Association of cognitive reserve with the risk of dementia in the UK Biobank: role of polygenic factors.

BACKGROUND: It remains unclear whether cognitive reserve can attenuate dementia risk among people with different genetic predispositions. AIMS: We aimed to examine the association between cognitive reserve and dementia, and further to explore whether and to what extent cognitive reserve may modify the risk effect of genetic factors on dementia. METHOD: Within the UK Biobank, 210 631 dementia-free participants aged ≥60 years were followed to detect incident dementia. Dementia was ascertained through medical and death records. A composite cognitive reserve indicator encompassing education, occupation and multiple cognitively loaded activities was created using latent class analysis, categorised as low, moderate and high level. Polygenic risk scores for Alzheimer's disease were constructed to evaluate genetic risk for dementia, categorised by tertiles (high, moderate and low). Data were analysed using Cox models and Laplace regression. RESULTS: In multi-adjusted Cox models, the hazard ratio (HR) of dementia was 0.66 (95% confidence interval (CI) 0.61-0.70) for high cognitive reserve compared with low cognitive reserve. In Laplace regression, participants with high cognitive reserve developed dementia 1.62 (95% CI 1.35-1.88) years later than those with low cognitive reserve. In stratified analysis by genetic risk, high cognitive reserve was related to more than 30% lower dementia risk compared with low cognitive reserve in each stratum. There was an additive interaction between low cognitive reserve and high genetic risk on dementia (attributable proportion 0.24, 95% CI 0.17-0.31). CONCLUSIONS: High cognitive reserve is associated with reduced risk of dementia and may delay dementia onset. Genetic risk for dementia may be mitigated by high cognitive reserve. Our findings underscore the importance of enhancing cognitive reserve in dementia prevention.

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry.

AIMS: Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association. METHODS AND RESULTS: Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD-dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27-1.58) for 1 CMD and 2.10 (1.73-2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD-dementia association was attenuated among monozygotic [0.99 (0.50-1.98)] but not dizygotic [1.55 (1.15-2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia. CONCLUSION: Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.

Systematic analysis of approaches used in cardiac arrest trials to inform relatives about trial enrolment of non-surviving patients.

BACKGROUND: The recruitment of patients to emergency research studies without the requirement for prior informed consent has furthered the conduct of randomised studies in cardiac arrest. Frameworks enabling this vary around the world depending on local legal or ethical requirements. When an enrolled patient does not survive, researchers may take one of three approaches to inform relatives of their enrolment: a direct (active) approach, providing information indirectly (passively) and inviting relatives to seek further information if they choose, or providing no information about the trial (no attempt). Previous studies have described experiences of US researchers' active approach but there is little known about approaches elsewhere.We aimed to conduct a structured investigation of methods used in cardiac arrest trials to provide information about trial enrolment to relatives of non-surviving patients. METHODS: We systematically searched trial registries to identify randomised clinical trials that recruited cardiac arrest patients. Trials were eligible for inclusion if they recruited adults during cardiac arrest (or within 1 hour of return of spontaneous circulation) between 2010 and 2022 (in the decade prior to study conception). We extracted data from trial registries and, where relevant, published papers and protocols. Investigators were contacted and asked to describe the style, rationale and timing of approach to relatives of non-surviving patients. We present descriptive statistics. RESULTS: Our trial registry search identified 710 unique trials, of which 108 were eligible for inclusion. We obtained information from investigators for 64 (62%) trials. Approximately equal numbers of trials attempted to actively inform relatives of non-survivors (n=28 (44% (95% CI; 31% to 57%))), or made no attempt (n=25 (39% (95% CI; 27% to 52%))). The remaining studies provided general information about the trial to relatives but did not actively inform them (n=11 (17% (95% CI; 8% to 29%))). CONCLUSIONS: There is wide variability in the approach taken to informing relatives of non-surviving patients enrolled in cardiac arrest randomised clinical trials.

High lifelong cognitive reserve prolongs disability-free survival: The role of cognitive function.

