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Xiaolei Han,1,2,* Yongxiang Wang,2,3,* Ziying Jiang,1 Yuanjing Li,4 Yi Dong,1 Lin Cong,1– 3 Tingting Hou,1– 3 Yajun Liang,4,5 Erika J Laukka,4 Yifeng Du,1– 3 Chengxuan Qiu1,4 1Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong Province, People’s Republic of China; 4Aging Research Center and Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Stockholm University, Stockholm, Sweden; 5Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden*These authors contributed equally to this workCorrespondence: Yifeng Du, Department of Neurology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324 Jingwuweiqi Road, Jinan, Shandong, 250021, People’s Republic of China, Tel +86-531-68776354, Fax +86-531-68773274, Email du-yifeng@hotmail.comPurpose: We explore the associations of individual and composite cardiovascular health metrics with all-cause dementia, Alzheimer’s disease, and vascular dementia among rural-dwelling older adults and the potential age variations in their associations.Patients and Methods: This community-based cross-sectional study included 4980 older adults (age ≥ 65 years; 57.23% women) from the baseline examination of MIND-China. In March–September 2018, data were collected via face-to-face interviews, clinical examinations, and laboratory test. We defined six cardiovascular health metrics according to the modified American Heart Association’s recommendations. We diagnosed dementia and its subtypes following the international criteria. Data were analyzed using logistic regression models.Results: Of all the participants, 250 were diagnosed with dementia, including 165 with Alzheimer’s disease and 75 with vascular dementia. Ideal composite global cardiovascular health metrics (vs poor composite metrics) were associated with a multi-adjusted odds ratio (95% confidence interval) of 0.62 (0.42– 0.93) for dementia, 0.88 (0.52– 1.48) for Alzheimer’s disease, and 0.31 (0.16– 0.60) for vascular dementia. Moreover, ideal biological cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.52 (0.28– 0.95) for dementia and 0.21 (0.06– 0.77) for vascular dementia in young–old adults (65– 74 years), whereas ideal behavioral cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.48 (0.26– 0.89) for dementia and 0.16 (0.06– 0.43) for vascular dementia in old–old adults (≥ 75 years).Conclusion: Our results suggest that ideal cardiovascular health metrics are cross-sectionally associated with a low likelihood of dementia and vascular dementia among rural-dwelling older Chinese adults. The associations vary with age, components of cardiovascular health metrics, and dementia subtypes.Keywords: cardiovascular health, dementia, Alzheimer’s disease, vascular dementia, population-based study

Background/Aim: Alzheimer’s disease (AD) is one of the most important causes of old-age cognitive impairment. We aimed to examine the influence of history of vascular disease on cognition in preclinical and early AD. Methods: Participants from a population-based study were assessed twice with a test of global cognition. The study sample was nondemented at baseline. Three years later, 138 persons were diagnosed with AD and 783 persons remained nondemented. History of vascular disease (heart disease, cerebrovascular disease) was assessed at both occasions. Results: Analyses of covariance revealed significant main effects of group (AD; comparison group) and vascular disease (present; absent) at baseline and follow-up (p < 0.01). At follow-up, a significant interaction indicated that the AD group was more negatively affected by vascular disease (p < 0.01). The fastest rate of cognitive decline was observed for those persons with preclinical AD who had new recordings of vascular disease. Conclusions: History of vascular disease has a negative impact on cognition in old age. This effect is most pronounced in persons in the earliest clinical phases of AD. Treatment of vascular risk factors in early AD might postpone time of diagnosis and slow down dementia progression. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: In a previous study, the authors found no accelerated decline in close proximity to death for a measure of global cognitive functioning, after excluding persons in a preclinical phase of dementia. However, specific cognitive tasks might be more sensitive to terminal-decline effects. The purpose of this study was to explore possible terminal-decline effects for a range of cognitive tasks after controlling for preclinical dementia. Design: Community-based cohort study. Setting: The Kungsholmen district of Stockholm. Participants: A total of 585 persons (75+ years) were repeatedly assessed over an 11-year period. Level and change in cognitive performance were compared for three groups: persons in close proximity to death, persons in a preclinical phase of dementia, and persons who remained alive and nondemented throughout the study. Measurements: Tasks assessing primary and episodic memory, verbal ability, and visuospatial skill. Results: Compared with an analysis where all dead subjects were included in the impending-death group, removing the preclinical dementia cases resulted in markedly attenuated mortality-related effects. However, the impending-death group still declined at a faster rate relative to the comparison group on Digit Span-forward, word recognition, and category fluency. Notably, these were tasks for which the comparison group showed no significant decline. Conclusions: A considerable proportion of the terminal-decline effect is accounted for by the impact of preclinical dementia. However, for tasks that are relatively resistant to age-related change, such effects might be detected independently of preclinical dementia. [ABSTRACT FROM AUTHOR]

