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.

Association of past and current sleep duration with structural brain differences: A large population-based study from the UK Biobank.

OBJECTIVE: This study aimed to examine the association between past/current sleep duration and macro-/micro-structural brain outcomes and explore whether hypertension or social activity plays a role in such association. METHODS: Within the UK Biobank, 40 436 dementia-free participants (age 40-70 years) underwent a baseline assessment followed by a brain magnetic resonance imaging (MRI) scan 9 years later. Past (baseline) and current (MRI scans) sleep duration (hours/day) were recorded and classified as short (≤5), intermediate (6-8), and long (≥9). Brain structural volumes and diffusion markers were assessed by MRI scans. RESULTS: Compared with past intermediate sleep, past short sleep was related to smaller cortex volumes (standardized ß [95 % CI]: -0.04 [-0.07, -0.02]) and lower regional fractional anisotropy (FA) (-0.08 [-0.13, -0.03]), while past long sleep was related to smaller regional subcortical volumes (standardized ß: -0.04 to -0.07 for thalamus, accumbens, and hippocampus). Compared to current intermediate sleep, current short sleep was associated with smaller cortex volumes (-0.03 [-0.05, -0.01]), greater white matter hyperintensities (WMH) volumes (0.04 [0.01, 0.08]), and lower regional FA (-0.07 [-0.11, -0.02]). However, current long sleep was related to smaller total brain (-0.03 [-0.05, -0.02]), grey matter (-0.05 [-0.07, -0.03]), cortex (-0.05 [-0.07, -0.03]), regional subcortical volumes [standardized ß: -0.05 to -0.09 for putamen, thalamus, hippocampus, and accumbens]), greater WMH volumes (0.06 [0.03, 0.09]), as well as lower regional FA (-0.05 [-0.09, -0.02]). The association between current long sleep duration and poor brain health was stronger among people with hypertension or low frequency of social activity (all Pinteraction <0.05). CONCLUSIONS: Both past and current short/long sleep are associated with smaller brain volume and poorer white matter health in the brain, especially in individuals with hypertension and low frequency of social activity. Our findings highlight the need to maintain 6-8 h' sleep duration for healthy brain aging.

Cardiometabolic disease, cognitive decline, and brain structure in middle and older age.

INTRODUCTION: The presence of multiple cardiometabolic diseases (CMDs) has been linked to increased dementia risk, but the combined influence of CMDs on cognition and brain structure across the life course is unclear. METHODS: In the UK Biobank, 46,562 dementia-free participants completed a cognitive test battery at baseline and a follow-up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs (diabetes, heart disease, and stroke) were ascertained from medical records. Data were analyzed using age-stratified (middle age [< 60] versus older [≥ 60]) mixed-effects models and linear regression. RESULTS: A higher number of CMDs was associated with significantly steeper global cognitive decline in older (ß = -0.008; 95% confidence interval: -0.012, -0.005) but not middle age. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, and hippocampal volume and larger white matter hyperintensity volume, even in middle age. DISCUSSION: CMDs are associated with cognitive decline in older age and poorer brain structural health beginning already in middle age. Highlights: We explored the association of CMDs with cognitive decline and brain MRI measures.CMDs accelerated cognitive decline in older (≥60y) but not middle (<60) age.CMDs were associated with poorer brain MRI parameters in both middle and older age.Results highlight the connection between CMDs and cognitive/brain aging.

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.

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.

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.

Association of Anemia with Cognitive Function and Dementia Among Older Adults: The Role of Inflammation.

