General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components: gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 29 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.18 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

Epigenetic scores of blood-based proteins as biomarkers of general cognitive function and brain health.

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, PFDR < 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.

Design and Evaluation of Wearable Multimodal RF Sensing System for Vascular Dementia Detection.

Vascular dementia is the second most common form of dementia and a leading cause of death. Brain stroke and brain atrophy are the major degenerative pathologies associated with vascular dementia. Timely detection of these progressive pathologies is critical to avoid brain damage. Brain imaging is an important diagnostic tool and determines future treatment options available to the patient. Traditional medical technologies are expensive, require extensive supervision and are not easily accessible. This article presents a novel concept of low- complexity wearable sensing system for the detection of brain stroke and brain atrophy using RF sensors. This multimodal RF sensing system provides a first-of-its-kind RF sensing solution for the detection of cerebral blood density variations and blood clots at an initial stage of neurodegeneration. A customized microwave imaging algorithm is presented for the reconstruction of images in affected areas of the brain. Designs are validated using software simulations and hardware modeling. Fabricated sensors are experimentally validated and can effectively detect blood density variation (1050 ± 50 Kg/m3), artificial stroke targets with a volume of 27 mm3 and density of 1025-1050 Kg/m3, and brain atrophy with a cavity of 58 mm3 within a realistic brain phantom. The safety of the proposed wearable RF sensing system is studied through the evaluation of the Specific Absorption Rate (SAR < 1.4 W/Kg, 100 mW) and thermal conductivity of the brain (<0.152 °C). The results indicate that the device is viable as an efficient, portable, and low-cost substitute for vascular dementia detection.

Identifying dementia using medical data linkage in a longitudinal cohort study: Lothian Birth Cohort 1936.

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.

Influences of genetically predicted and attained education on geographic mobility and their association with mortality.

INTRODUCTION: Both educational attainment and genetic propensity to education (PGSEdu) have been associated with geographic mobility. Socioeconomic conditions are, in turn, associated with individuals' health. Geographic mobility could therefore lead to better health for some since it could provide better opportunities, like education. Our aim was to study how attained education and genetic predisposition for higher education are related to geographic mobility, and how they affect the association between geographic mobility and mortality. METHODS: We used data from the Swedish Twin Registry (twins born 1926-1955; n = 14,211) in logistic regression models to test if attained education and PGSEdu predicted geographic mobility. Cox regression models were then performed to test if geographic mobility, attained education, and PGSEdu were associated with mortality. RESULTS: The results show that both attained education and PGSEdu predicted geographic mobility, in both independent and joint effect models, with higher education associated with higher mobility. Geographic mobility was associated with lower mortality in the independent effect model, but joint effect models showed that this association was completely explained by attained education. CONCLUSIONS: To conclude, both attained education and PGSEdu were associated with geographic mobility. Moreover, attained education explained the relationship between geographic mobility and mortality.

General and specific patterns of cortical gene expression as spatial correlates of complex cognitive functioning.

Gene expression varies across the brain. This spatial patterning denotes specialised support for particular brain functions. However, the way that a given gene's expression fluctuates across the brain may be governed by general rules. Quantifying patterns of spatial covariation across genes would offer insights into the molecular characteristics of brain areas supporting, for example, complex cognitive functions. Here, we use principal component analysis to separate general and unique gene regulatory associations with cortical substrates of cognition. We find that the region-to-region variation in cortical expression profiles of 8235 genes covaries across two major principal components : gene ontology analysis suggests these dimensions are characterised by downregulation and upregulation of cell-signalling/modification and transcription factors. We validate these patterns out-of-sample and across different data processing choices. Brain regions more strongly implicated in general cognitive functioning (g; 3 cohorts, total meta-analytic N = 39,519) tend to be more balanced between downregulation and upregulation of both major components (indicated by regional component scores). We then identify a further 41 genes as candidate cortical spatial correlates of g, beyond the patterning of the two major components (|ß| range = 0.15 to 0.53). Many of these genes have been previously associated with clinical neurodegenerative and psychiatric disorders, or with other health-related phenotypes. The results provide insights into the cortical organisation of gene expression and its association with individual differences in cognitive functioning.

Low-level lithium in drinking water and subsequent risk of dementia: Cohort study.