INTRODUCTION: The association between cognitive reserve (CR) and survival with independence is unknown. We examined whether lifelong CR accumulation is associated with disability-free survival and explored the extent to which cognitive function mediates this association. METHODS: Within the Rush Memory and Aging Project, 1633 dementia- and disability-free participants were followed annually for up to 22 years. Lifelong CR including education, early-/mid-/late-life cognitive activities, and late-life social activity was assessed and tertiled. RESULTS: CR score was dose-dependently associated with disability/death (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.93-0.99). Compared to low CR, the HR (95% CI) of disability/death was 0.82 (0.70-0.95) for high CR. The median disability-free survival time was prolonged by 0.99 (95% CI 0.28-1.71) years for participants with high CR. Cognitive function mediated 35.7% of the association between CR and disability-free survival. DISCUSSION: High lifelong CR was associated with prolonged disability-free survival. Cognitive function mediates about one-third of this association. Our findings underscore the importance of CR for healthy aging.

Association of life-course traumatic brain injury with dementia risk: A nationwide twin study.

INTRODUCTION: The impact of life-course traumatic brain injury (TBI) on dementia is unclear. METHODS: Within the Swedish Twin Registry (STR), 35,312 dementia-free twins were followed for up to 18 years. TBI history was identified via medical records. Data were analyzed using generalized estimating equation (GEE) and conditional logistic regression. RESULTS: In multi-adjusted GEE models, the odds ratio (OR, 95% confidence interval [CI]) of dementia was 1.27 (1.03-1.57) for TBI at any age, 1.55 (1.04-2.31) for TBI at 50 to 59 years, and 1.67 (1.12-2.49) for TBI at 60 to 69 years. Cardiometabolic diseases (CMDs) increased dementia risk associated with TBI at age 50 to 69 years. The ORs in GEE and conditional logistic regression did not differ significantly (P = .37). DISCUSSION: TBI, especially between ages 50 and 69 years, is associated with an increased risk of dementia, and this is exacerbated among people with CMDs. Genetic and early-life environmental factors may not account for the TBI-dementia association.

Association of impaired kidney function with dementia and brain pathologies: A community-based cohort study.

INTRODUCTION: The relationship between impaired kidney function (KF), dementia, and brain pathologies remains unclear. METHODS: A total of 1354 dementia- and kidney disease-free participants including 895 with normal and 459 with impaired KF were followed from 2002 until 2020 (median [interquartile range]: 5 [2-9]) to detect incident dementia. KF was assessed at baseline and categorized as normal or impaired. Over the follow-up, 453 participants died and underwent autopsies for neuropathological assessment. RESULTS: Compared to those with normal KF, the hazard ratios (95% confidence intervals [CIs]) of those with impaired KF was 1.48 (1.15, 1.90)/1.44 (1.10, 1.88) for dementia/Alzheimer's dementia. Furthermore, impaired KF was related to a significantly higher burden of cerebral amyloid angiopathy (CAA; odds ratio = 1.96, 95% CI: 1.17, 3.30), but not to other brain pathologies. DISCUSSION: Impaired KF is associated with an increased risk of dementia and Alzheimer's dementia. CAA may underlie, in part, this association. HIGHLIGHTS: Impaired kidney function (KF) was associated with higher dementia and Alzheimer's dementia risk. Impaired KF anticipated dementia and Alzheimer's dementia onset by more than 1.5 years. Impaired KF was significantly related to a higher burden of cerebral amyloid angiopathy (CAA) but not to other brain pathologies.

Doublesex controls specification and maintenance of the gonad stem cell niches in Drosophila.

Sex-specific development of the gonads is a key aspect of sexual dimorphism that is regulated by Doublesex/Mab3-related transcription factors (DMRTs) in diverse animal species. We find that in mutants for Drosophila dsx, important components of the male and female gonad stem cell niches (hubs and terminal filaments/cap cells, respectively) still form. Initially, gonads in all dsx mutants (both XX and XY) initiate the male program of development, but later half of these gonads switch to form female stem cell niche structures. One individual can have both male-type and female-type gonad niches; however, male and female niches are usually not observed in the same gonad, indicating that cells make a 'group decision' about which program to follow. We conclude that dsx does not act in an instructive manner to regulate male versus female niche formation, as these structures form in the absence of dsx function. Instead, dsx acts to 'tip the balance' between the male or female programs, which are then executed independently of dsx We show that bric a brac acts downstream of dsx to control the male versus female niche decision. These results indicate that, in both flies and mammals, the sexual fate of the somatic gonad is remarkably plastic and is controlled by a combination of autonomous and non-autonomous cues.

