Association between plasma phospho-tau181 and cognitive change from age 73 to 82: Lothian Birth Cohort 1936

INTRODUCTION: Plasma phospho-tau 181 (p-tau181) is a promising blood biomarker for Alzheimer's disease. However, its predictive validity for age-related cognitive decline without dementia remains unclear. Several forms of p-tau have been shown to contribute to synapse degeneration, but it is unknown whether p-tau181 is present in synapses. Here, we tested whether plasma p-tau181predicts cognitive decline and whether it is present in synapses in human brain. METHODS: General cognitive ability and plasma p-tau181 concentration were measured in 195 participants at ages 72 and 82. Levels of p-tau181 in total homogenate and synaptic fractions were compared with western blot (n=10-12 per group), and synaptic localisation was examined using array tomography. RESULTS: Elevated baseline plasma p-tau181 and increasing p-tau181 over time predicted steeper general cognitive decline. We observe p-tau181 in neurites, presynapses, and post-synapses in the brain. DISCUSSION: Baseline and subsequent change in plasma p-tau181 may represent rare biomarkers of differences in cognitive ageing across the 8th decade of life and may play a role in synaptic function in the brain.

The genetic and epigenetic profile of serum S100β in the Lothian Birth Cohort 1936 and its relationship to Alzheimer’s disease

Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer’s disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer’s disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer’s disease. Colocalisation between S100β and Alzheimer’s disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P<5x10-8) with S100β protein levels. The lead variant was located in the S100β gene (rs8128872, P=5.0x10-17). We found evidence that two independent causal variants existed for both transcription of S100β and S100β protein levels in our eQTL analyses. No CpG sites were associated with S100β levels at the epigenome-wide significant level (P<3.6x10-8); the lead probe was cg06833709 (P=5.8x10-6), which mapped to the LGI1 gene. There was no evidence of a causal association between S100β levels and Alzheimer’s disease or vice versa and no evidence for colocalisation between S100β and Alzheimer’s disease loci. Conclusions: These data provide insight into the molecular regulators of S100β levels. This context may aid in understanding the role of S100β in brain inflammation and neurological disease.

Heterogeneity of Frailty Trajectories and Associated Factors in the Lothian Birth Cohort 1936

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> A quadratic latent class mixed model found 3 distinct groupings, which followed a low (61%, <i>n</i> = 632), medium (36%, <i>n</i> = 368), or high (3%, <i>n</i> = 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. <b><i>Discussion/Conclusion:</i></b> 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.

Topological relationships between perivascular spaces and progression of white matter hyperintensities: a pilot study in a sample of the Lothian Birth Cohort 1936

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesised to also have topological proximity. However, this, and the influence of their spatial proximity on WMH progression are unknown. We analysed longitudinal MRI data from 29/32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive ageing, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (Wave 1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (Waves 1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each if these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest deep WMH clusters preferentially form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.

Is life-course neighbourhood deprivation associated with frailty and frailty progression from age 70 to 82 in the Lothian Birth Cohort 1936?

Background Neighbourhood features have been postulated as key predictors of frailty. However, evidence is mainly limited to cross-sectional studies without indication of long-term impact and developmental timing of the exposures. This study explored how neighbourhood social deprivation (NSD) across the life course is associated with frailty and frailty progression among older Scottish adults. Methods Participants (n=323) were from the Lothian Birth Cohort 1936 with historical measures of NSD in childhood (1936-1955), early adulthood (1956-1975) and mid-to-late adulthood (1976-2014). Frailty was measured five times between the ages of 70 and 82 years using the Frailty Index. Confounder-adjusted life-course models were assessed using a structured modelling approach with least angle regression; associations were estimated for frailty at baseline using linear regression, and for frailty progression using linear mixed-effects models. Results Accumulation was the most appropriate life-course model for males; greater accumulated NSD was associated with higher frailty at age 70 (b=0.017; 95%CI: 0.005, 0.029; P=0.007) with dominant exposure times in childhood and mid-to-late adulthood. Among females, mid-to-late adulthood sensitive period was the best-fit life-course model and higher NSD in this period was associated with widening frailty trajectories between age 70 and 82 (b=0.005; 95%CI: 0.0004, 0.009, P=0.033). Conclusions This is the first investigation of the life-course impact of neighbourhood deprivation on frailty in a cohort of older adults with residential information across their lives. Future research should explore neighbourhood mechanisms linking deprivation to frailty. Policies designed to address neighbourhood deprivation and inequalities across the full life course may support healthy ageing.

The Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ): Responses and non-musical correlates in the Lothian Birth Cohort 1936

There is growing evidence of the potential effects of musical training on the human brain, as well as increasing interest in the potential contribution of musical experience to healthy ageing. Conducting research on these topics with older adults requires a comprehensive assessment of musical experience across the lifespan, as well as an understanding of which variables might correlate with musical training and experience (such as personality traits or years of education). The present study introduces a short questionnaire for assessing lifetime musical training and experience in older populations: the Edinburgh Lifetime Musical Experience Questionnaire (ELMEQ). 420 participants from the Lothian Birth Cohort 1936 completed the ELMEQ at a mean age of 82 years. We used their responses to the ELMEQ to address three objectives: 1) to report the prevalence of lifetime musical experience in a sample of older adults; 2) to demonstrate how certain item-level responses can be used to model latent variables quantifying experience in different musical domains (playing a musical instrument, singing, self-reported musical ability, and music listening); and 3) to examine non-musical (lifespan) correlates of these domains. In this cohort, 420 of 431 participants (97%) completed the questionnaire. 40% of participants reported some lifetime experience of playing a musical instrument, starting at a median age of 10 years and playing for a median of 5 years. 38% of participants reported some lifetime experience of singing in a group. Non-musical variables of childhood environment, years of education, childhood cognitive ability, female sex, extraversion, history of arthritis and fewer constraints on activities of daily living were found to be associated, variously, with the domains of playing a musical instrument, singing, self-reported musical ability, and music listening. The ELMEQ was found to be an effective research tool with older adults and is made freely available for future research.