Objective: Past research has linked more frequent social contacts with better cognition and slower cognitive decline in older adults. An open question is whether face-to-face and remote contact with one's grandchildren can be beneficial., Methods: We analyzed data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) covering a span of 12 years and two age cohorts (young-old < 78, N = 1100; old-old ≥ 78 years, N = 705). We used latent growth curve models, to examine whether frequency of face-to-face or remote grandchild contact was associated with cognitive levels and decline and applied (random intercept) cross-lagged models to investigate if these associations were reciprocal., Results: Face-to-face contact with grandchildren was positively linked to levels of cognition in young-old adults only. We found no associations with cognitive decline. Results of cross-lagged models suggested that grandparents with better cognition had more face-to-face (for young-old adults only) or remote (for old-old adults only) grandchild contact at subsequent waves. However, more grandchild contact was not associated with later cognition., Discussion: Our findings suggest that grandparents with better cognition engage more with their grandchildren, but that frequency of grandchild contact is not a protective factor against later cognitive decline in older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: Research suggests that physical activity (PA) improves cognitive function across various domains. However, the specific role of different PA measures, including step count, remains to be explored. Our aim was to assess the correlation between objectively measured PA and cognitive function., Methods: We included 663 adults, aged ≥66 years, from the Swedish SNAC-K study (2016-2019). Global cognition and three cognitive domains (processing speed, executive function, and episodic memory) were assessed with validated tests. PA was measured through ActivPAL3 accelerometers. We applied age-stratified (<70 vs. ≥80 years), multi-adjusted, quantile regression to examine the cross-sectional associations between cognitive function and PA, considering steps/day and time spent in moderate-to-vigorous PA (MVPA)., Results: Each 1000-step increment (β = 0.04; 95% CI: 0.01, 0.07) and each additional hour of MVPA per day (β = 0.28; 95% CI: 0.02, 0.54) were correlated with better processing speed in the youngest-old, but not in the oldest-old. When further stratifying by MVPA (<60 min vs. ≥60 min/week), each 1000-step increment was associated with better processing speed in the youngest-old, regardless of their MVPA levels., Conclusion: Our study links accelerometer-assessed PA (steps and MVPA) with better processing speed in the youngest-old adults. Step count correlated with processing speed regardless of intensity. Further research is needed to determine the directionality of these associations., Competing Interests: DISCLOSURES The authors declare no conflict of interest. Data collection of the Swedish National study on Aging and Care (SNAC-K) was supported by the Swedish Research Council (ongoing/current grant: 2021-00178); the Swedish Ministry of Health and Social Affairs; the participating County Councils and Municipalities. In addition, this study was supported by grants from the Strategic Research Area Health Care Science (SFO-V) at Karolinska Institutet (PI: AKW, grant number 2-3226/2023)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We sought to examine the associations of the Lifestyle for Brain Health (LIBRA) index with cognitive function among rural Chinese older adults and to explore the potential role of cluster of differentiation 33 gene (CD33) in the associations., Methods: This population-based cross-sectional study included 4914 dementia-free participants (age ≥60 years; 56.43 % women) in the 2018 baseline examination of MIND-China. The LIBRA index was generated from 11 factors. We used a neuropsychological test battery to assess episodic memory, verbal fluency, attention, executive function, and global cognition. The CD33(rs3865444) polymorphism was detected using multiple-polymerase chain reaction amplification. Data were analyzed using the general linear regression models., Results: A higher LIBRA index was associated with multivariable-adjusted β-coefficient (95 %CI) of -0.011(-0.020- -0.001) for global cognitive z-score, -0.020(-0.033- -0.006) for episodic memory, and -0.016(-0.029- -0.004) for verbal fluency. The CD33(rs3865444) was associated with a lower global cognitive z-score in the additive (CA vs. CC: β-coefficient=0.042; 95 %CI=0.008-0.077), the dominant (CA+AA vs. CC: 0.040; 0.007-0.073), and the over-dominant (CA vs. CC+AA: 0.043; 0.009-0.077) models. Similar results were obtained for verbal fluency and attention. The CD33 gene showed statistical interactions with LIBRA index on cognitive function (P interaction <0.05) such that a higher LIBRA index was significantly associated with lower z-scores of global cognition and attention only among CD33 CC carriers (P < 0.05)., Conclusions: This population-based study reveals for the first time that a higher LIBRA index is associated with worse cognitive performance in rural Chinese older adults and that CD33 gene could modify the association., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: We investigated the association of peak expiratory flow (PEF) with dementia; cognitive impairment, no dementia (CIND); and transition from CIND to dementia, and possible underlying neuropathological mechanisms., Methods: A population-based cohort of adults aged 60+ was followed over 15 years to detect dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria), CIND (assessed through a cognitive battery), and progression from CIND to dementia, in relation to baseline PEF observations. A subsample (n = 462) had 6-year follow-up data on brain magnetic resonance imaging markers of neurodegeneration and small vessel disease., Results: In fully adjusted models, poor PEF performance (< 10th vs. ≥ 80th percentile) was associated with increased hazards for dementia (hazard ratio [HR] = 1.89; 95% confidence interval [CI] = 1.23-2.92) and CIND (HR = 1.55; 95% CI = 1.01-2.38) and CIND progression to dementia, although not statistically significantly (HR = 2.44; 95% CI = 0.78-6.88). People with poor PEF also experienced the fastest ventricular enlargement (β coefficient = 0.67 mL/year; 95% CI = 0.13-1.21) and had the highest likelihood of developing lacunes (odds ratio = 5.05; 95% CI = 1.01-25.23)., Discussion: Poor lung function contributes to cognitive deterioration possibly through accelerated brain atrophy and microvascular damage., Highlights: Poor lung function increased the risk of dementia and mild cognitive impairment (MCI). Poor lung function accelerated the progression from MCI to dementia. Poor lung function was linked to brain microvascular damage and global brain atrophy., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The present study aimed to characterize profiles of cognitive aging and how these can be predicted from interindividual differences in demographic, lifestyle, health, and genetic factors. The participants were 1,966 older adults (mean baseline age = 71.6 years; 62.9% female), free from dementia at baseline and with at least two cognitive assessments over the 15-year follow-up, from the population-based Swedish National Study on Aging and Care in Kungsholmen. The cognitive assessment comprised tests of semantic and episodic memory, letter and category fluency, perceptual speed, and executive function. First, we estimated the level and change within each of the cognitive domains with linear mixed effect models, based on which we grouped our sample into participants with "maintained high cognition," "moderate cognitive decline," or "accelerated cognitive decline." Second, we analyzed determinants of group membership within each cognitive domain with multinomial logistic regression. Third, group memberships within each cognitive domain were used to derive general cognitive aging profiles with latent class analysis. Fourth, the determinants of these profile memberships were analyzed with multinomial logistic regression. Follow-up analyses targeted profiles and predictors specifically related to the rate of cognitive change. We identified three latent profiles of overall cognitive performance during the follow-up period with 31.6% of the sample having maintained high cognition, 50.6% having moderate cognitive decline, and 17.8% having accelerated cognitive decline. In multiadjusted analyses, maintained high cognition was predicted by female sex, higher education, and faster walking speed. Smoking, loneliness, and being an ε4 carrier were associated with a lower likelihood of maintained high cognition. Higher age, diagnosis of diabetes, depression, and carrying the apolipoprotein E ε4 allele increased the likelihood of accelerated cognitive decline. Factors at baseline that could significantly predict profile membership within the specific cognitive domains included age, sex, years of education, walking speed, diabetes, and the ε4 allele. Of note, these factors differed across cognitive domains. In sum, we identified demographic, lifestyle, health, and genetic factors of interindividual differences in domain-specific and general cognitive aging profiles, some of which are modifiable. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Introduction: We investigated the association of cognitive reserve (CR) with transitions across cognitive states and death., Methods: This population-based cohort study included 2631 participants (age ≥60 years) who were dementia-free at baseline and regularly examined up to 15 years. Data were analyzed using the Markov multistate models., Results: Each 1-point increase in the composite CR score (range: -4.25 to 3.46) was significantly associated with lower risks of transition from normal cognition to cognitive impairment, no dementia (CIND) (multivariable-adjusted hazards ratio = 0.78; 95% confidence interval = 0.72-0.85) and death (0.85; 0.79-0.93), and from CIND to death (0.82; 0.73-0.91), but not from CIND to normal cognition or dementia. A greater composite CR score was associated with a lower risk of transition from CIND to death in people aged 60-72 but not in those aged ≥ 78 years., Discussion: CR contributes to cognitive health by delaying cognitive deterioration in the prodromal phase of dementia., Highlights: We use Markov multistate model to examine the association between cognitive reserve and transitions across cognitive states and death. A great cognitive reserve contributes to cognitive health by delaying cognitive deterioration in the prodromal phase of dementia. A great cognitive reserve is associated with a lower risk of transition from cognitive impairment, no dementia to death in people at the early stage of old age, but not in those at the late stage of old age., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition., Methods: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K)., Findings: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K., Interpretation: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms., Funding: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society., Translation: For the Swedish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 ( β  = -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., Competing Interests: The authors have no conflicts of interest to disclose., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: This study aimed to assess the associations of orthostatic hypotension (OH), in the presence or absence of frailty, with dementia and mortality in older adults., Methods: We conducted a 15-year population-based cohort study including 2 703 baseline dementia-free individuals from the Swedish National Study on Aging and Care in Kungsholmen. At baseline, OH was defined as a decline in systolic/diastolic blood pressure ≥20/10 mm Hg 1 minute after standing up from a supine position. Frailty status was defined following Fried's frailty phenotype. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders-fourth edition criteria. Multistate flexible parametric survival models were used to estimate associations of OH and frailty with dementia and mortality., Results: Robust people with OH (adjusted hazard ratio [HR] = 2.28; 95% confidence interval [CI] = 1.47-3.54) and frail people without OH (HR = 1.98; 95% CI = 1.40-2.82) or with OH (HR = 2.73; 95% CI = 1.82-4.10) had a higher dementia risk than OH-free and robust people. Moreover, frail people, independently of the presence of OH, had higher mortality rate than OH-free and robust people. In individuals who developed dementia during the follow-up period, neither OH nor frailty was significantly associated with mortality., Conclusions: Older adults with OH, whether robust or frail, may have a higher dementia risk than those without OH. Older adults with OH, when having frailty, may have a higher mortality rate than those without OH. The concurrent assessments of OH and frailty may provide prognostic values in terms of dementia and mortality risk in older adults., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Previous research on associations between cardiovascular health, measured at a single timepoint, and rate of age-related cognitive decline shows divergent findings dependent on the participants' age and the health metric studied. The aim of this study was to add to the knowledge in this field by investigating whether change in cardiovascular health, assessed with Life's Simple 7 (LS7) score, is associated with rate of cognitive change in young-old and old-old adults., Methods: The study included 1022 participants aged ≥ 60 years from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, and perceptual speed) across up to 15 years. LS7, composed of seven cardiovascular health metrics (smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure), was assessed at baseline and at the 6-year follow-up. Change in LS7 was calculated as the difference between baseline and 6 years (range - 5 to 8 points) and categorised into worse (-5 to -2 points), stable (-1 to 1 points), and improved (2 to 8 points). Change in cognitive performance as a function of LS7 change categories was estimated using linear mixed-effects models., Results: Participants were classified as stable (67.1%), improved (21.0%), or worse (11.8%) according to changes in LS7 score. Both the worse and improved categories were associated with faster cognitive decline. Age-stratified analyses revealed that worsening of LS7 was clearly associated with faster cognitive decline in the old-old (≥ 78 years), whereas improvement tended be associated with faster cognitive decline in the young-old (< 78 years) group., Conclusions: Change in cardiovascular health in old age may lead to accelerated cognitive decline, particularly in late senescence. These results suggest that it is important to monitor and maintain cardiovascular health status in very old adults., (© 2024. The Author(s).)