BACKGROUND: The association of anemia with cognitive function and dementia remains unclear. OBJECTIVE: We aimed to investigate the association of anemia with cognitive function and dementia risk and to explore the role of inflammation in these associations. METHODS: Within the UK Biobank, 207,203 dementia-free participants aged 60+ were followed for up to 16 years. Hemoglobin (HGB) and C-creative protein (CRP) were measured from blood samples taken at baseline. Anemia was defined as HGB <13 g/dL for males and <12 g/dL for females. Inflammation was categorized as low or high according to the median CRP level (1.50 mg/L). A subset of 18,211 participants underwent cognitive assessments (including global and domain-specific cognitive). Data were analyzed using linear mixed-effects model, Cox regression, and Laplace regression. RESULTS: Anemia was associated with faster declines in global cognition (ß= -0.08, 95% confidence interval [CI]: -0.14, -0.01) and processing speed (ß= -0.10, 95% CI: -0.19, -0.01). During the follow-up of 9.76 years (interquartile range 7.55 to 11.39), 6,272 developed dementia. The hazard ratio of dementia was 1.57 (95% CI: 1.38, 1.78) for people with anemia, and anemia accelerated dementia onset by 1.53 (95% CI: 1.08, 1.97) years. The risk of dementia tended to be higher in people with both anemia and high CRP (1.89, 95% CI: 1.60, 2.22). There was a statistically significant interaction between anemia and CRP on dementia risk (p-interaction = 0.032). CONCLUSIONS: Anemia is associated with cognitive decline (specifically for processing speed) and increased risk of dementia, especially in people with high inflammation.

Association of Motor Function With Cognitive Trajectories and Structural Brain Differences: A Community-Based Cohort Study.

BACKGROUND AND OBJECTIVES: The association of motor function with cognitive health remains controversial, and the mechanisms underlying this relationship are unclear. We aimed to examine the association between motor function and long-term cognitive trajectories and further explore the underlying mechanisms using brain MRI. METHODS: In the Rush Memory and Aging Project, a prospective cohort study, a total of 2,192 volunteers were recruited from the communities in northeastern Illinois and followed up for up to 22 years (from 1997 to 2020). Individuals with dementia, disability, missing data on motor function at baseline, and missing follow-up data on cognitive function were excluded. At baseline, global motor function was evaluated using the averaged z scores of 10 motor tests covering dexterity, gait, and hand strength; the composite score was tertiled as low, moderate, or high. Global and domain-specific cognitive functions-including episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed-were measured annually through 19 cognitive tests. A subsample (n = 401) underwent brain MRI scans and regional brain volumes were measured. Data were analyzed using linear mixed-effects models and linear regression. RESULTS: Among the 1,618 participants (mean age 79.45 ± 7.32 years) included in this study, baseline global motor function score ranged from 0.36 to 1.82 (mean 1.03 ± 0.22). Over the follow-up (median 6.03 years, interquartile range 3.00-10.01 years), low global motor function and its subcomponents were related to significantly faster declines in global cognitive function (ß = -0.005, 95% CI -0.006 to -0.005) and each of the 5 cognitive domains. Of the 344 participants with available MRI data, low motor function was also associated with smaller total brain (ß = -25.848, 95% CI -44.902 to -6.795), total white matter (ß = -18.252, 95% CI -33.277 to -3.226), and cortical white matter (ß = -17.503, 95% CI -32.215 to -2.792) volumes, but a larger volume of white matter hyperintensities (ß = 0.257, 95% CI 0.118-0.397). DISCUSSION: Low motor function is associated with an accelerated decline in global and domain-specific cognitive functions. Both neurodegenerative and cerebrovascular pathologies might contribute to this association.

Association of lifespan reproductive duration with depression in Swedish twins: The role of hormone replacement therapy.

OBJECTIVE: To examine the association between reproductive duration and postmenopausal depression (taking the use of hormone replacement therapy [HRT] into account). METHODS: In this population-based cohort study, 11 320 postmenopausal women (mean age 63.6 years) were followed for up to 18 years. Reproductive duration was categorized into three groups: short (≤34 years), average (35-39 years), and long (≥40 years). Depression was ascertained from the Sweden National Patient Registry. RESULTS: During the follow up, 593 (5.24%) women developed depression. In the multi-adjusted generalized estimating equation model, the odds ratios (ORs) of depression were 1.28 (95% confidence interval [CI] 1.05-1.55) and 1.25 (95% CI 1.01-1.55) for women with short and long reproductive durations, respectively, compared with those women with average reproductive duration. Women with a non-typical reproductive duration (≤34 or ≥40 years) who received HRT were at a higher risk of depression (OR 1.82, 95% CI 1.42-2.33). There was a significant additive interaction between non-typical reproductive duration and the use of HRT on depression (attributable proportion 0.26, 95% CI 0.03-0.50). CONCLUSION: Women with a short or long reproductive duration, especially those with a history of HRT use, have a higher risk of depression after menopause compared with those with an average reproductive duration.

