Delirium and incident dementia in hospital patients in New South Wales, Australia: retrospective cohort study.

OBJECTIVES: To determine the strength and nature of the association between delirium and incident dementia in a population of older adult patients without dementia at baseline. DESIGN: Retrospective cohort study using large scale hospital administrative data. SETTING: Public and private hospitals in New South Wales, Australia between July 2001 and March 2020. PARTICIPANTS: Data were extracted for 650 590 hospital patients aged ≥65 years. Diagnoses of dementia and delirium were identified from ICD-10 (international classification of diseases, 10th revision) codes. Patients with dementia at baseline were excluded. Delirium-no delirium pairs were identified by matching personal and clinical characteristics, and were followed for more than five years. MAIN OUTCOME MEASURES: Cox proportional hazards models and Fine-Gray hazard models were used to estimate the associations of delirium with death and incident dementia, respectively. Delirium-outcome dose-response associations were quantified, all analyses were performed in men and women separately, and sensitivity analyses were conducted. RESULTS: The study included 55 211 matched pairs (48% men, mean age 83.4 years, standard deviation 6.5 years). Collectively, 58% (n=63 929) of patients died and 17% (n=19 117) had a newly reported dementia diagnosis during 5.25 years of follow-up. Patients with delirium had 39% higher risk of death (hazard ratio 1.39, 95% confidence interval 1.37 to 1.41) and three times higher risk of incident dementia (subdistribution hazard ratio 3.00, 95% confidence interval 2.91 to 3.10) than patients without delirium. The association with dementia was stronger in men (P=0.004). Each additional episode of delirium was associated with a 20% increased risk of dementia (subdistribution hazard ratio 1.20, 95% confidence interval 1.18 to 1.23). CONCLUSIONS: The study findings suggest delirium was a strong risk factor for death and incident dementia among older adult patients. The data support a causal interpretation of the association between delirium and dementia. The clinical implications of delirium as a potentially modifiable risk factor for dementia are substantial.

Frailty is associated with the clinical expression of neuropsychological deficits in older adults.

BACKGROUND AND PURPOSE: The aim was to determine whether frailty is associated with the relationship between neuropsychological markers and global cognition in older adults. METHODS: Cross-sectional analyzes were conducted of baseline data from three large cohort studies: National Alzheimer's Coordinating Center (NACC), Rush Memory and Aging Project (MAP) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Studies recruited North American participants along the spectrum of cognitive functioning (44% no cognitive impairment at baseline). A frailty index was computed in each dataset. Frailty indices, neuropsychological tests (including measures of processing speed, episodic, semantic and working memory) and Mini-Mental State Examination (MMSE) scores were the variables of interest, with age, sex, education and apolipoprotein E ε4 evaluated as confounders. RESULTS: Across all studies, 23,819 participants aged 55-104 (57% female) were included in analyzes. Frailty index scores were significantly and inversely associated with MMSE scores and significantly moderated relationships between neuropsychological test scores and MMSE scores. In participants with higher frailty index scores, lower neuropsychological test scores were more strongly associated with lower MMSE scores (standardized interaction coefficients ranged from -0.19 to -1.17 in NACC, -0.03 to -2.27 in MAP and -0.04 to -0.38 in ADNI, depending on the neuropsychological test). These associations were consistent across the different databases and were mostly independent of the composition of frailty indices (i.e., after excluding possible symptoms of dementia). CONCLUSIONS: Amongst older Americans, frailty is associated with the cognitive expression of neuropsychological deficits. Implementation of frailty assessment in routine neurological and neuropsychological practice should be considered to optimize care outcomes for older adults.

Investigating Sex Differences in Risk and Protective Factors in the Progression of Mild Cognitive Impairment to Dementia: A Systematic Review.