Study Objectives: We examined and compared cross-sectional and longitudinal associations between self-reported sleep disturbances and various cognitive domains in five separate Nordic European longitudinal aging studies (baseline N = 5631, mean age = 77.7, mean follow-up = 4.16 years)., Methods: Comparable sleep parameters across studies included reduced sleep duration/quality, insomnia symptoms (sleep latency, waking up at night, and early awakenings), short and long sleep duration, and daytime napping. The cognitive domains were episodic memory, verbal fluency, perceptual speed, executive functioning, and global cognition (aggregated measure). A series of mixed linear models were run separately in each study and then compared to assess the level and rate of change in cognitive functioning across each sleep disturbance parameter. Models were adjusted for age, sex, education, hypnotic usage, depressive symptoms, lifestyle factors, cardiovascular, and metabolic conditions. By using a coordinated analytic approach, comparable construct-level measurements were generated, and results from identical statistical models were qualitatively compared across studies., Results: While the pattern of statistically significant results varied across studies, subjective sleep disturbances were consistently associated with worse cognition and steeper cognitive decline. Insomnia symptoms were associated with poorer episodic memory and participants sleeping less or more than 7-8 hours had a steeper decline in perceptual speed. In addition, daytime napping (>2 hours) was cross-sectionally and longitudinally associated with all examined cognitive domains. Most observed associations were study-specific (except for daytime napping), and a majority of association estimates remained significant after adjusting for covariates., Conclusion: This rigorous multicenter investigation further supports the importance of sleep disturbance, including insomnia, long and short sleep duration, and daytime napping on baseline cognitive functioning and rate of change among older adults. These sleep factors may be targeted in future lifestyle interventions to reduce cognitive decline., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society.)

Background and Aims: Transportation noise is an environmental exposure with mounting evidence of adverse health effects. Besides the increased risk of cardiovascular and metabolic diseases, recent studies suggest that long-term noise exposure might accelerate cognitive decline in older age. We examined the association between transportation noise and cognitive function in a cohort of older adults., Methods: The present study is based on 2594 dementia-free participants aged 60 + years from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K). Global cognition score and CIND (cognitive impairment, no dementia) were assessed with a comprehensive neuropsychological battery at baseline and up to 16 years. Residential transportation noise resulting from road traffic, railway, and aircraft were estimated at the most exposed façade and the time-weighted average exposure was assessed. Linear mixed-effect models were used to assess the effect of long-term traffic noise exposure on the rate of change in global cognition score. Hazard ratios (HRs) and 95 % confidence intervals (CIs) of CIND by transportation noise exposure were obtained with Cox proportional hazard models., Results: Global cognition score decreased at an average rate of -0.041 (95 %CI -0.043, -0.039) per year. Aircraft noise was associated with a 0.007 (per 10 dB L den ; 95 %CI -0.012, -0.001) faster annual rate of decline. Global cognition score seems to be not affected by road traffic and railway noise. During the follow-up, 422 (21 %) participants developed CIND. A 10-dB L den difference in exposure to aircraft and railway noise was associated with a 16 % (HR 1.16, 95 %CI 0.91, 1.49) and 26 % (HR 1.26, 95 %CI 1.01, 1.56) increased hazard of CIND in the multi-pollutant model, respectively. No association was found for road traffic (HR 1.00, 95 %CI 0.83, 1.21)., Conclusions: Transportation noise was linked to cognitive impairment and faster cognitive decline among older adults. Future studies are warranted to confirm our results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults., Methods: We included 390 dementia-free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes., Results: Compared to non-multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (β*time -0.03, 95% CI -0.05, -0.01) and hippocampal (β*time -0.05, 95% CI -0.08, -0.03) volumes, the greatest ventricular enlargement (β*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (β*time 0.04, 95% CI 0.01, 0.07)., Discussion: Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology., Highlights: Multimorbidity accelerates structural brain changes in cognitively intact older adults These brain changes encompass both neurodegeneration and cerebrovascular pathology The complexity of multimorbidity is associated with the rate of brain changes' progression., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: We investigated whether vascular risk factors (VRFs), assessed with Life's Simple 7 (LS7), are associated with the rate of cognitive decline in the years preceding a dementia diagnosis., Method: This study included 1,449 stroke-free participants aged ≥60 years from the Swedish National Study on Aging and Care in Kungsholmen, who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, perceptual speed) across 12 years. The LS7 score, assessed at baseline, included smoking, diet, physical activity, body mass index, plasma glucose, total cholesterol, and blood pressure. Preclinical dementia was defined as being dementia-free at baseline and diagnosed with dementia during follow-up. Level and change in cognitive performance as a function of LS7 category (poor vs. intermediate to optimal) and future dementia status were estimated using linear mixed-effect models., Results: Participants who later developed dementia had, on average, a poorer LS7 score compared to those who remained dementia-free. For individuals aged 60-72 years, poor diet was associated with accelerated decline in perceptual speed (β = -0.05, 95% CI [-0.08, -0.02]), and a poor glucose score was associated with faster rates of verbal fluency (β = -0.019, 95% CI [-0.09, -0.01]) and global cognitive (β = -0.028, 95% CI [-0.06, 0.00]) decline in the preclinical dementia group., Conclusions: VRFs exacerbate rate of cognitive decline in the years preceding a dementia diagnosis. This effect was most pronounced in young-old age and primarily driven by diet and glucose. The effect of VRFs may be especially detrimental for cognitive decline trajectories of individuals with impending dementia. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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 (β -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 (β -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)., Competing Interests: Declaration of interests All authors have completed the ICMJE uniform disclosure form. All authors report no disclosures relevant to the manuscript., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

