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Introduction: Recent research suggests that the experience of frailty progression may be heterogeneous, with latent subpopulations of older adults following distinct trajectories of frailty. We aimed to investigate this notion and determine whether certain factors are associated with the membership of these subpopulations. Methods: Data from 5 data waves collected over 12 years in participants of the Lothian Birth Cohort 1936, aged 70 at baseline, were used to derive the frailty index (FI) (NW1 = 1,091, NW5 = 431). These were used in latent class mixed modelling to estimate subpopulations of frailty trajectories. Results: A quadratic latent class mixed model found 3 distinct groupings, which followed a low (61%, n = 632), medium (36%, n = 368), or high (3%, n = 28) FI trajectory. Each grouping had different intercepts and slopes, with the high grouping following the steepest trajectory indicating a rapid increase in frailty. Findings showed that in general, those in the low grouping were younger, had higher education, higher age 11 cognitive ability, and were from a higher social class than those in the medium and high groupings. Discussion/Conclusion: Our findings demonstrate heterogeneity in frailty trajectories over 12 years in individuals aged 70 years at baseline. Membership of higher frailty trajectory groupings was associated with lower social class, less education, and lower childhood cognitive ability, indicating the potential for future interventions to target individuals who are at the greatest risk of belonging to the high frailty trajectory. Future research is required to continue this line of inquiry by exploring other risk and protective factors, and importantly, to assess whether it is possible to realign an individual's membership to a less detrimental grouping of frailty trajectory. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has impacted daily life worldwide, with possible negative consequences for cognitive health. Self‐reported cognitive symptoms are linked to the development of Alzheimer's disease and related dementias (ADRDs). Identifying risk and protective factors for cognitive symptoms during the pandemic is an important step towards the development of ADRD prevention efforts. We aimed to examine correlates of cognitive symptoms among middle‐ and older‐age adults in Latin America before the availability of vaccines to prevent COVID‐19, including sociodemographic factors and changes in life. Method: Spanish‐speaking adults ages 55‐95 (N = 2,382, Table 1) living in Latin America completed an online survey between May and December 2020. Cognitive symptoms were assessed via the 12‐item Everyday Cognition (ECog) questionnaire. Negative (e.g., economic difficulties, limited social activities) and positive (e.g., more quality time with close others, increased time in nature/outside) life changes associated with the pandemic were measured via a subset of items from the Epidemic‐Pandemic Impacts Inventory. Sociodemographic factors included age, years of education, gender, occupation and socioeconomic status (SES). Covariates included time since March 2020 (estimated onset of the pandemic in Latin America), country of survey completion, and having experienced COVID‐19 symptoms. Multivariable linear regression models were ran on ECog total scores including covariates and sociodemographic factors (Model 1), and then adding terms for negative and positive life changes and their interaction (Model 2). Results: Model 1 showed female gender (p =.04), not currently working (p =.02) and lower SES (p<.001) were independently associated with more cognitive symptoms. Model 2 showed a significant interaction between negative and positive life changes (p<.001), indicating that negative life changes were significantly associated with more cognitive symptoms, but this association was weaker among participants who reported at least one positive life change during the pandemic (Figure 1). Conclusion: Cognitive symptoms might be more common among certain segments of the Latin American population, including women, and those who are not working and have low SES. The experience of positive life changes during the pandemic might buffer the detrimental impact of negative life changes on cognitive symptoms. These risk and protective factors might be considered in ADRD prevention efforts. [ABSTRACT FROM AUTHOR]

Background: Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD. Methods: Cognitively healthy middle-aged adults (aged 40–59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction. Results: In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p =.009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = − 0.31, p =.009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results. Conclusions: Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major ‘silent’ contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia. [ABSTRACT FROM AUTHOR]

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, we report an integrated DNA methylation and phenotypic study of the circulating proteome in relation to brain health. Methylome-wide association studies of 4058 plasma proteins are performed (N = 774), identifying 2928 CpG-protein associations after adjustment for multiple testing. These are independent of known genetic protein quantitative trait loci (pQTLs) and common lifestyle effects. Phenome-wide association studies of each protein are then performed in relation to 15 neurological traits (N = 1,065), identifying 405 associations between the levels of 191 proteins and cognitive scores, brain imaging measures or APOE e4 status. We uncover 35 previously unreported DNA methylation signatures for 17 protein markers of brain health. The epigenetic and proteomic markers we identify are pertinent to understanding and stratifying brain health. Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers. [ABSTRACT FROM AUTHOR]

Background: Macrostructural brain alterations in the form of brain atrophy or cortical thinning typically occur during the prodromal Alzheimer's disease stage. Mixed findings largely dependent on the age of the examined cohorts have been reported during the preclinical, asymptomatic disease stage. In the present study, our aim was to examine the association of midlife dementia risk with brain macrostructural alterations. Methods: Structural 3T MRI scans were acquired for 647 cognitively normal middle-aged (40–59 years old) participants in the PREVENT-Dementia study. Cortical thickness, volumes of subcortical structures, the hippocampus and hippocampal subfields were quantified using Freesurfer version 7.1. The clarity of the hippocampal molecular layer was evaluated based on T2-weighted hippocampal scans. Associations of structural measures with apolipoprotein ε4 (APOE4) genotype and dementia family history (FHD), were investigated using linear regression. Correlations between the CAIDE dementia risk score (incorporating information about blood pressure, cholesterol, physical activity, body mass index, education, age and sex) and structural measures were further investigated. Results: A higher CAIDE score was associated with thinner cortex and a larger hippocampal fissure. APOE4 genotype was associated with reduced molecular layer clarity. Conclusions: Our findings suggest that a higher CAIDE score is associated with widespread cortical thinning. Conversely, APOE4 carriers and participants with FHD do not demonstrate prominent macrostructural alterations at this age range. These findings indicate that cardiovascular and not inherited risk factors for dementia are associated with macrostructural brain alterations at midlife. [ABSTRACT FROM AUTHOR]