BACKGROUND: Developing effective strategies for reducing dementia risk requires a detailed understanding of the risk and protective factors associated with the progression of mild cognitive impairment (MCI) to dementia. OBJECTIVE: We aimed to systematically review the evidence for sex differences in these factors. METHODS: Five online databases (PubMed/CINAHL/EMBASE/PsycINFO/Cochrane) were searched from inception until 17 October 2022 for cohort studies that focused on sex differences in risk and protective factors in the progression of MCI to dementia. RESULTS: A total of 2,972 studies were identified, of which 12 studies from five countries were included in the systematic review. There was substantial variability in study designs, study populations and outcome measures. Sex differences were present in the associations of sociodemographic, health, psychological factors, genetic and other biomarkers with the progression of MCI to dementia. APOE ɛ4 status and depression appeared to increase the risk of progression for females, whereas history of stroke, MRI markers and cerebrospinal fluid biomarkers appeared to increase the risk of progression for males. APOE ɛ2 status and marital status (unmarried) were observed to reduce risk of progression in males and females, respectively. CONCLUSIONS: The ability of studies to accurately detail risk factors for dementia are likely limited when solely controlling for the effects of sex. Although the heterogeneity and underpowered nature of the studies made it difficult to synthesize the findings for each risk factor, this study highlights the apparent need for further research examining risk factors for dementia in males and females with MCI separately.

Frailty, lifestyle, genetics and dementia risk.

OBJECTIVE: To optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics. METHODS: We explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data. RESULTS: The analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28). CONCLUSION: Frailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk.

10-year frailty trajectory is associated with Alzheimer's dementia after considering neuropathological burden.

MAIN PROBLEM: Frailty is an established risk factor for cognitive decline and Alzheimer's disease. Few studies have examined the longitudinal relationship between frailty and cognition. METHODS: Participants of Rush Memory and Aging project (n = 625, 67.5% female, 83.2 ± 5.9 years at baseline) underwent annual clinical evaluations (average follow-up 5.6 ± 3.7 years) followed by neuropathologic assessment after death. A frailty index was calculated from 41 health variables at each evaluation. Clinical diagnosis of MCI and/or dementia was ascertained by clinical data review (blinded to neuropathological data) after death. Age, sex, education, and neuropathological burden (10-item index) were evaluated as covariates. Frailty trajectories were calculated using a mixed effects model. RESULTS: At baseline the mean frailty index = 0.24 ± 0.12 and increased at rate of 0.026 or ~1 deficit per year. At death, 27.7% of the sample had MCI, and 38.6% had dementia. Frailty trajectories were significantly steeper among those individuals who were ultimately diagnosed as clinically impaired prior to death, even after controlling for age, sex, education, and neuropathological index. CONCLUSIONS: Findings suggest a strong link between health status (frailty index) and dementia, even after considering neuropathology. Frailty trajectories were associated with risk for MCI and dementia, underscoring the importance of addressing frailty to manage dementia risk.

Frailty and Risk of Dementia in Mild Cognitive Impairment Subtypes.

Risk factors for developing dementia from mild cognitive impairment (MCI) probably differ between MCI subtypes. We investigated how frailty relates to dementia risk in amnestic MCI (a-MCI; n = 2,799) and non-amnestic MCI (na-MCI; n = 629) in the National Alzheimer's Coordinating Center database. Although higher frailty increased dementia risk for people with either a-MCI or na-MCI, the larger risk was in na-MCI (interaction hazard ratio = 1.35 [95% confidence interval = 1.15-1.59], p < 0.001). Even after the onset of clinically significant cognitive impairment, poor general health, quantified by a high degree of frailty, is a significant risk for dementia. ANN NEUROL 2021;89:1221-1225.

Strong age but weak sex effects in eye movement performance in the general adult population: Evidence from the Rhineland Study.