We investigated the association of load and accumulation of white matter hyperintensities (WMHs) with rate of cognitive decline. This population-based study included 510 dementia-free people (age ≥60 years) who had repeated measures of global and regional (lobar, deep, periventricular) WMHs up to 6 years (from 2001-2003 to 2007-2010) and repeated measures of cognitive function (episodic memory, semantic memory, category fluency, letter fluency, executive function, perceptual speed) up to 15 years (from 2001-2004 to 2016-2019). We found that greater baseline loads of global and regional WMHs were associated with faster decline in letter fluency, perceptual speed, and global cognition. Furthermore, faster accumulation of global, deep, and periventricular WMHs was related to accelerated cognitive decline, primarily in perceptual speed. These data show that WMHs are associated with decline in perceptual speed rather than episodic or semantic memory and that cognitive change is more vulnerable to WMH accumulations in deep and periventricular regions., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The independent and joint effect of ischemic heart disease (IHD) and coexisting atrial fibrillation (AF) and heart failure (HF) on dementia risk is largely unknown., Methods: This population-based cohort study included 2568 dementia-free participants (age ≥60 years) in SNAC-K, who were regularly examined from 2001-2004 through 2013-2016. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria. Global cognitive function was assessed using a global cognitive composite z-score derived from five cognitive domains. Data were analyzed using Cox, Fine-Gray, and linear mixed-effects models., Results: Overall, IHD at baseline was associated with multivariable-adjusted hazard ratio (HR) of 1.39 (95% confidence interval = 1.06-1.82) for dementia and multivariable-adjusted β-coefficient of -0.02 (-0.03 to -0.01) for annual changes in global cognitive z-score, independent of AF, HF, and cerebrovascular disease. Coexisting AF or HF did not add further risk to dementia and cognitive decline., Discussion: IHD is independently associated with dementia and cognitive decline in older adults, whereas coexisting AF/HF is not associated with an increased risk., Highlights: Is a history of ischemic heart disease (IHD) associated with a risk for dementia? How do coexisting heart diseases affect this association? IHD was an independent risk factor for dementia in older adults. This association was independent of coexisting heart and cerebrovascular diseases. The coexistence of heart diseases did not confer additional risk for dementia., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Several chronic diseases accelerate cognitive decline; however, it is still unknown how different patterns of multimorbidity influence individuals' trajectories across the cognitive continuum., Objectives: We aimed to investigate the impact of multimorbidity and of specific multimorbidity patterns on the transitions across cognitive stages (normal cognition, cognitive impairment, no dementia [CIND], dementia) and death., Methods: We included 3122 dementia-free individuals from the Swedish National study on Aging and Care in Kungsholmen. Using fuzzy c-means cluster analysis, multimorbid participants were classified into mutually exclusive groups characterized by commonly coexisting chronic diseases. Participants were followed up to 18 years to detect incident CIND, dementia, or death. Transition hazard ratios (HRs), life expectancies, and time spent in different cognitive stages were estimated using multistate Markov models., Results: At baseline, five multimorbidity patterns were identified: neuropsychiatric, cardiovascular, sensory impairment/cancer, respiratory/metabolic/musculoskeletal, and unspecific. Compared to the unspecific pattern, the neuropsychiatric and sensory impairment/cancer ones showed reduced hazards of reverting from CIND to normal cognition (HR 0.53, 95% CI 0.33-0.85 and HR 0.60, 95% CI 0.39-0.91). Participants in the cardiovascular pattern exhibited an increased hazard of progression from CIND to dementia (HR 1.70, 95% CI 1.15-2.52) and for all transitions to death. Subjects with the neuropsychiatric and cardiovascular patterns showed reduced life expectancy at age 75, with an anticipation of CIND (up to 1.6 and 2.2 years, respectively) and dementia onset (up to 1.8 and 3.3 years, respectively)., Conclusions: Multimorbidity patterns differentially steer individual trajectories across the cognitive continuum of older adults and may be used as a risk stratification tool., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Acute clinical events, such as pneumonia, may impact physical functionality but their effect on cognition and the possible duration of this effect remains to be quantified. This study investigated the impact of pneumonia on cognitive trajectories and dementia development in older people., Methods: Data were obtained from 60+ years old individuals, who were assessed from 2001 to 2018 in the population-based SNAC-K study (Sweden). Participants were eligible if they were not institutionalized, had no dementia, and did not experience pneumonia 5 years prior to baseline (N = 2 063). A propensity score was derived to match 1:3 participants hospitalized with a diagnosis of pneumonia (N = 178), to nonexposed participants (N = 534). Mixed linear models were used to model cognitive decline. The hazard of dementia, clinically diagnosed by physicians following Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, was estimated using Cox regression models., Results: We found a transient impact of pneumonia on cognitive decline in the first 2.5 years (B = -0.94, 95% confidence interval [CI] -1.75, -0.15). The hazard ratio (HR) for dementia was not statistically significantly increased in pneumonia participants (HR = 1.17, 95%CI 0.82, 1.66)., Conclusions: The transient impact of pneumonia on cognitive function suggests an increased need of health care for patients after a pneumonia-related hospitalization and reinforces the relevance of pneumonia prevention., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Life's Simple 7 (LS7) aims to promote ideal cardiovascular health (CVH). Its association with different cognitive states in the older old is unclear., Objectives: To assess the associations of LS7 with transitions across normal cognition, cognitive impairment, no dementia (CIND), and dementia and evaluate cognitive impairment-free years of life by LS7-defined CVH levels in older adults., Methods: This cohort study included 2746 participants from the Swedish National Study on Aging and Care in Kungsholmen, regularly examined over 15 years. Total LS7 scores were created and dichotomized into worse and better CVH categories. The associations of LS7 total scores and CVH categories with cognitive states were assessed with multistate models in the whole sample and in younger old (<78 years) and older old adults (≥78 years) separately. Cognitive impairment-free life years by CVH categories were then predicted., Results: A 1-point increment in the LS7 total score was associated with lower dementia risk in younger old adults (hazard ratio: 0.87 [0.78-0.97]) but not in older old adults (1.04 [0.97-1.13]). Better CVH was also associated with a lower risk of transition from normal cognition to CIND (0.76 [0.61-0.95]) and from normal cognition to dementia (0.42 [0.21-0.82]) in younger old adults. In younger old adults, those with better CVH were predicted to have two-to-three more cognitive impairment-free life years than those with worse CVH., Conclusion: Maintaining LS7-defined ideal CVH seems relevant in younger old adults but not in older old adults when considering the potential protective effects against cognitive impairment., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: We evaluated markers of olfactory dysfunction (OD) for estimating hazard of dementia in older adults., Methods: Mild (hyposmia) and severe (anosmia) OD was classified in a population-based study of dementia-free persons (SNAC-K; n = 2473; mean age = 70 years) using the Sniffin sticks odor identification task. Combined variables were created for objective and subjective OD and for OD and APOE status. Hazard of dementia across 12 years was estimated with Cox regression., Results: OD was associated with increased hazard of dementia (2.01; 95% confidence interval [CI] 1.60-2.52), with the strongest association for anosmia (2.92; 95% CI 2.14-3.98). Results remained consistent after adjusting for potential confounders and across age and sex subgroups. APOE ε4 carriers with anosmia had the highest hazard of dementia (ε4: 6.95; 95% CI 4.16-11.62; ε4/ε4: 19.84; 95% CI 6.17-63.78)., Discussion: OD is associated with increased risk of dementia, especially severe impairment in combination with genetic risk of Alzheimer's disease., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: There is an urgent need for novel blood biomarkers for the detection of Alzheimer's disease (AD). We previously showed that levels of the bisecting N-acetylglucosamine glycan epitope was elevated in cerebrospinal fluid in AD. However, its diagnostic value in blood is unknown., Methods: We analyzed blood levels of bisecting N-acetylglucosamine and total tau in a retrospective cohort of 233 individuals. Progression to AD was compared between the groups using Cox regression. The predictive value of the biomarkers was determined by logistic regression., Results: Bisecting N-acetylglucosamine correlated with tau levels (p < 0.0001). Individuals with an intermediate tau/bisecting N-acetylglucosamine ratio had elevated AD risk (hazard ratio = 2.06, 95% confidence interval [CI]: 1.18-3.6). Moreover, a combined model including tau/bisecting N-acetylglucosamine ratio, apolipoprotein E (APOE) ε4 status, and Mini-Mental State Examination score predicted future AD (area under the curve = 0.81, 95% CI: 0.68-0.93)., Discussion: Bisecting N-acetylglucosamine in combination with tau is a valuable blood biomarker for predicting AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Orthostatic hypotension (OH) has been associated with elevated risk of cardiovascular diseases (CVDs) and dementia risk. To better understand the OH-dementia association, we assessed the associations of OH with CVD and subsequent dementia in older adults and considered the temporality of CVD and dementia onset., Methods: This 15-year population-based cohort study included, at baseline, 2703 dementia-free participants (mean age, 73.7 years) who were divided into a CVD-free cohort (n=1986) and a CVD cohort (n=717). OH was defined as a systolic/diastolic blood pressure decline of ≥20/10 mm Hg after standing up from a supine position. CVDs and dementia were ascertained by physicians or identified from registers. Multistate Cox regressions were applied to assess the associations of OH with CVD and subsequent dementia in the CVD-free and dementia-free cohort. The OH-dementia association in the CVD cohort was examined with Cox regressions., Results: OH was present in 434 (21.9%) individuals in the CVD-free cohort and 180 (25.1%) individuals in the CVD cohort. OH was associated with a hazard ratio of 1.33 (95% CI, 1.12-1.59) for CVD. OH was not significantly associated with incident dementia in the absence of CVD occurring before dementia diagnosis (hazard ratio, 1.22 [95% CI, 0.83-1.81]). In the CVD cohort, individuals with OH had a higher dementia risk than those without OH (hazard ratio, 1.54 [95% CI, 1.06-2.23])., Conclusions: The association between OH and dementia may partly be explained by the intermediate development of CVD. In addition, in people with CVD, those with OH may have a poorer cognitive prognosis., Competing Interests: Disclosures None.

