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Background: Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typically derived via penalised regression, whereby a linear weighted sum of DNA methylation (DNAm) levels at CpG sites are predictive of protein levels. Here, we examine 84 previously published protein EpiScores as possible biomarkers of cross-sectional and longitudinal measures of general cognitive function and brain health, and incident dementia across three independent cohorts., Results: Using 84 protein EpiScores as candidate biomarkers, associations with general cognitive function (both cross-sectionally and longitudinally) were tested in three independent cohorts: Generation Scotland (GS), and the Lothian Birth Cohorts of 1921 and 1936 (LBC1921 and LBC1936, respectively). A meta-analysis of general cognitive functioning results in all three cohorts identified 18 EpiScore associations (absolute meta-analytic standardised estimates ranged from 0.03 to 0.14, median of 0.04, P FDR  < 0.05). Several associations were also observed between EpiScores and global brain volumetric measures in the LBC1936. An EpiScore for the S100A9 protein (a known Alzheimer disease biomarker) was associated with general cognitive functioning (meta-analytic standardised beta: - 0.06, P = 1.3 × 10 -9 ), and with time-to-dementia in GS (Hazard ratio 1.24, 95% confidence interval 1.08-1.44, P = 0.003), but not in LBC1936 (Hazard ratio 1.11, P = 0.32)., Conclusions: EpiScores might make a contribution to the risk profile of poor general cognitive function and global brain health, and risk of dementia, however these scores require replication in further studies., (© 2024. The Author(s).)

Background: Motoric Cognitive Risk (MCR) syndrome is a high-risk state for adverse health outcomes in older adults characterised by measured slow gait speed and self-reported cognitive complaints. The recent addition to the Lothian Birth Cohort 1936 of robust dementia outcomes enabled us to assess the prognostic value of MCR for dementia and explore the various trajectories of participants diagnosed with MCR., Methods: We classified 680 community-dwelling participants free from dementia into non-MCR or MCR groups at mean [SD] age 76.3 [0.8] years. We used Cox and competing risk regression methods, adjusted for potential confounders, to evaluate the risk of developing all-cause incident dementia over 10 years of follow-up. Secondarily, we followed the trajectories for individuals with and without MCR at baseline and categorised them into subgroups based on whether MCR was still present at the next research wave, three years later., Results: The presence of MCR increased the risk of incident dementia (adjusted HR 2.34, 95%CI 1.14-4.78, p  = 0.020), as did fewer years of education and higher depression symptoms. However, MCR has a heterogenous progression trajectory. The MCR progression subgroups each have different prognostic values for incident dementia., Conclusion: MCR showed similar prognostic ability for dementia in a Scottish cohort as for other populations. MCR could identify a target group for early interventions of modifiable risk factors to prevent incident dementia. This study illustrates the heterogeneous nature of MCR progression. Exploring the underlying reasons will be important work in future work., Competing Interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article. DAG is a part-time employee of Optima partners, a health data science consultancy company. Optima had no role or influence in this study., (© 2023 The Authors. Published by Elsevier B.V.)