Assessing physiological changes that occur with healthy ageing is prerequisite for understanding pathophysiological age-related changes. Eye movements are studied as biomarkers for pathological changes because they are altered in patients with neurodegenerative disorders. However, there is a lack of data from large samples assessing age-related physiological changes and sex differences in oculomotor performance. Thus, we assessed and quantified cross-sectional relations of age and sex with oculomotor performance in the general population. We report results from the first 4,000 participants (aged 30-95 years) of the Rhineland Study, a community-based prospective cohort study in Bonn, Germany. Participants completed fixation, smooth pursuit, prosaccade and antisaccade tasks. We quantified associations of age and sex with oculomotor outcomes using multivariable linear regression models. Performance in 12 out of 18 oculomotor measures declined with increasing age. No differences between age groups were observed in five antisaccade outcomes (amplitude-adjusted and unadjusted peak velocity, amplitude gain, spatial error and percentage of corrected errors) and for blink rate during fixation. Small sex differences occurred in smooth pursuit velocity gain (men have higher gain) and blink rate during fixation (men blink less). We conclude that performance declines with age in two thirds of oculomotor outcomes but that there was no evidence of sex differences in eye movement performance except for two outcomes. Since the percentage of corrected antisaccade errors was not associated with age but is known to be affected by pathological cognitive decline, it represents a promising candidate preclinical biomarker of neurodegeneration.

Cumulative health deficits, APOE genotype, and risk for later-life mild cognitive impairment and dementia.

OBJECTIVE: To determine whether health-deficit accumulation is associated with the risks of mild cognitive impairment (MCI) and dementia independently of APOE genotype. METHODS: A frailty index was calculated using the deficit-accumulation approach in participants aged 50 years and older from the National Alzheimer's Coordinating Center. Cognitive status was determined by clinical evaluation. Using multistate transition models, we assessed the extent to which an increasing degree of frailty affected the probabilities of transitioning between not cognitively impaired (NCI), MCI, and dementia. RESULTS: Participants (n=14 490) had a mean age of 72.2 years (SD=8.9 years; range=50-103 years). Among those NCI at baseline (n=9773), each 0.1 increment increase in the frailty index was associated with a higher risk of developing MCI and a higher risk of progressing to dementia. Among those with MCI at baseline (n=4717), higher frailty was associated with a higher risk of progressing to dementia, a lower probability of being reclassified as NCI, and a higher likelihood of returning to MCI in those that were reclassified as NCI. These risk effects were present and similar in both carriers and non-carriers of the APOE ε4 allele. CONCLUSION: Among older Americans, health-deficit accumulation affects the likelihood of progressive cognitive impairment and the likelihood of cognitive improvement independently of a strong genetic risk factor for dementia. Frailty represents an important risk factor for cognitive dysfunction and a marker of potential prognostic value.

Perceived stress but not hair cortisol concentration is related to adult cognitive performance.

Chronic stress detrimentally affects cognition but evidence from population-based studies is scarce and largely based on one-dimensional stress assessments. In this study, we aimed to investigate associations of subjective and psychological chronic stress measures with cognition in a population-based sample of adults aged 30-95 years from the Rhineland Study. Participants completed the Perceived Stress Scale (subjective measure) and a cognitive test battery (N = 1766). Hair cortisol concentration (physiological measure) was assessed by liquid chromatography tandem mass spectrometry in 1098 participants. Cross-sectional associations between the two measures of chronic stress and cognition were investigated using multivariable linear regression models. Subjective and physiological measures of chronic stress were not associated with each other (B = 0.005 [95 %CI = -0.005 - 0.015]). Participants with higher perceived stress and specifically lower perceived self-efficacy performed worse in all cognitive domains (effect sizes ranged from ß = -0.129 [95 %CI = -0.177 - -0.080] to -0.054 [95 %CI = -0.099 - -0.009]; and from ß = 0.052 [95 %CI = 0.005 - 0.098] to 0.120 [95 %CI = 0.072 - 0.167], respectively). Relationships between subjective chronic stress measures and executive functioning were stronger in men compared to women (interaction ß = -0.144 [95 %CI = -0.221 - -0.067]). Relationships between perceived stress and working memory, and between perceived self-efficacy and executive functioning, processing speed, verbal episodic and working memory, increased with older age. Hair cortisol concentration was not associated with performance in any cognitive domain. Our results suggest that subjective and physiological measures capture different aspects of chronic stress in the general population.