Human olfaction can be extraordinarily sensitive, and its most common assessment method is odor identification (OID), where everyday odors are matched to word labels in a multiple-choice format. However, many older persons are unable to identify familiar odors, a deficit that is associated with the risk of future dementia and mortality. The underlying processes subserving OID in older adults are poorly understood. Here, we analyzed error patterns in OID to test whether errors could be explained by perceptual and/or semantic similarities among the response alternatives. We investigated the OID response patterns in a large, population-based sample of older adults in Sweden (n = 2479; age 60-100 years). Olfaction was assessed by a 'Sniffin ́ TOM OID test with 16 odors; each trial involved matching a target odor to a correct label among three distractors. We analyzed the pattern of misidentifications, and the results showed that some distractors were more frequently selected than others, suggesting cognitive or perceptual factors may be present. Relatedly, we conducted a large online survey of older adults (n = 959, age 60-90 years) who were asked to imagine and rate the perceptual similarity of the target odors and the three corresponding distractors (e.g. "How similar are these smells: apple and mint?"). We then used data from the Swedish web corpus and the Word2Vec neural network algorithm to quantify the semantic association strength between the labels of each target odor and its three distractors. These data sources were used to predict odor identification errors. We found that the error patterns were partly explained by both the semantic similarity between target-distractor pairs, and the imagined perceptual similarity of the target-distractor pair. Both factors had, however, a diminished prediction in older ages, as responses became gradually less systematic. In sum, our results suggest that OID tests not only reflect olfactory perception, but also likely involve the mental processing of odor-semantic associations. This may be the reason why these tests are useful in predicting dementia onset. Our insights into olfactory-language interactions could be harnessed to develop new olfactory tests that are tailored for specific clinical purposes., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The engagement in cognitively stimulating activities has been found to be associated with slower rates of cognitive decline in old age. In which type of activities people engage in may depend on their personality traits, which thus might have an impact on later cognitive fitness. To study these potential links, we examined the associations between Neuroticism, Extraversion, and Openness; different types of leisure activities (e.g., social, mental, physical); and cognitive ability levels and decline in older adults. Analyses were based on a sample of young-old (60-72 years old; n = 1,609) and old-old (78 years or older; n = 1,085) adults from the Swedish National Study on Aging and Care in Kungsholmen, who participated in up to five repeated measurements of cognitive abilities spanning 12 years. We used latent growth curve models to estimate cognitive levels and decline, as well as the correlations with initial personality trait levels and leisure activity engagement. In both groups, lower Neuroticism, higher Extraversion, and higher Openness levels were moderately associated with stronger engagement in all types of activities. Lower Neuroticism, higher Extraversion, and a more activity lifestyle were weakly to moderately associated with slower cognitive decline in the old-old age group. There, personality traits and activities explained 9.3% of the variance in cognitive decline after controlling for age, sex, education, and chronic diseases (which explained 9.0%). Taken together, this study provides further evidence for the connection between personality traits, activity engagement, and later cognitive decline in old age. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective: Individual aspects of social health (SH; eg, network, engagement, support) have been linked to cognitive health. However, their combined effect and the role of the structural properties of the brain (brain reserve [BR]) remain unclear. We investigated the interplay of SH and BR on cognitive change in older adults., Methods: Within the Swedish National Study on Aging and Care-Kungsholmen, 368 dementia-free adults aged ≥60 years with baseline brain magnetic resonance imaging were followed over 12 years to assess cognitive change. A measure of global cognition was computed at each of the 5 waves of assessment by averaging domain-specific Z scores for episodic memory, perceptual speed, semantic memory, and letter and category fluency. An SH composite score was computed at baseline by combining leisure activities and social network. BR was proxied by total brain tissue volume (TBTV). Linear mixed models (adjusted for sociodemographic, vascular, and genetic factors) were used to estimate cognitive trajectories in relation to SH and TBTV. Interaction analysis and stratification were used to examine the interplay between SH and TBTV., Results: Moderate-good SH (n = 245; vs poor, β-slope = 0.01, 95% confidence interval [CI] = 0.002-0.02, p = 0.018) and moderate-to-large TBTV (n = 245; vs small, β-slope = 0.03, 95% CI = 0.02-0.04, p < 0.001) were separately associated with slower cognitive decline. In stratified analysis, moderate-good SH was associated with higher cognitive levels (but not change) only in participants with moderate-to-large TBTV (β-intercept = 0.21, 95% CI = 0.06-0.37, p < 0.01; interaction SH * TBTV, p < 0.05)., Interpretation: Our findings highlight the interplay between SH and BR that likely unfolds throughout the entire life course to shape old-age cognitive outcomes. ANN NEUROL 2023;93:844-855., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Mapping the preclinical dementia phase is important for early detection and evaluation of interventions. We assessed the trajectories of cognitive decline in preclinical dementia over 12 years and investigated whether being a fast decliner across 6 years is associated with increased risk of dementia the following 6 years., Methods: Rates of cognitive decline were determined using mixed-effects models for 1646 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) cohort. Cox regression was used to assess the future likelihood of dementia for fast decliners (declining ≥1.5 standard deviations [SDs] faster than the age-specific rates)., Results: Participants in a preclinical phase of dementia showed increased rates of decline in all cognitive tests compared to the no-dementia group, particularly closer (0-6 years) to diagnosis. Participants declining fast in three or more cognitive tests 12-6 years before diagnosis demonstrated a high risk of dementia 6 years later (hazard ratio [HR] 3.90, 95% confidence interval [CI] 2.28-6.69)., Discussion: Being a fast decliner is linked to increased risk of future dementia., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function., Methods: In the Swedish National Study on Aging and Care in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns., Results: Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval [CI]: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline., Conclusion: Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Olfactory impairment is a potential marker for prodromal dementia, but the underlying mechanisms are poorly understood. This population-based study included 4214 dementia-free participants (age ≥65 years). Olfaction was assessed using the 16-item Sniffin' Sticks identification test. In the subsamples, we measured plasma amyloid beta (Aβ)40, Aβ42, total tau, and neurofilament light chain (NfL; n = 1054); and quantified hippocampal, entorhinal cortex, and white matter hyperintensity (WMH) volumes, and Alzheimer's disease (AD)-signature cortical thickness (n = 917). Data were analyzed with logistic and linear regression models. In the total sample, mild cognitive impairment (MCI) was diagnosed in 1102 persons (26.2%; amnestic MCI, n = 931; non-amnestic MCI, n = 171). Olfactory impairment was significantly associated with increased likelihoods of MCI, amnestic MCI, and non-amnestic MCI. In the subsamples, anosmia was significantly associated with higher plasma total tau and NfL concentrations, smaller hippocampal and entorhinal cortex volumes, and greater WMH volume, and marginally with lower AD-signature cortical thickness. These results suggest that cerebral neurodegenerative and microvascular lesions are common neuropathologies linking anosmia with MCI in older adults., (© 2022 the Alzheimer's Association.)