BACKGROUND: Lithium, a mood stabilizer, is known to exhibit neuroprotective effects in animal models and may have anti-dementia effects. AIMS: We used data from Scottish Mental Survey 1932, a population-based cohort study, to investigate the association between lithium in drinking water and dementia rate in humans. METHOD: Lithium levels in drinking water from 285 sampling sites across Scotland dating from 2014 were obtained from the sole public water provider (Scottish Water). Dementia and non dementia cases were identified from cohort data by electronic health records until 2012, and linked to postcode. RESULTS: The mean lithium level at all sampling sites was 1.45 µg/L (SD 1.83, range 0.5-18.2) and was 1.26 (SD 0.63, range 0.55-9.19) for sites matched to participant data. Of 37,597 study members, 3605 developed dementia until June 2012. Lithium levels were positively associated with the risk of dementia in women (highest in second quartile, HR 1.17, 95%CI 1.04-1.32), but there was no relationship in men (highest in second quartile, HR 0.95, 95% CI 0.81-1.12). The pattern of association was explored further by decile, and in females there was an association between lithium level and increased dementia risk compared to the lowest decile (0.55-0.68 µg/L) in all deciles except the highest, corresponding with lithium levels 0.68-2.1 µg/L. CONCLUSIONS: Lithium levels in drinking water are very low across Scotland which limited detection of potential effect. Our results do not support an association between extremely low levels of lithium and later dementia risk. We found a trend to increased risk in females at lithium levels below but not above 2.1 µg/L.

Socioeconomic status as a risk factor for motoric cognitive risk syndrome in a community-dwelling population: A longitudinal observational study.

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.

Anticholinergic burden in middle and older age is associated with lower cognitive function, but not with brain atrophy.

AIMS: The aim of this study is to estimate the association between anticholinergic burden, general cognitive ability and various measures of brain structural MRI in relatively healthy middle-aged and older individuals. METHODS: In the UK Biobank participants with linked health-care records (n = 163,043, aged 40-71 at baseline), of whom about 17 000 had MRI data available, we calculated the total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general cognitive ability, 9 separate cognitive domains, brain atrophy, volumes of 68 cortical and 14 subcortical areas and fractional anisotropy and median diffusivity of 25 white-matter tracts. RESULTS: Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests (7/9 FDR-adjusted significant associations, standardised betas (ß) range: -0.039, -0.003). When using the anticholinergic scale exhibiting the strongest association with cognitive functions, anticholinergic burden due to only some classes of drugs exhibited negative associations with cognitive function, with ß-lactam antibiotics (ß = -0.035, PFDR < 0.001) and opioids (ß = -0.026, PFDR < 0.001) exhibiting the strongest effects. Anticholinergic burden was not associated with any measure of brain macrostructure or microstructure (PFDR > 0.08). CONCLUSIONS: Anticholinergic burden is weakly associated with poorer cognition, but there is little evidence for associations with brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability.

Are neuropsychiatric symptoms a marker of small vessel disease progression in older adults? Evidence from the Lothian Birth Cohort 1936.

BACKGROUND: Neuropsychiatric symptoms could form part of an early cerebral small vessel disease prodrome that is detectable before stroke or dementia onset. We aimed to identify whether apathy, depression, anxiety, and subjective memory complaints associate with longitudinal white matter hyperintensity (WMH) progression. METHODS: Community-dwelling older adults from the observational Lothian Birth Cohort 1936 attended three visits at mean ages 73, 76, and 79 years, repeating MRI, Mini-Mental State Examination, neuropsychiatric (Dimensional Apathy Scale, Hospital Anxiety and Depression Scale), and subjective memory symptoms. We ran regression and mixed-effects models for symptoms and normalised WMH volumes (cube root of WMH:ICV × 10). RESULTS: At age 73, 76, and 79, m = 672, n = 476, and n = 382 participants attended MRI respectively. Worse apathy at age 79 was associated with WMH volume increase (ß = 0.27, p = 0.04) in the preceding 6 years. A 1SD increase in apathy score at age 79 associated with a 0.17 increase in WMH (ß = 0.17 normalised WMH percent ICV, p = 0.009). In apathy subscales, executive (ß = 0.13, p = 0.05) and emotional (ß = 0.13, p = 0.04) scores associated with increasing WMH more than initiation scores (ß = 0.11, p = 0.08). Increasing WMH also associated with age (ß = 0.40, p = 0.002) but not higher depression (ß = -0.01, p = 0.78), anxiety (ß = 0.05, p = 0.13) scores, or subjective memory complaints (ß = 1.12, p = 0.75). CONCLUSIONS: Apathy independently associates with preceding longitudinal WMH progression, while depression, anxiety, and subjective memory complaints do not. Patients with apathy should be considered for enrolment to small vessel disease trials.

Predictors of longitudinal cognitive ageing from age 70 to 82 including APOE e4 status, early-life and lifestyle factors: the Lothian Birth Cohort 1936.