Childhood Socioeconomic Status Does Not Predict Late-Life Cognitive Decline in the 1936 Lothian Birth Cohort

This study examined childhood socioeconomic status (SES) as a predictor of later life cognitive decline. Data came from 519 participants in the Lothian Birth Cohort 1936 (LBC1936) study. SES measures at 11 years of age included parental educational attainment, father’s occupational status, household characteristics and a composite measure of global childhood SES (i.e., a total of low SES childhood indicators). Cognitive abilities were assessed by the Mini-Mental State Exam at ages 69.8, 72.8 and 76.7 years. Most indicators of low childhood SES (i.e., father manual worker, less than secondary school father education, household overcrowding, exterior located toilet, and global childhood SES) did not predict cognitive decline between the ages of 69.8 and 76.7. Participants with less educated mothers showed an increase in cognitive decline (β = −0.132, p = 0.048, and CI = −0.80, −0.00). The relationship between maternal educational attainment and cognitive decline became non-significant when controlling for adult SES (i.e., participant educational attainment and occupation). Adult SES did not mediate the latter relationship. This study provides new evidence that childhood SES alone is not strongly associated with cognitive decline. New knowledge is critical to improving population health by identifying life span stages in which interventions might be effective in preventing cognitive decline.

Impact of COVID-19 lockdown on psychosocial factors, health, and lifestyle in Scottish octogenarians: The Lothian Birth Cohort 1936 study

Background Little is known about effects of COVID-19 lockdown on psychosocial factors, health and lifestyle in older adults, particularly those aged over 80 years, despite the risks posed by COVID-19 to this age group. Methods Lothian Birth Cohort 1936 members, residing mostly in Edinburgh and the surrounding Lothians regions in Scotland, mean age 84 years (SD = 0.3), responded to an online questionnaire in May 2020 (n = 190). We examined responses (experience and knowledge of COVID-19; adherence to guidance; impact on day-to-day living; social contact; self-reported physical and mental health; loneliness; and lifestyle) and relationships between previously-measured characteristics and questionnaire outcomes. Results Four respondents experienced COVID-19; most had good COVID-19 knowledge (94.7%) and found guidance easy to understand (86.3%). There were modest declines in self-reported physical and mental health, and 48.2% did less physical activity. In multivariable regression models, adherence to guidance by leaving the house less often associated with less professional occupational class (OR = 0.71, 95%CI 0.51–0.98) and poorer self-rated general health (OR = 0.62, 95%CI 0.42–0.92). Increased internet use associated with female sex (OR = 2.32, 95%CI 1.12–4.86) and higher general cognitive ability (OR = 1.53, 95%CI 1.03–2.33). Loneliness associated with living alone (OR = 0.15, 95%CI 0.07–0.31) and greater anxiety symptoms (OR = 1.76, 95%CI 0.45–1.24). COVID-19 related stress associated with lower emotional stability scores (OR = 0.40, 95%CI 0.24–0.62). Decreased physical activity associated with less professional occupational class (OR = 1.43, 95%CI 1.04–1.96), and lower general cognitive ability (OR = 0.679, 95%CI 0.491–0.931). Conclusions Characteristics including cognitive function, occupational class, self-rated health, anxiety, and emotional stability, may be related to risk of poorer lockdown-related psychosocial and physical outcomes.

Cerebral small vessel disease burden and longitudinal cognitive decline from age 73 to 82: the Lothian Birth Cohort 1936

Slowed processing speed is considered a hallmark feature of cognitive decline in cerebral small vessel disease (SVD); however, it is unclear whether SVD’s association with slowed processing might be due to its association with overall declining general cognitive ability. We quantified the total MRI-visible SVD burden of 540 members of the Lothian Birth Cohort 1936 (age: 72.6 ± 0.7 years; 47% female). Using latent growth curve modelling, we tested associations between total SVD burden at mean age 73 and changes in general cognitive ability, processing speed, verbal memory and visuospatial ability, measured at age 73, 76, 79 and 82. Covariates included age, sex, vascular risk and childhood cognitive ability. In the fully adjusted models, greater SVD burden was associated with greater declines in general cognitive ability (standardised β: −0.201; 95% CI: [−0.36, −0.04]; pFDR = 0.022) and processing speed (−0.222; [−0.40, −0.04]; pFDR = 0.022). SVD burden accounted for between 4 and 5% of variance in declines of general cognitive ability and processing speed. After accounting for the covariance between tests of processing speed and general cognitive ability, only SVD’s association with greater decline in general cognitive ability remained significant, prior to FDR correction (−0.222; [−0.39, −0.06]; p = 0.008; pFDR = 0.085). Our findings do not support the notion that SVD has a specific association with declining processing speed, independent of decline in general cognitive ability (which captures the variance shared across domains of cognitive ability). The association between SVD burden and declining general cognitive ability supports the notion of SVD as a diffuse, whole-brain disease and suggests that trials monitoring SVD-related cognitive changes should consider domain-specific changes in the context of overall, general cognitive decline.