Association of retinal layer measurements and adult cognitive function: A population-based study.

OBJECTIVE: To quantify the associations of peripapillary retinal nerve fiber layer (pRNFL) thickness and macular ganglion cell layer (mGCL) volume with cognitive functioning and to investigate how demographic and vascular health factors affect these associations in a population-based sample of adults. METHODS: The sample included the first 3,000 participants (age range 30-95 years) of the Rhineland Study (recruited from March 2016 to December 2018) who underwent spectral-domain optical coherence tomography and cognitive assessment at 1 of 2 identical study centers in Bonn, Germany. We used multiple linear regression models to examine the relationships between retinal layer measurements and cognitive functioning after adjustment for confounders, and we examined the moderating effects of demographic and vascular health factors. RESULTS: The analytical sample included 2,483 participants who were 54.3 years old (SD 13.8 years) on average. After full adjustment, each 1-SD decrease in mGCL volume was associated with a greater decrease in global function than that of pRNFL thickness (ß = -0.048 [95% confidence interval (CI) -0.077 to -0.018] vs ß = -0.021 [95% CI -0.049 to 0.007]). These relationships increased in strength with advancing age, were stronger in participants with hypertension, and were reversed in current smokers relative to nonsmokers. CONCLUSIONS: mGCL volume is more strongly related to adult cognitive functioning than pRNFL thickness, making it a better potential biomarker of neurodegeneration. Age and vascular health factors play important roles in determining the strength and direction of this association.

The BDNF Val66Met Polymorphism Modulates Resilience of Neurological Functioning to Brain Ageing and Dementia: A Narrative Review.

Brain-derived neurotropic factor (BDNF) is an abundant and multi-function neurotrophin in the brain. It is released following neuronal activity and is believed to be particularly important in strengthening neural networks. A common variation in the BDNF gene, a valine to methionine substitution at codon 66 (Val66Met), has been linked to differential expression of BDNF associated with experience-dependent plasticity. The Met allele has been associated with reduced production of BDNF following neuronal stimulation, which suggests a potential role of this variation with respect to how the nervous system may respond to challenges, such as brain ageing and related neurodegenerative conditions (e.g., dementia and Alzheimer's disease). The current review examines the potential of the BDNF Val66Met variation to modulate an individual's susceptibility and trajectory through cognitive changes associated with ageing and dementia. On balance, research to date indicates that the BDNF Met allele at this codon is potentially associated with a detrimental influence on the level of cognitive functioning in older adults and may also impart increased risk of progression to dementia. Furthermore, recent studies also show that this genetic variation may modulate an individual's response to interventions targeted at building cognitive resilience to conditions that cause dementia.

Impact of APOE and BDNF Val66Met Gene Polymorphisms on Cognitive Functions in Patients with Amnestic Mild Cognitive Impairment.

Apolipoprotein (APOE) ɛ4 is a well-known risk factor for late-onset Alzheimer's disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age = 72.2) were recruited from the Czech Brain Aging Study and, based on APOE and BDNF genes polymorphisms, were divided into four groups: ɛ4-BDNFVal/Val (n = 37), ɛ4-BDNFMet (n = 19), ɛ4+BDNFVal/Val (n = 35), and ɛ4+BDNFMet (n = 16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOEɛ4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ɛ4+BDNFMet group. Our findings suggest that carriage of ɛ4+BDNFMet is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOEɛ4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes.

The Influence of Genetic Factors and Cognitive Reserve on Structural and Functional Resting-State Brain Networks in Aging and Alzheimer's Disease.