Background: Motoric cognitive risk (MCR) is a syndrome characterised by measured slow gait speed and self-reported cognitive complaints. MCR is a high-risk state for adverse health outcomes in older adults, particularly cognitive impairment and dementia. Previous studies have identified risk factors for MCR, but the effect of socioeconomic status has, to date, been insufficiently examined. This study explored the association between MCR and socioeconomic status, as determined by occupational social class and years of education., Methods: Some 692 community-based adults of the Lothian Birth Cohort 1936 (LBC1936), aged 70 years at baseline, were followed up after 6 years and classified into non-MCR and MCR groups. We applied logistic regression analyses adjusting for demographic, lifestyle, and health covariates to investigate the association between MCR and years of education and occupational social class, categorised into manual versus non-manual occupations., Results: MCR prevalence at age 76 years was 5.6% (95% CI 4.0-7.6). After multivariate adjustment, participants of lower socioeconomic status (manual occupation) had a greater than three-fold increased likelihood of MCR (adjusted odds ratio 3.55, 95% CI 1.46-8.74; p = 0.005) compared with those of higher socioeconomic status (non-manual occupation)., Conclusions: Working in a manual job earlier in life triples the risk of MCR later in life, regardless of education. Unravelling this association will likely reveal important pathophysiological mechanisms underlying MCR and may unearth modifiable risk factors which could be targeted to reduce the incidence of MCR and, ultimately, dementia. Policy and healthcare practice addressing dementia risks such as MCR in their social context and early in the lifecourse could be effective strategies for reducing health inequalities in older age., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The Lothian Birth Cohort 1936 (LBC1936) is a longitudinal study of ageing with well-characterised assessments, but until now, it has relied on self-report or proxies for dementia such as cognitive tests. Our aims were twofold: a) to describe a framework for identifying dementia in a cohort study. b) to report the age-specific incidence and prevalence of all-cause dementia and dementia subtypes in 865 individuals in the LBC1936., Methods: Electronic Health Records (EHR) of all participants were reviewed, and relevant information was extracted to form case vignettes for everyone with any record of cognitive dysfunction. The EHR data sources include hospital and clinic letters, general practitioner and hospital referrals, prescribed medications, imaging and laboratory results. Death certificate data were obtained separately. Clinician assessments were performed when there was concern about a participant's cognition. A diagnosis of probable dementia, possible dementia, or no dementia was agreed upon by a consensus diagnostic review board, comprised of a multidisciplinary team of clinical dementia experts who reviewed case vignettes and clinician assessment letters. For those with probable dementia, a subtype was also determined, where possible. We compared the agreement between our newly ascertained dementia diagnoses with the existing self-reported dementia diagnoses., Results: Self-reported dementia diagnoses were positive in only 17.8% of ascertained dementia diagnoses. The EHR review identified 163/865 (18.8%) individuals as having cognitive dysfunction. At the consensus diagnostic review board, 118/163 were diagnosed with probable all-cause dementia, a prevalence of 13.6%. Age-specific dementia prevalence increased with age from 0.8% (65-74.9 years) to 9.93% (85-89.9 years). Prevalence rates for women were higher in nearly all age groups. The most common subtype was dementia due to Alzheimer disease (49.2%), followed by mixed Alzheimer and cerebrovascular disease (17.0%), dementia of unknown or unspecified cause (16.1%), and dementia due to vascular disease (8.5%)., Conclusions: We present a robust systematic framework and guide for other cohort teams wanting to ascertain dementia diagnoses. The newly ascertained dementia diagnosis provides vital data for further analyses of LBC1936 to allow exploration of lifecourse predictors of dementia., (© 2023. The Author(s).)

We aimed to refine the hypothesis that motoric cognitive risk (MCR), a syndrome combining measured slow gait speed and self-reported cognitive complaints, is prognostic of incident dementia and other major causes of morbidity in older age. We propose mechanisms on the relationship between motor and cognitive function and describe a roadmap to validate these hypotheses. We systematically searched major electronic databases from inception to August 2021 for original longitudinal cohort studies of adults aged ≥60 years that compared an MCR group to a non-MCR group with any health outcome. Fifteen cohorts were combined by meta-analysis. Participants with MCR were at an increased risk of cognitive impairment (adjusted hazard ratio [aHR] 1.76, 95% CI 1.49-2.08; I 2  = 24.9%), dementia (aHR 2.12, 1.85-2.42; 33.1%), falls (adjusted Relative Risk 1.38, 1.15-1.66; 62.1%), and mortality (aHR 1.49, 1.16-1.91; 79.2%). The prognostic value of MCR is considerable and mechanisms underlying