be due to well-developed non-episodic strategies not present in those with higher abilities, who are more sensitive to age-related memory decline attributable to medial temporal lobe changes. Our findings emphasize the importance of considering individual differences when studying cognitive aging trajectories.

Project description:Growing evidence supports the use of plasma levels of tau phosphorylated at threonine 181, amyloid-β, neurofilament light and glial fibrillary acidic protein as promising biomarkers for Alzheimer's disease. While these blood biomarkers are promising for distinguishing people with Alzheimer's disease from healthy controls, their predictive validity for age-related cognitive decline without dementia remains unclear. Further, while tau phosphorylated at threonine 181 is a promising biomarker, the distribution of this phospho-epitope of tau in the brain is unknown. Here, we tested whether plasma levels of tau phosphorylated at threonine 181, amyloid-β, neurofilament light and fibrillary acidic protein predict cognitive decline between ages 72 and 82 in 195 participants in the Lothian birth cohorts 1936 study of cognitive ageing. We further examined post-mortem brain samples from temporal cortex to determine the distribution of tau phosphorylated at threonine 181 in the brain. Several forms of tau phosphorylated at threonine 181 have been shown to contribute to synapse degeneration in Alzheimer's disease, which correlates closely with cognitive decline in this form of dementia, but to date, there have not been investigations of whether tau phosphorylated at threonine 181 is found in synapses in Alzheimer's disease or healthy ageing brain. It was also previously unclear whether tau phosphorylated at threonine 181 accumulated in dystrophic neurites around plaques, which could contribute to tau leakage to the periphery due to impaired membrane integrity in dystrophies. Brain homogenate and biochemically enriched synaptic fractions were examined with western blot to examine tau phosphorylated at threonine 181 levels between groups (n = 10-12 per group), and synaptic and astrocytic localization of tau phosphorylated at threonine 181 were examined using array tomography (n = 6-15 per group), and localization of tau phosphorylated at threonine 181 in plaque-associated dystrophic neurites with associated gliosis were examined with standard immunofluorescence (n = 8-9 per group). Elevated baseline plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein predicted steeper general cognitive decline during ageing. Further, increasing tau phosphorylated at threonine 181 over time predicted general cognitive decline in females only. Change in plasma tau phosphorylated at threonine 181 remained a significant predictor of g factor decline when taking into account Alzheimer's disease polygenic risk score, indicating that the increase of blood tau phosphorylated at threonine 181 in this cohort was not only due to incipient Alzheimer's disease. Tau phosphorylated at threonine 181 was observed in synapses and astrocytes in both healthy ageing and Alzheimer's disease brain. We observed that a significantly higher proportion of synapses contain tau phosphorylated at threonine 181 in Alzheimer's disease relative to aged controls. Aged controls with pre-morbid lifetime cognitive resilience had significantly more tau phosphorylated at threonine 181 in fibrillary acidic protein-positive astrocytes than those with pre-morbid lifetime cognitive decline. Further, tau phosphorylated at threonine 181 was found in dystrophic neurites around plaques and in some neurofibrillary tangles. The presence of tau phosphorylated at threonine 181 in plaque-associated dystrophies may be a source of leakage of tau out of neurons that eventually enters the blood. Together, these data indicate that plasma tau phosphorylated at threonine 181, neurofilament light and fibrillary acidic protein may be useful biomarkers of age-related cognitive decline, and that efficient clearance of tau phosphorylated at threonine 181 by astrocytes may promote cognitive resilience.

Dataset Information

Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities.

Publications

Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities.

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