Healthy lifestyle counteracts the risk effect of genetic factors on incident gout: a large population-based longitudinal study.

BACKGROUND: Risk genes linked to the development of gout have been identified, and lifestyle factors are related to gout risk. It remains unclear whether healthy lifestyle factors can mitigate the genetic risk of gout. Therefore, we aimed to explore whether and to what extent a healthy lifestyle can mitigate the risk of gout related to genetic factors. METHODS: Within the UK Biobank, 416,481 gout-free participants (aged 37-74) were identified at baseline. Polygenic risk for gout was assessed and categorized as low (lowest tertile), middle (tertile 2), and high (highest tertile). Healthy lifestyle factors included no/moderate alcohol consumption, no smoking, physical activity, and a healthy diet. Participants were categorized into three groups according to their number of healthy lifestyle factors: unfavorable (0 or 1), intermediate (any 2), and favorable (3 or 4). Data were analyzed using Cox proportional hazard models. RESULTS: Over the follow-up (median: 12.1 years), 6206 participants developed gout. Compared to low genetic risk, the hazard ratios (HRs) and 95% confidence intervals (CIs) of gout was 1.44 (1.35-1.54) for middle and 1.77 (1.66-1.89) for high genetic risk. The HRs (95% CIs) of gout were 0.63 (0.59-0.67) for a favorable lifestyle and 0.79 (0.75-0.85) for an intermediate lifestyle, compared to an unfavorable lifestyle. In joint effect analysis, compared to participants with low genetic predisposition and a favorable lifestyle, the HRs (95% CIs) of gout were 2.39 (2.12-2.70)/3.12 (2.79-3.52) in those with middle and high genetic predisposition plus unfavorable lifestyle profiles, and 1.53 (1.35-1.74)/1.98 (1.75-2.24) for those with middle and high genetic predisposition plus favorable lifestyle profiles, respectively. Moreover, compared to an unfavorable lifestyle, the HRs of gout related to a favorable lifestyle was 0.64 (95% CI, 0.56-0.73) for low genetic risk, 0.65 (95% CI, 0.58-0.72) for middle genetic risk, and 0.62 (95% CI, 0.57-0.69) for high genetic risk. There was a significant additive interaction between unfavorable lifestyle and high genetic risk on gout. CONCLUSIONS: Healthy lifestyle was associated with a lower risk of gout and may attenuate the risk of gout related to genetic factors by almost a third.

Injurious falls before, during and after dementia diagnosis: a population-based study.

BACKGROUND: the timing of incident injurious falls at different stages of dementia diagnosis is unclear. OBJECTIVES: to identify when the occurrence of injurious falls begins to increase among individuals who are going to develop dementia, to explore the time point at which people living with dementia are at highest risk of injurious falls and to ascertain differences in fall-related factors pre- and post-dementia diagnosis. DESIGN: this study included 2,707 participants with incident dementia and 2,707 1:1 matched (i.e. same birth year and sex) controls without dementia. METHODS: dementia diagnosis and date of onset were identified from the National Patient Registry (NPR) and the Swedish Cause of Death Register following international criteria. Information on injurious falls and history of chronic disease was obtained from the NPR. Data were analysed using conditional Poisson regression and generalized estimating equation models. RESULTS: compared with controls, the incidence of injurious falls among participants with dementia started to increase beginning 4 years pre-diagnosis (incidence rate ratio [IRR] 1.70, 95% confidence interval [CI] 1.30-2.22), reaching a peak (IRR 3.73, 95% CI 3.16-4.41) in the year of dementia diagnosis. Heavy drinking, physically active and cardiometabolic diseases (CMDs) were associated with incident falls among those with dementia. CONCLUSION: people with dementia have a higher incidence of injurious falls beginning 4 years leading up to diagnosis and peaking during the year of diagnosis. Older age, female, heavy drinking, physically active and CMDs may predict injurious falls among people with dementia.