Magnetic resonance imaging (MRI) offers significant insight into the complex organization of neural networks within the human brain. Using resting-state functional MRI data, topological maps can be created to visualize changes in brain activity, as well as to represent and assess the structural and functional connections between different brain regions. Crucially, Alzheimer's disease (AD) is associated with progressive loss in this connectivity, which is particularly evident within the default mode network. In this paper, we review the recent literature on how factors that are associated with risk of dementia may influence the organization of the brain network structures. In particular, we focus on cognitive reserve and the common genetic polymorphisms of APOE and BDNF Val66Met.

Validation of a Dynamic Measure of Current Cognitive Reserve in a Longitudinally Assessed Sample of Healthy Older Adults: The Tasmanian Healthy Brain Project.

Cognitive reserve (CR) is a theoretical construct describing the underlying cognitive capacity of an individual that confers differential levels of resistance to, and recovery from, brain injuries of various types. To date, estimates of an individual's level of CR have been based on single proxy measures that are retrospective and static in nature. To develop a measure of dynamic change in CR across a lifetime, we previously identified a latent factor, derived from an exploratory factor analysis of a large sample of healthy older adults, as current CR (cCR). In the present study, we examined the longitudinal results of a sample of 272 older adults enrolled in the Tasmanian Healthy Brain Project. Using results from 12-month and 24-month reassessments, we examined the longitudinal validity of the cCR factor using confirmatory factor analyses. The results of these analyses indicate that the cCR factor structure is longitudinally stable. These results, in conjunction with recent results from our group demonstrating dynamic increases in cCR over time in older adults undertaking further education, lend weight to this cCR measure being a valid estimate of dynamic change in CR over time.

The BDNF Val66Met polymorphism moderates the effect of cognitive reserve on 36-month cognitive change in healthy older adults.

INTRODUCTION: Cognitive reserve (CR) and BDNF Val66Met are independently associated with the rate of cognitive decline in preclinical Alzheimer's disease. This study was designed to investigate the interactive effects of these variables on 36-month cognitive change in cognitively intact older adults. METHODS: Data for this investigation were obtained from 445 community-residing participants of the Tasmanian Healthy Brain Project, who underwent genetic screening and annual assessment of neuropsychological, health, and psychosocial function. RESULTS: Our main result was that BDNF Val66Met moderated the relationship between baseline CR and change in executive function performance, in that CR-related differences in function decreased across the follow-up period in BDNF Val homozygotes, but became more pronounced in BDNF Met carriers. Similar effects were not observed within the other memory- and language-related cognitive domains. DISCUSSION: Inheritance of BDNF Met may be associated with a detrimental influence on the relationship between CR and cognitive change in cognitively intact older adults, but this effect may be restricted to the executive function domain.

Age is no barrier: predictors of academic success in older learners.

Although predictors of academic success have been identified in young adults, such predictors are unlikely to translate directly to an older student population, where such information is scarce. The current study aimed to examine cognitive, psychosocial, lifetime, and genetic predictors of university-level academic performance in older adults (50-79 years old). Participants were mostly female (71%) and had a greater than high school education level (M = 14.06 years, SD = 2.76), on average. Two multiple linear regression analyses were conducted. The first examined all potential predictors of grade point average (GPA) in the subset of participants who had volunteered samples for genetic analysis (N = 181). Significant predictors of GPA were then re-examined in a second multiple linear regression using the full sample (N = 329). Our data show that the cognitive domains of episodic memory and language processing, in conjunction with midlife engagement in cognitively stimulating activities, have a role in predicting academic performance as measured by GPA in the first year of study. In contrast, it was determined that age, IQ, gender, working memory, psychosocial factors, and common brain gene polymorphisms linked to brain function, plasticity and degeneration (APOE, BDNF, COMT, KIBRA, SERT) did not influence academic performance. These findings demonstrate that ageing does not impede academic achievement, and that discrete cognitive skills as well as lifetime engagement in cognitively stimulating activities can promote academic success in older adults.