Background and Objective: The life's simple 7 approach was proposed to define cardiovascular health (CVH) metrics. We sought to investigate the associations between behavioral, biological, and genetic markers for CVH and vascular brain aging in older adults., Methods: This population-based cohort study included participants who had repeated brain MRI measures from 2001 to 2003 to 2007-2010 (i.e., count of perivascular spaces, volumes of white matter hyperintensity [WMH] and gray matter, and lacunes). At baseline, global, behavioral, and biological CVH metrics were defined and scored following the life's simple 7 approach and categorized into unfavorable, intermediate, and favorable profiles according to tertiles. The metabolic genetic risk score was calculated by counting 15 risk alleles associated with hypertension, diabetes, or dyslipidemia. Data were analyzed using linear mixed-effects and Cox proportional hazards models, adjusting for age, sex, and education., Results: The study sample consisted of 317 participants (age 60 years or older; 61.8% women). Favorable and intermediate (vs unfavorable) global CVH profiles were related to slower WMH progression, with β-coefficients (95% CI) being -0.019(-0.035-0.002) and -0.018(-0.034-0.001), respectively. Favorable and intermediate (vs unfavorable) biological CVH profiles were significantly related to slower WMH increase only in people aged 60-72 years. CVH profiles were not related to progression of other brain measures. Furthermore, a higher metabolic genetic risk score (range: 6-21) was associated with faster WMH increase (β-coefficient = 0.005; 95% CI: 0.003-0.008). There were statistical interactions of metabolic genetic risk score with global and behavioral CVH profiles on WMH accumulation. A higher metabolic genetic risk score was related to faster WMH accumulation, with β-coefficients being 0.015(0.007-0.023), 0.005(0.001-0.009), and 0.003(-0.001 to 0.006) among people with unfavorable, intermediate, and favorable global CVH profiles, respectively; the corresponding β-coefficients were 0.013(0.006-0.020), 0.006(0.003-0.009), and 0.002(-0.002 to 0.006) among people with unfavorable, intermediate, and favorable behavioral CVH profiles., Discussion: Intermediate to favorable global CVH profiles in older adults are associated with slower vascular brain aging. The association of metabolic genetic risk load with accelerated vascular brain aging was evident among people with unfavorable to intermediate, but not favorable, CVH profiles. These findings highlight the importance of adhering to favorable CVH profiles, especially healthy behaviors, in vascular brain health., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Epidemiological studies of mild cognitive impairment (MCI) and subtypes of MCI have rarely focused on rural residents in China., Methods: This population-based study included 5068 participants (age ≥60 years) who were living in rural communities. We defined MCI, amnestic MCI (aMCI), and non-amnestic MCI (naMCI) following the Petersen's criteria that integrated neuropsychological assessments with in-person clinical evaluations., Results: The overall prevalence of MCI, aMCI, and naMCI was 26.48%, 22.30%, and 4.18%, respectively. The prevalence of MCI increased with age. The adjusted odds ratio (OR) of MCI was 0.71 (95% confidence interval [CI] 0.61 to 0.82) for primary school (vs. illiteracy), 0.30 (0.24 to 0.39) for middle school or above, 1.35 (1.09 to 1.67) for being farmers, 0.65 (0.54 to 0.78) for alcohol consumption, 1.43 (1.20 to 1.70) for stroke history, and 1.14 (0.95 to 1.36) for any apolipoprotein E (APOE) ε4 allele (vs ε3/ε3)., Conclusions: MCI affects over one-fourth of rural older adults in China. Overall MCI was associated with demographic factors, non-alcohol consumption, and stroke, but not with APOE genotype and cardiometabolic factors., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample ( n = 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gustavsson, Papenberg, Falahati, Laukka and Kalpouzos.)