Poor pulmonary function is associated with mild cognitive impairment, its progression to dementia, and brain pathologies: A community-based cohort study.

INTRODUCTION: The relationship between pulmonary function (PF) and mild cognitive impairment (MCI), dementia, and brain pathologies remains unclear. METHODS: A total of 1312 dementia-free participants, including a cognitively intact group (n = 985) and an MCI group (n = 327), were followed for up to 21 years to detect incident MCI and dementia. PF was assessed at baseline with a composite score and tertiled. Over follow-up, 540 participants underwent autopsies for neuropathological assessment. RESULTS: Compared to the highest PF, the hazard ratios (95% confidence intervals [CIs]) of the lowest PF were 1.95 (1.43-2.66) for MCI in the cognitively intact group and 1.55 (1.03-2.33) for dementia in the MCI group. Low PF was further related to Alzheimer's disease pathology (odds ratio [OR] 1.32, 95% CI 1.19-1.47) and vascular pathology (OR 3.05, 95% CI 1.49-6.25). DISCUSSION: Low PF increases MCI risk and accelerates MCI progression to dementia. Both neurodegenerative and vascular mechanisms may underlie the PF-dementia association.

Cardiometabolic multimorbidity accelerates cognitive decline and dementia progression.

INTRODUCTION: Cardiometabolic diseases (CMDs) have been individually associated with adverse cognitive outcomes, but their combined effect has not been investigated. METHODS: A total of 2577 dementia-free participants 60 years of age or older were followed for 12 years to observe changes in cognitive function and to detect incident cognitive impairment, no dementia (CIND) and dementia. CMDs (including type 2 diabetes, heart disease, and stroke) were assessed at baseline through medical records and clinical examinations. Cardiometabolic multimorbidity was defined as the presence of two or more CMDs. Data were analyzed using multi-adjusted linear mixed-effects models, Cox regression, and Laplace regression. RESULTS: CMD multimorbidity was associated with cognitive decline, CIND (hazard ratio [HR] 1.73; 95% confidence interval CI 1.23 to 2.44), and its progression to dementia (HR 1.86; 95% CI 1.17 to 2.97). CMD multimorbidity accelerated the onset of CIND by 2.3 years and dementia by 1.8 years. CONCLUSIONS: CMD multimorbidity accelerates cognitive decline and increases the risk of both CIND and its conversion to dementia. HIGHLIGHTS: We explored the combined impact of cardiometabolic diseases (CMDs) on cognition. An increasing number of CMDs dose-dependently accelerated cognitive decline. CMD multimorbidity increased the risk of both cognitive impairment and dementia. Co-morbid CMDs could be ideal targets for interventions to protect cognitive health.

Pulmonary function is associated with cognitive decline and structural brain differences.

The association of poor pulmonary function (PF) with cognitive trajectories and structural brain differences remains unclear. Within the Rush Memory and Aging Project, 1377 dementia-free subjects were followed up to 21 years. PF was assessed with a composite score measured at baseline. Global and domain-specific cognitive function was assessed annually constructed from 19 cognitive tests. A subsample of 351 participants underwent brain magnetic resonance imaging to investigate the cross-sectional association between PF and structural brain volumes. We found that low PF was related to faster decline in global cognition, and domain-specific function including episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed. In addition, low PF was associated with smaller volumes of total brain, white matter and gray matter, and larger white matter hyperintensities volume. Our results suggest that low PF is associated with faster cognitive decline, and both neurodegeneration and vascular brain lesions may underlie the association.

Association of life satisfaction with disability-free survival: role of chronic diseases and healthy lifestyle.