Sending your grandparents to university increases cognitive reserve: The Tasmanian Healthy Brain Project.

OBJECTIVE: Increasing an individual's level of cognitive reserve (CR) has been suggested as a nonpharmacological approach to reducing the risk for Alzheimer's disease. We examined changes in CR in older adults participating over 4 years in the Tasmanian Healthy Brain Project. METHOD: A sample of 459 healthy older adults between 50 and 79 years of age underwent a comprehensive annual assessment of current CR, neuropsychological function, and psychosocial factors over a 4-year period. The intervention group of 359 older adults (M = 59.61 years, SD = 6.67) having completed a minimum of 12 months part-time university study were compared against a control reference group of 100 adults (M = 62.49 years, SD = 6.24) who did not engage in further education. RESULTS: Growth mixture modeling demonstrated that 44.3% of the control sample showed no change in CR, whereas 92.5% of the further education participants displayed a significant linear increase in CR over the 4 years of the study. These results indicate that older adults engaging in high-level mental stimulation display an increase in CR over a 4-year period. CONCLUSION: Increasing mental activity in older adulthood may be a viable strategy to improve cognitive function and offset cognitive decline associated with normal aging. (PsycINFO Database Record

Modeling cognitive reserve in healthy middle-aged and older adults: the Tasmanian Healthy Brain Project.

BACKGROUND: Cognitive reserve (CR) is a protective factor that supports cognition by increasing the resilience of an individual's cognitive function to the deleterious effects of cerebral lesions. A single environmental proxy indicator is often used to estimate CR (e.g. education), possibly resulting in a loss of the accuracy and predictive power of the investigation. Furthermore, while estimates of an individual's prior CR can be made, no operational measure exists to estimate dynamic change in CR resulting from exposure to new life experiences. METHODS: We aimed to develop two latent measures of CR through factor analysis: prior and current, in a sample of 467 healthy older adults. RESULTS: The prior CR measure combined proxy measures traditionally associated with CR, while the current CR measure combined variables that had the potential to reflect dynamic change in CR due to new life experiences. Our main finding was that the analyses uncovered latent variables in hypothesized prior and current models of CR. CONCLUSIONS: The prior CR model supports multivariate estimation of pre-existing CR and may be applied to more accurately estimate CR in the absence of neuropathological data. The current CR model may be applied to evaluate and explore the potential benefits of CR-based interventions prior to dementia onset.

APOE and BDNF Val66Met polymorphisms combine to influence episodic memory function in older adults.

Genetic polymorphisms of apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) have shown inconsistent associations with healthy adult cognitive functions. Recent investigations have suggested that APOE polymorphisms do not contribute to non-pathological cognitive function and that any effect is likely due to prodromal Alzheimer's disease (AD). Similarly, although BDNF Val66Met polymorphisms affect hippocampal morphology and function, associations with learning and/or memory have not always been found. This study sought to determine whether APOE and BDNF polymorphisms were associated, either independently or in combination, with adult cognition. Comprehensive neuropsychological assessments were conducted on 433 older adults, aged 50-79 years (M=62.16, SD=6.81), which yielded measures of episodic memory, working memory, executive function, and language processing. Participants underwent comprehensive neuropsychological assessment to ensure that only cognitively intact individuals comprised the sample. APOE and BDNF polymorphic data were used as predictors in general linear models that assessed composite cognitive domain variables, while covarying for education and age. Although no main effects for APOE or BDNF were found, the analysis identified a significant APOE×BDNF interaction that predicted episodic memory performance (p=.02, η(2)=.02). Post-hoc analyses demonstrated that in BDNF Val homozygotes, the cognitive consequences of APOE polymorphisms were minimal. However, in BDNF Met carriers, the hypothesized beneficial/detrimental effects of APOE polymorphisms were found. Our data show that concurrent consideration of both APOE and BDNF polymorphisms are required in order to witness a cognitive effect in healthy older adults.