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.

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.

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.

Pulmonary Function Trajectories Preceding Death Among Older Adults: A Long-Term Community-Based Cohort Study.

BACKGROUND: Poor pulmonary function (PF) has been linked to mortality, but the timing of PF changes before death remains unclear. We aimed to examine the association between PF and mortality and identify different PF trajectories precedes death. METHODS: Within the Rush Memory and Aging Project, 1 438 participants without chronic obstructive pulmonary disease were followed for up to 22 years. PF was assessed annually using a composite score (tertiled as low, medium, and high) based on forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), and peak expiratory flow (PEF). Survival status was observed during the follow-up period. Data were analyzed using Cox regression, Laplace regression, and mixed-effect models. RESULTS: During the follow-up, 737 (51.25%) participants died. Compared to high PF, the hazard ratio (95% confidence interval [CI]) of mortality was 1.35 (1.05, 1.72)/1.63 (1.25, 2.12) for medium/low PF. The median survival time (95% CI) was shortened by 0.80 (0.01-1.61)/1.72 (0.43-3.01) years for participants with medium/low PF, compared to high PF. In multiadjusted trajectory analysis, the significant differences between decedents and survivors occurred at 7 years before death for composite PF (mean difference [95% CI]: 0.14 [0.02-0.25]), 6 years for FEV1 (0.21 [0.08-0.33]) and FVC (0.21 [0.08-0.34]), and 8 years for PEF (0.21 [0.06-0.37]), and became greater thereafter. CONCLUSION: Poor PF is associated with elevated mortality and shortens survival for nearly 2 years. An acceleration in PF decline tends to occur 7 years before death. Poor PF, together with its decline, might be a predictor of mortality among community-dwelling older adults.

Association Between Late-Life Weight Change and Dementia: A Population-based Cohort Study.

BACKGROUND: The impact of late-life weight changes on incident dementia is unclear. We aimed to investigate the associations of body mass index (BMI) and weight changes with dementia and to explore the role of APOE ɛ4 in these associations. METHODS: A total of 1 673 dementia-free participants aged ≥60 and older were followed for an initial 6 years to detect changes in BMI/weight and then for an additional 6 years to detect incident dementia. BMI change ([BMIfirst 6-year follow-up - BMIbaseline]/BMIbaseline) was categorized as stable (≤5%), and moderate (5%-10%) or large (>10%) gain or loss. Weight change (weightfirst 6-year follow-up - weightbaseline) was categorized as stable (≤2.5 kg), and moderate (2.5-7.5 kg) or large (>7.5 kg) gain or loss. Dementia was diagnosed following standard criteria. Data were analyzed using Cox regression models. RESULTS: Over the second 6-year follow-up period, 102 incident dementia cases were identified. Compared with stable BMI, the hazard ratios (95% CI) of dementia were 2.61 (1.09-5.54) and 2.93 (1.72-4.91) for BMI gain or loss >10%, respectively. The risk of dementia was higher among APOE ɛ4 carriers experiencing a large BMI gain (9.93 [3.49-24.6]) or loss (6.66 [2.83-14.4]) than APOE ɛ4 noncarriers with stable BMI. Similar results were observed for weight change and dementia associations. CONCLUSIONS: BMI and weight changes showed U-shaped associations with dementia risk. Large bodyweight gain and loss alike are associated with an almost 3-fold higher risk of dementia, which may be amplified by APOE ɛ4.

Trajectories of olfactory identification preceding incident mild cognitive impairment and dementia: a longitudinal study.