the syndrome are proposed., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objectives: Motoric Cognitive Risk (MCR) is a gait-based predementia syndrome that is easy to measure and prognostic of dementia and falls. We aimed to examine the prevalence and risk factors for MCR, and assess its overlap with Mild Cognitive Impairment, Prefrailty, and Frailty, in a cohort of older Scottish adults without dementia., Methods: In this longitudinal prospective study, we classified 690 participants (mean [SD] age 76.3 [0.8] years; wave 3) of the Lothian Birth Cohort 1936 (LBC1936) into non-MCR or MCR groups. We examined their baseline (age 69.5 [0.8] years; wave 1) risk factors for MCR at waves 3, 4, and 5 (6, 9, and 12 years later respectively)., Results: MCR prevalence rate ranged from 5.3% to 5.7% across the three waves. The presence of MCR was associated with older baseline age (6 and 9 years later), lower occupational socioeconomic status (6 years later), and worse scores in a range of tests of executive function (6, 9 and 12 years later). Approximately 46% of the MCR group also had Mild Cognitive Impairment, and almost everyone in the MCR group had either Prefrailty or Frailty., Conclusions: The prevalence of MCR in this Scottish cohort is lower than the pooled global average, possibly reflecting the general good health of the LBC cohort. However, it is higher than the prevalence in two neighbouring countries' cohorts, which may reflect the younger average ages of those cohorts. Future LBC1936 research should assess the risk factors associated with MCR to validate previous findings and analyse novel predictive factors, particularly socioeconomic status., (© 2022 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Background and Objectives: There is an urgent need to better understand frailty and its predisposing factors. Although numerous cross-sectional studies have identified various risk and protective factors of frailty, there is a limited understanding of longitudinal frailty progression. Furthermore, discrepancies in the methodologies of these studies hamper comparability of results. Here, we use a coordinated analytical approach in 5 independent cohorts to evaluate longitudinal trajectories of frailty and the effect of 3 previously identified critical risk factors: sex, age, and education., Research Design and Methods: We derived a frailty index (FI) for 5 cohorts based on the accumulation of deficits approach. Four linear and quadratic growth curve models were fit in each cohort independently. Models were adjusted for sex/gender, age, years of education, and a sex/gender-by-age interaction term., Results: Models describing linear progression of frailty best fit the data. Annual increases in FI ranged from 0.002 in the Invecchiare in Chianti cohort to 0.009 in the Longitudinal Aging Study Amsterdam (LASA). Women had consistently higher levels of frailty than men in all cohorts, ranging from an increase in the mean FI in women from 0.014 in the Health and Retirement Study cohort to 0.046 in the LASA cohort. However, the associations between sex/gender and rate of frailty progression were mixed. There was significant heterogeneity in within-person trajectories of frailty about the mean curves., Discussion and Implications: Our findings of linear longitudinal increases in frailty highlight important avenues for future research. Specifically, we encourage further research to identify potential effect modifiers or groups that would benefit from targeted or personalized interventions., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Mild cognitive impairment (MCI) describes a borderland between healthy cognition and dementia. Progression to and reversion from MCI is relatively common but more research is required to understand the factors affecting this fluidity and improve clinical care interventions., Objective: We explore these transitions in MCI status and their predictive factors over a six-year period in a highly-phenotyped longitudinal study, the Lothian Birth Cohort 1936., Methods: MCI status was derived in the LBC1936 at ages 76 (n = 567) and 82 years (n = 341) using NIA-AA diagnostic guidelines. Progressions and reversions between healthy cognition and MCI over the follow-up period were assessed. Multinomial logistic regression assessed the effect of various predictors on the likelihood of progressing, reverting, or maintaining cognitive status., Results: Of the 292 participants who completed both time points, 41 (14%) participants had MCI at T1 and 56 (19%) at T2. Over the follow-up period, 74%remained cognitively healthy, 12%transitioned to MCI, 7%reverted to healthy cognition, and 7%maintained their baseline MCI status. Findings indicated that membership of these transition groups was affected by age, cardiovascular disease, and number of depressive symptoms., Conclusion: Findings that higher baseline depressive symptoms increase the likelihood of reverting from MCI to healthy cognition indicate that there may be an important role for the treatment of depression for those with MCI. However, further research is required to identify prevention strategies for those at high risk of MCI and inform effective interventions that increase the likelihood of reversion to, and maintenance of healthy cognition.