BACKGROUND: this article investigates the association between life satisfaction and disability-free survival, and explores the roles of chronic diseases and healthy lifestyle in this association. METHOD: a cohort of 2,116 functionally independent adults aged ≥60 was followed up to 12 years. At baseline, life satisfaction was assessed with the Life Satisfaction Index A (LSI-A). Disability-free survival was defined as the survival till the first occurrence of either death, dementia or physical disability. Information on lifestyle factors was collected via questionnaire. Chronic diseases were ascertained through clinical examinations at baseline and each follow-up. Data were analysed using Cox proportional hazard regression models and Laplace regression. RESULTS: over follow-up, 1,121 participants died, developed dementia, or became disabled. High LSI-A versus Low LSI-A had a lower risk of death, dementia and physical disability (hazard ratio [HR] 0.79, 95% confidence intervals [CI] 0.67-0.94), and had a longer disability-free period by 1.73 (95% CI 0.18-3.32) years. In mediation analysis, accumulation of chronic diseases mediated 17.8% of the association between LSI-A and disability-free survival. In joint effect analysis, participants with high LSI-A and a favourable lifestyle profile had a HR of 0.53 (95% CI 0.41-0.69) for the composite endpoint, and lived 3.2 (95% CI 1.35-5.11) disability-free years longer than those with low life satisfaction and an unfavourable lifestyle profile. DISCUSSION: high life satisfaction is independently associated with longer disability-free survival. This association is partially mediated by a lower burden of chronic diseases and is reinforced by healthy lifestyle.

Development and Validation of a Prevalence Model for Latent Autoimmune Diabetes in Adults (LADA) Among Patients First Diagnosed with Type 2 Diabetes Mellitus (T2DM).

BACKGROUND We designed this study to develop and validate a prevalence model for latent autoimmune diabetes in adults (LADA) among people initially diagnosed with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The study recruited 930 patients aged ≥18 years who were diagnosed with T2DM within the past year. Demographic information, medical history, and clinical biochemistry records were collected. Logistic regression was used to develop a regression model to distinguish LADA from T2DM. Predictors of LADA were identified in a subgroup of patients (n=632) by univariate logistic regression analysis. From this we developed a prediction model using multivariate logistic regression analysis and tested its sensitivity and specificity among the remaining patients (n=298). RESULTS Among 930 recruited patients, 880 had T2DM (96.4%) and 50 had LADA (5.4%). Compared to T2DM patients, LADA patients had fewer surviving b cells and reduced insulin production. We identified age, ketosis, history of tobacco smoking, 1-hour plasma glucose (1hPG-AUC), and 2-hour C-peptide (2hCP-AUC) as the main predictive factors for LADA (P<0.05). Based on this, we developed a multivariable logistic regression model: Y=-8.249-0.035(X1)+1.755(X2)+1.008(X3)+0.321(X4)-0.126(X5), where Y is diabetes status (0=T2DM, 1=LADA), X1 is age, X2 is ketosis (1=no, 2=yes), X3 is history of tobacco smoking (1=no, 2=yes), X4 is 1hPG-AUC, and X5 is 2hCP-AUC. The model has high sensitivity (78.57%) and selectivity (67.96%). CONCLUSIONS This model can be applied to people newly diagnosed with T2DM. When Y ≥0.0472, total autoantibody screening is recommended to assess LADA.

The impact of diabetes on cognitive impairment and its progression to dementia.

INTRODUCTION: Diabetes is a well-established risk factor for dementia, but its impact on the prodromal phase of dementia is unclear. METHODS: Cohorts of older adults who were cognitively healthy (n = 1840) or had cognitive impairment-no dementia (CIND; n = 682) were followed over 12 years to detect incident CIND and dementia, respectively. RESULTS: Poorly controlled diabetes (glycated hemoglobin [HbA1c] ≥7.5%; reference = normoglycemia) was associated with double the risk of CIND (Cox regression multi-adjusted hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.13-3.58) and triple the risk CIND progressing to dementia (HR 2.87, 95% CI 1.20-6.85). Co-morbid diabetes and heart disease doubled the risk of incident CIND and dementia, although neither disease conferred a significant risk of either outcome alone. Elevated systemic inflammation contributed to the diabetes-associated increased dementia risk. CONCLUSIONS: Diabetes characterized by poor glycemic control or cardiovascular complications is related to a greater risk of the development and progression of cognitive impairment. Inflammation may play a role in these relationships.

Does Time-in-Range Matter? Perspectives From People With Diabetes on the Success of Current Therapies and the Drivers of Improved Outcomes.