Background: Olfactory impairment is associated with dementia in clinical settings. We examined the relationship of olfactory identification function with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD) and assessed the discriminative ability of the Sniffin' Sticks Identification Test (SSIT), the self-rated Ascertain Dementia 8-item Questionnaire (AD8), and their combination for dementia detection among rural-dwelling older adults in China., Methods: This population-based cross-sectional study included 4481 participants (age ≥ 65 years; 56.8% women; 38.1% illiteracy) living in rural communities. The 16-item SSIT was performed to assess olfactory identification function. The self-rated AD8 was administered to participants for cognitive status. We diagnosed dementia, AD, and VaD following the international criteria. Data were analyzed with logistic regression models and receiver operating characteristic curve., Results: Of the 4481 participants, dementia was diagnosed in 139 persons (3.1%), including 92 with AD and 42 with VaD. The SSIT score (range, 0-16) was associated with multiadjusted odds ratios of 0.83 (95% CI: 0.79-0.88) for dementia, 0.84 (0.79-0.90) for AD, and 0.79 (0.71-0.87) for VaD. The area under the curve for the discrimination between participants with and without dementia was 0.73 (95% CI: 0.69-0.77) for SSIT score ≤ 8 alone, 0.86 (0.82-0.89) for self-rated AD8 score ≥ 3 alone, and 0.89 (0.86-0.92) for their combination using a logistic model., Conclusions: Olfactory impairment is a clinical marker for all-cause dementia, AD, and VaD. The smell identification test, in combination with the brief self-rated cognitive screening tool, is accurate for screening dementia among rural-dwelling Chinese older adults with no or limited education., (© 2021 The American Geriatrics Society.)

We investigated progression and interrelationships of cerebral small vessel disease (cSVD) markers. This population-based cohort study included 325 participants (age ≥ 60 years) who had repeated measures of cSVD markers over 6 years: white-matter hyperintensity (WMH), perivascular spaces (PVS), lacunes, and grey-matter (GM) and ventricular volumes. We found that all cSVD markers, except PVS, progressed faster with increasing age. Regional WMH progressed faster in males and less-educated people (p < 0.05). Each 10-point increment in global WMH score was associated with multi-adjusted hazard ratio of 1.78 (95% CI = 1.50‒2.10) for incident lacunes and multi-adjusted β-coefficients of 0.15 (0.08-0.22), -0.37 (-0.58‒-0.16), and 0.11 (0.03‒0.18) for annual changes of global WMH score, GM volume, and ventricular volume, respectively. The corresponding figures associated with per 10-PVS increment were 1.14 (1.01‒1.28), 0.07 (0.03‒0.11), -0.18 (-0.32‒-0.04), and 0.02 (-0.03‒0.07). Prevalent lacunes were related to multi-adjusted β-coefficients of 0.29 (0.00‒0.58), 0.22 (0.05‒0.38), 0.10 (0.01‒0.18), and -0.93 (-1.83‒-0.03) for annual changes of global, deep, and periventricular WMH scores and GM volume, respectively. These results suggest that cSVD progresses faster in older, male, and less-educated people, and that greater loads of WMH, PVS, and lacunes anticipate faster cSVD progression., (Copyright © 2022. Published by Elsevier Inc.)

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele., (© 2022. The Author(s).)

Background and Aim: Accumulation of evidence has raised concern regarding the harmful effect of air pollution on cognitive function, but results are diverging. We aimed to investigate the longitudinal association of long-term exposure to air pollutants and cognitive impairment and its further progression to dementia in older adults residing in an urban area., Methods: Data were obtained from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Cognitive impairment, no dementia (CIND) was assessed by a comprehensive neuropsychological battery (scoring ≥1.5 standard deviations below age-specific means in ≥1 cognitive domain). We assessed long-term residential exposure to particulate matters (PM 2.5 and PM 10 ) and nitrogen oxides (NO x ) with dispersion modeling. The association with CIND was estimated using Cox proportional hazards models with 3-year moving average air pollution exposure. We further estimated the effect of long-term air pollution exposure on the progression of CIND to dementia using Cox proportional hazards models., Results: Among 1987 cognitively intact participants, 301 individuals developed CIND during the 12-year follow-up. A 1-μg/m 3 increment in PM 2.5 exposure was associated with a 75% increased risk of incident CIND (HR = 1.75, 95 %CI: 1.54, 1.99). Weaker associations were found for PM 10 (HR for 1-μg/m 3  = 1.08, 95 %CI: 1.03-1.14) and NO x (HR for 10 μg/m 3  = 1.18, 95 %CI: 1.04-1.33). Among those with CIND at baseline (n = 607), 118 participants developed dementia during follow-up. Results also show that exposure to air pollution was a risk factor for the conversion from CIND to dementia (PM 2.5 : HR for 1-μg/m 3  = 1.90, 95 %CI: 1.48-2.43; PM 10 : HR for 1-μg/m 3  = 1.14, 95 %CI: 1.03-1.26; and NO x : HR for 10 μg/m 3  = 1.34, 95 %CI: 1.07-1.69)., Conclusion: We found evidence of an association between long-term exposure to ambient air pollutants and incidence of CIND. Of special interest is that air pollution also was a risk factor for the progression from CIND to dementia., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Olfactory impairment is increasingly common with older age, which may be in part explained by cumulative effects of exposure to inhaled toxins. However, population-based studies investigating the relationship between air pollution and olfactory ability are scarce., Objectives: We aimed to investigate associations between exposure to common air pollutants and longitudinal change in odor identification., Methods: Our study of 2,468 participants ( mean age = 72.3 y ; 61.1% female), of which 1,774 participants ( mean age = 70.5 y ; 61.9% female) had at least two olfactory assessments over 12 y of follow-up from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), Stockholm, Sweden. Participants were free from cognitive impairment and neurodegenerative disease at baseline. Odor identification ability was assessed with Sniffin' Sticks. Change in olfactory performance was estimated with linear mixed models. Exposure to two major airborne pollutants [particulate matter with aerodynamic diameter ≤ 2.5 μ m ( PM 2.5 ) and nitrogen oxides ( NO x )] for the 5 y preceding baseline was assessed using spatiotemporal dispersion models for outdoor levels at residential addresses., Results: Participants showed significant decline in odor identification ability for each year in the study { β = - 0.20 [95% confidence interval (CI): - 0.22 , 0.18 ; p < 0.001 ]}. After adjustment for all covariates, residents of third [ β = - 0.09 (95% CI: - 0.14 , - 0.04 ; p < 0.001 )] and fourth [ β = - 0.07 (95% CI: - 0.12 , - 0.02 ; p = 0.005 )] exposure quartiles of PM 2.5 had faster rates of olfactory decline than residents from the first quartile. Similar results were observed for the third [ β = - 0.05 (95% CI: - 0.10 , - 0.01 ; p = 0.029 )] and fourth [ β = - 0.07 (95% CI: - 0.11 , - 0.02 ; p = 0.006 ) quartiles of NO x ]., Discussion: Our results suggest an association between air pollution exposure and subsequent olfactory decline. We speculate that cumulative effects of airborne pollutants on the olfactory system may be one underlying cause of olfactory impairment in aging. https://doi.org/10.1289/EHP9563.

Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health., Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association., Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4-11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor)., Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95%CI 1.08-1.67; SNAC-K: HR 2.16, 95%CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk., Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

Odor identification is a common assessment of olfaction, and it is affected in a large number of diseases. Identification abilities decline with age, but little is known about whether there are perceptual odor features that can be used to predict identification. Here, we analyzed data from a large, population-based sample of 2,479 adults, aged 60 years or above, from the Swedish National study on Aging and Care in Kungsholmen. Participants performed both free and cued odor identification tests. In a separate experiment, we assessed perceived pleasantness, familiarity, intensity, and edibility of all odors in the first sample, and examined how odor identification performance is associated with these variables. The analysis showed that high-intensity odors are easier to identify than low-intensity odors overall, but also that they are more susceptible to the negative repercussions of old age. This result indicates that sensory decline is a major aspect of age-dependent odor identification impairment, and suggests a framework where identification likelihood is proportional to the perceived intensity of the odor. Additional analyses further showed that high-performing individuals can discriminate target odors from distractors along the pleasantness and edibility dimensions and that unpleasant and inedible odors show smaller age-related differences in identification. Altogether, these results may guide further development and optimization of brief and efficient odor identification tests as well as influence the design of odorous products targeted toward older consumers., (© The Author(s) 2022. Published by Oxford University Press.)

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., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

[Figure: see text].

Background: Brain iron overload is linked to brain deterioration, and cognitive and motor impairment in neurodegenerative disorders and normal aging. Mutations in the HFE gene are associated with iron dyshomeostasis and are risk factors for peripheral iron overload. However, links to brain iron load and cognition are less consistent and data are scarce., Aims and Methods: Using quantitative susceptibility mapping with magnetic resonance imaging, we investigated whether C282Y and H63D contributed to aging-related increases in brain iron load and lower cognitive and motor performance in 208 healthy individuals aged 20-79 years. We also assessed the modulatory effects of HFE mutations on associations between performance and brain iron load, as well as peripheral iron metabolism., Results: Independent of age, carriers of either C282Y and/or H63D (HFE-pos group, n = 66) showed a higher load of iron in putamen than non-carriers (HFE-neg group, n = 142), as well as higher transferrin saturation and lower transferrin and transferrin receptors in blood. In the HFE-neg group, higher putaminal iron was associated with lower working memory. In the HFE-pos group, higher putaminal iron was instead linked to higher executive function, and lower plasma transferrin was related to higher episodic memory. Iron-performance associations were modest albeit reliable., Conclusion: Our findings suggest that HFE status is characterized by higher regional brain iron load across adulthood, and support the presence of a modulatory effect of HFE status on the relationships between iron load and cognition. Future studies in healthy individuals are needed to confirm the reported patterns., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background and Objectives: Cognitive reserve (CR) is meant to account for the mismatch between brain damage and cognitive decline or dementia. Generally, CR has been operationalized using proxy variables indicating exposure to enriching activities ( activity-based CR). An alternative approach defines CR as residual variance in cognition, not explained by the brain status ( residual-based CR). The aim of this study is to compare activity-based and residual-based CR measures in their association with cognitive trajectories and dementia. Furthermore, we seek to examine if the two measures modify the impact of brain integrity on cognitive trajectories and if they predict dementia incidence independent of brain status., Methods: We used data on 430 older adults aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen, followed for 12 years. Residual-based reserve was computed from a regression predicting episodic memory with a brain-integrity index incorporating six structural neuroimaging markers (white-matter hyperintensities volume, whole-brain gray matter volume, hippocampal volume, lateral ventricular volume, lacunes, and perivascular spaces), age, and sex. Activity-based reserve incorporated education, work complexity, social network, and leisure activities. Cognition was assessed with a composite of perceptual speed, semantic memory, letter-, and category fluency. Dementia was clinically diagnosed in accordance with DSM-IV criteria. Linear mixed models were used for cognitive change analyses. Interactions tested if reserve measures modified the association between brain-integrity and cognitive change. Cox proportional hazard models, adjusted for brain-integrity index, assessed dementia risk., Results: Both reserve measures were associated with cognitive trajectories [β × time (top tertile, ref.: bottom tertile) = 0.013; 95% CI: -0.126, -0.004 ( residual-based ) and 0.011; 95% CI: -0.001, 0.024, ( activity-based )]. Residual-based , but not activity-based reserve mitigated the impact of brain integrity on cognitive decline [β (top tertile × time × brain integrity) = -0.021; 95% CI: -0.043, 0.001] and predicted 12-year dementia incidence, after accounting for the brain-integrity status [HR (top tertile) = 0.23; 95% CI: 0.09, 0.58]., Interpretation: The operationalization of reserve based on residual cognitive performance may represent a more direct measure of CR than an activity-based approach. Ultimately, the two models of CR serve largely different aims. Accounting for brain integrity is essential in any model of reserve., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gallo, Kalpouzos, Laukka, Wang, Qiu, Bäckman, Marseglia, Fratiglioni and Dekhtyar.)