BACKGROUND: The pattern of olfactory identification change in the early phases of dementing disorders is unclear. We aimed to assess olfactory identification trajectories preceding incident mild cognitive impairment (MCI) and dementia and explore the role of brain pathologies in these trajectories. METHODS: Within the Rush Memory and Aging Project, 1318 dementia-free older adults were followed annually for up to 11 years. Olfactory identification was assessed using the Brief Smell Identification Test annually. Of 900 cognitively intact participants, incident MCI and dementia were diagnosed following standard criteria. Over follow-up, 518 participants died and underwent brain autopsies for neuropathological assessment. Data were analyzed using mixed-effect models with backward timescales. FINDINGS: Compared to participants who remained cognitively intact, olfactory identification declined faster among those who developed MCI (ß -0.09 [95% CI -0.13, -0.05]), leading to a significantly lower olfactory identification starting from five years preceding MCI diagnosis (mean difference at year -5: -0.39 [-0.71, -0.07]). Among participants with incident MCI, olfactory identification declined faster in those who developed dementia compared to those who did not (ß -0.19 [-0.36, -0.01]), leading to a significantly lower olfactory identification starting from three years preceding dementia diagnosis (mean difference at year -3: -0.95 [-1.67, -0.23]). A faster decline in olfactory identification was associated with higher burdens of global Alzheimer's disease pathology, neurofibrillary tangles, and amyloid beta load. INTERPRETATION: Olfactory identification declined faster preceding dementia disorders and Alzheimer's pathology may underlie these faster declines. FUNDING: This study was funded by the National Institutes of Health (R01AG17917) and Swedish Research Council (2021-01647).

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.

Body Mass Index Trajectories Preceding Incident Mild Cognitive Impairment and Dementia.

Importance: Body mass index (BMI) trajectories before the onset of mild cognitive impairment (MCI) and during the progression from MCI to dementia remain unclear. Objective: To assess the long-term BMI trajectories preceding incident MCI and dementia and explore whether they are associated with brain pathologies. Design, Setting, and Participants: The Rush Memory and Aging Project (MAP) was an ongoing community-based cohort study. This study included cognitively intact participants aged 60 to 90 years at baseline with annual follow-up from October 1997 to December 2020 (maximum follow-up of 22 years). During the follow-up, participants underwent brain autopsies. Data were analyzed from August 2021 to February 2022 using mixed-effect models. Exposures: BMI was calculated using height and weight measured at baseline and follow-ups. Main Outcomes and Measures: Incident MCI and dementia were diagnosed following standard criteria. Neuropathological assessments (including global Alzheimer disease and vascular pathology) were performed for autopsies. Results: A total of 1390 participants (mean [SD] age, 78.4 [6.5] years; 1063 female [76.5%]) were included in the study. In the analysis of BMI trajectories before MCI (n = 939), during the follow-up (median [IQR] duration, 6 [3-9] years), 371 participants (39.5%) developed MCI, of whom 88 (23.7%) progressed to dementia. Those who developed MCI were older (mean [SD] age, 79.6 [5.9] years vs 76.9 [6.6] years), consumed less alcohol (median [IQR] consumption, 0 [0-5.8] g/day vs 1.1 [0-6.9] g/day), had a lower BMI (mean [SD], 27.2 [4.9] vs 28.2 [5.9]), and were more likely to be apolipoprotein E (APOE) ε4 carriers (89 of 371 [24.0%] vs 98 of 568 [17.3%]) compared with those who remained cognitively intact over follow-up. Those who developed dementia were older (mean [SD] age, 81.0 [5.2] years vs 79.1 [6.0] years), had a lower level of physical activity (median [IQR] activity, 1.0 [0-2.5] h/week vs 1.8 [0.2-3.8] h/week), and were more likely to be APOE ε4 carriers than those who were dementia-free (33 of 88 [37.5%] vs 56 of 283 [19.8%]). Compared with participants who remained cognitively intact, in those with incident MCI, BMI tended to decline earlier and faster. From 7 years before diagnosis, people with incident MCI had an associated significantly lower BMI (mean difference, -0.96; 95% CI, -1.85 to -0.07) than those who were cognitively intact. Among people with incident MCI, the slopes of BMI decline did not differ significantly between those who did and did not develop dementia (ß, -0.03; 95% CI, -0.21 to 0.15). In the analysis of BMI trajectories before autopsy (n = 358), BMI was associated with a faster declination among participants with a high burden of global Alzheimer disease pathology (ß for pathology × time highest vs lowest tertile, -0.14; 95% CI, -0.26 to -0.02) or vascular pathology (ß for pathology × time2 highest vs lowest tertile, 0.02; 95% CI, 0-0.05). Conclusions and Relevance: Results of this cohort study suggest that among cognitively intact people, significantly lower BMI occurs beginning approximately 7 years before MCI diagnosis. After MCI diagnosis, BMI declines at the same pace in people who develop dementia and those who do not. High brain pathologies may underly the BMI decline preceding dementing disorders.

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.