IN BRIEF After assessing patient perspectives on the success of current diabetes therapies and the factors that have the greatest impact on daily life, we show that time-in-range is a crucial outcome for people with diabetes and that current therapies are falling short on this metric. We also show that patients feel significant stress and worry, and they believe they are falling short in diet, exercise, and weight maintenance. In addition, they believe diet and exercise and in-range blood glucose are the biggest drivers of improved diabetes management and mindset. Together, these findings support the need for therapies that improve outcomes including and beyond A1C.

A nomogram for predicting disability-free survival in older adults over 15 years: A population-based cohort study.

BACKGROUND: This article aimed to develop and validate a simple-to-use nomogram to predict 15-year disability-free survival among older adults. METHODS: A cohort of 1878 disability-free participants aged ≥60 was followed for 15 years. Participants were randomly divided into a training cohort for nomogram development (n = 1314 [70 %]) and validation cohort to confirm the model's performance (n = 564 [30 %]). Information on socio-demographic, lifestyle factors, the Life Satisfaction Index A (LSI-A), chronic diseases, and Mini-Mental State Examination (MMSE) score, and biomarkers were collected through interviews, clinical and neuropsychological examinations, and medical records. Disability-free survival was defined as survival in the absence of dementia and physical disability, and the composite endpoint is first occurrence of events of death, dementia and physical disability. We developed a nomogram summing the number of risk points corresponding to weighted covariates to predict disability-free survival. Validation of the nomogram using C statistic, calibration plots, and Kaplan-Meier curves. RESULTS: In the multivariate-adjusted model, factors associated with composite end point were younger age, high MMSE (hazard ratio [HR], 0.93; [95 % CI, 0.87-0.99]), high LSI-A (0.78, [0.64-0.97]), non-smoking (0.74, [0.59-0.94]), engagement in physical leisure activity (0.62, [0.48-0.78]), and absence of chronic diseases (0.78, [0.66-0.91]). Incorporating these 6 factors, the nomogram achieved C-statistics of 0.78 (95 % CI, 0.75-0.81) and 0.77 (95 % CI, 0.74-0.80) in predicting disability-free survival in the training and validation cohorts, respectively, and had good calibration curves. CONCLUSION: The nomogram was able to predict long-term of disability-free survival and performed well on internal validation, and may be considered for use in effective surveillance, promote, management of clinical and public health ageing.

Association of Kidney Function With Dementia and Structural Brain Differences: A Large Population-Based Cohort Study.

BACKGROUND: The association between kidney function and dementia risk and the mechanisms underlying this relationship remain unclear. METHODS: Within the UK Biobank, 191 970 dementia-free participants aged ≥60 (mean age: 64.1 ± 2.9 years) were followed for 16 years to detect incident dementia. Serum creatinine and Cystatin C were measured at baseline to calculate estimated glomerular filtration rate (eGFR, mL/min/1.73 m2). Kidney function was categorized as normal (eGFR ≥ 90), mildly impaired (60 ≤ eGFR < 90), or moderately to severely impaired (eGFR < 60). Dementia was assessed based on self-reported medical history and medical records. During the follow-up, a subsample of 12 637 participants underwent brain MRI scans. Volumes of total brain, gray matter, white matter, hippocampus, and white matter hyperintensities were assessed. RESULTS: Over the follow-up, 5 327 (2.8%) participants developed dementia. Compared to normal kidney function, there was an increased risk of dementia with moderate to severely impaired kidney function (hazard ratio = 1.53, 95% confidence interval [CI]: 1.32-1.76) but not mildly impaired kidney function. In Laplace regression, dementia onset among people with moderate to severely impaired kidney function occurred 1.53 (95% CI: 0.98-2.08) years earlier than those with normal kidney function. Moderate to severely impaired kidney function was related to significantly lower gray matter volume (ß = -0.11, 95% CI: -0.19 to -0.03), but not to other brain magnetic resonance imaging measures. CONCLUSIONS: Impaired kidney function is associated with about 50% increased risk of dementia and anticipates dementia onset by more than 1.5 years. Brain neurodegeneration may underlie the kidney function-dementia association.

Associations Between Mid- to Late-Life Body Mass Index and Chronic Disease-Free Survival: A Nationwide Twin Study.

BACKGROUND: Some studies have linked late-life overweight to a reduced mortality risk compared to normal body mass index (BMI). However, the impact of late-life overweight and its combination with mid-life BMI status on healthy survival remains unclear. We aimed to investigate whether and to what extent mid- and/or late-life overweight are associated with chronic disease-free survival. METHODS: Within the Swedish Twin Registry, 11 597 chronic disease-free twins aged 60-79 years at baseline were followed up for 18 years. BMI (kg/m2) was recorded at baseline and 25-35 years before baseline (ie, midlife) and divided as underweight (<20), normal (≥20-25), overweight (≥25-30), and obese (≥30). Incident chronic diseases (cardiovascular diseases, type 2 diabetes, and cancer) and deaths were ascertained via registries. Chronic disease-free survival was defined as years lived until the occurrence of any chronic diseases or death. Data were analyzed using multistate survival analysis. RESULTS: Of all participants, 5 640 (48.6%) were overweight/obese at baseline. During the follow-up, 8 772 (75.6%) participants developed at least 1 chronic disease or died. Compared to normal BMI, late-life overweight and obesity were associated with 1.1 (95% CI, 0.3, 2.0) and 2.6 (1.6, 3.5) years shorter chronic disease-free survival. Compared to normal BMI through mid- to late life, consistent overweight/obesity and overweight/obesity only in mid-life led to 2.2 (1.0, 3.4) and 2.6 (0.7, 4.4) years shorter disease-free survival, respectively. CONCLUSIONS: Late-life overweight and obesity may shorten disease-free survival. Further research is needed to determine whether preventing overweight/obesity from mid- to late life might favor longer and healthier survival.

High cognitive reserve attenuates the risk of dementia associated with cardiometabolic diseases.

BACKGROUND: Cardiometabolic diseases (CMDs) including type 2 diabetes, heart disease, and stroke have been linked to a higher risk of dementia. We examined whether high levels of cognitive reserve (CR) can attenuate the increased dementia risk and brain pathologies associated with CMDs. METHODS: Within the UK Biobank, 216,178 dementia-free participants aged ≥ 60 were followed for up to 15 years. Baseline CMDs and incident dementia were ascertained from medical records, medication use, and medical history. Latent class analysis was used to generate an indicator of CR (low, moderate, and high) based on education, occupational attainment, confiding in others, social contact, leisure activities, and television watching time. A subsample (n = 13,663) underwent brain MRI scans during follow-up. Volumes of total gray matter (GMV), hippocampus (HV), and white matter hyperintensities (WMHV) were ascertained, as well as mean diffusivity (MD) and fractional anisotropy (FA) in white matter tracts. RESULTS: At baseline, 43,402 (20.1%) participants had at least one CMD. Over a mean follow-up of 11.7 years, 6,600 (3.1%) developed dementia. The presence of CMDs was associated with 57% increased risk of dementia (HR 1.57 [95% CI 1.48, 1.67]). In joint effect analysis, the HRs of dementia for people with CMDs and moderate-to-high CR and low CR were 1.78 [1.66, 1.91] and 2.13 [1.97, 2.30]), respectively (reference: CMD-free, moderate-to-high CR). Dementia risk was 17% lower (HR 0.83 [0.77, 0.91], p < 0.001) among people with CMDs and moderate-to-high compared to low CR. On brain MRI, CMDs were associated with smaller GMV (ß -0.18 [-0.22, -0.13]) and HV (ß -0.13 [-0.18, -0.08]) as well as significantly larger WMHV (ß 0.06 [0.02, 0.11]) and MD (ß 0.08 [0.02, 0.13]). People with CMDs and moderate-to-high compared to low CR had significantly larger GMV and HV, but no differences in WMHV, MD, or FA. CONCLUSIONS: Among people with CMDs, having a higher level of CR was associated with lower dementia risk and larger gray matter and hippocampal volumes. The results highlight a mentally and socially active life as a modifiable factor that may support cognitive and brain health among people with CMDs.