Discovering why some people's cognitive abilities decline more than others is a key challenge for cognitive ageing research. The most effective strategy may be to address multiple risk factors from across the life-course simultaneously in relation to robust longitudinal cognitive data. We conducted a 12-year follow-up of 1091 (at age 70) men and women from the longitudinal Lothian Birth Cohort 1936 study. Comprehensive repeated cognitive measures of visuospatial ability, processing speed, memory, verbal ability, and a general cognitive factor were collected over five assessments (age 70, 73, 76, 79, and 82 years) and analysed using multivariate latent growth curve modelling. Fifteen life-course variables were used to predict variation in cognitive ability levels at age 70 and cognitive slopes from age 70 to 82. Only APOE e4 carrier status was found to be reliably informative of general- and domain-specific cognitive decline, despite there being many life-course correlates of cognitive level at age 70. APOE e4 carriers had significantly steeper slopes across all three fluid cognitive domains compared with non-carriers, especially for memory (ß = -0.234, p < 0.001) and general cognitive function (ß = -0.246, p < 0.001), denoting a widening gap in cognitive functioning with increasing age. Our findings suggest that when many other candidate predictors of cognitive ageing slope are entered en masse, their unique contributions account for relatively small proportions of variance, beyond variation in APOE e4 status. We conclude that APOE e4 status is important for identifying those at greater risk for accelerated cognitive ageing, even among ostensibly healthy individuals.

Motoric cognitive risk syndrome trajectories and incident dementia over 10 years.

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.

Prevalence and predictors of Motoric Cognitive Risk syndrome in a community-dwelling older Scottish population: A longitudinal observational study.

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.

Cognitive Change Before Old Age (11 to 70) Predicts Cognitive Change During Old Age (70 to 82).

Identifying predictors of cognitive decline in old age helps us understand its mechanisms and identify those at greater risk. Here, we examined how cognitive change from ages 11 to 70 is associated with cognitive change at older ages (70 to 82 years) in the Lothian Birth Cohort 1936 longitudinal study (N = 1,091 at recruitment). Using latent-growth-curve models, we estimated rates of change from ages 70 to 82 in general cognitive ability (g) and in three cognitive domains: visuospatial, memory, and processing speed. We found that g accounted for 71.3% of interindividual change variance. Greater cognitive gain from ages 11 to 70 predicted slower decline in g over 12 subsequent years (ß = 0.163, p = .001), independently of cognitive level in childhood and at age 70, and domain-specific change beyond g. These results contribute to the goal of identifying people at higher risk of age-related cognitive decline.

Life-course exposure to air pollution and biological ageing in the Lothian Birth Cohort 1936.

BACKGROUND: Exposure to air pollution is associated with a range of diseases. Biomarkers derived from DNA methylation (DNAm) offer potential mechanistic insights into human health differences, connecting disease pathogenesis and biological ageing. However, little is known about sensitive periods during the life course where air pollution might have a stronger impact on DNAm, or whether effects accumulate over time. We examined associations between air pollution exposure across the life course and DNAm-based markers of biological ageing. METHODS: Data were derived from the Scotland-based Lothian Birth Cohort 1936. Participants' residential history was linked to annual levels of fine particle (PM2.5), sulphur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) around 1935, 1950, 1970, 1980, 1990, and 2001; pollutant concentrations were estimated using the EMEP4UK atmospheric chemistry transport model. Blood samples were obtained between ages of 70 and 80 years, and Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, DNAmGrimAge, and DNAm telomere length (DNAmTL) were computed. We applied the structured life-course modelling approach: least angle regression identified best-fit life-course models for a composite measure of air pollution (air quality index [AQI]), and mixed-effects regression estimated selected models for AQI and single pollutants. RESULTS: We included 525 individuals with 1782 observations. In the total sample, increased air pollution around 1970 was associated with higher epigenetic age (AQI: b = 0.322 year, 95 %CI: 0.088, 0.555) measured with Horvath DNAmAge in late adulthood. We found shorter DNAmTL among males with higher air pollution around 1980 (AQI: b = -0.015 kilobase, 95 %CI: -0.027, -0.004) and among females with higher exposure around 1935 (AQI: b = -0.017 kilobase, 95 %CI: -0.028, -0.006). Findings were more consistent for the pollutants PM2.5, SO2 and NO2. DISCUSSION: We tested the life-course relationship between air pollution and DNAm-based biomarkers. Air pollution around birth and in young-to-middle adulthood is linked to accelerated epigenetic ageing and telomere-associated ageing in later life.

Mitigating the impact of air pollution on dementia and brain health: Setting the policy agenda.

BACKGROUND: Emerging research suggests exposure to high levels of air pollution at critical points in the life-course is detrimental to brain health, including cognitive decline and dementia. Social determinants play a significant role, including socio-economic deprivation, environmental factors and heightened health and social inequalities. Policies have been proposed more generally, but their benefits for brain health have yet to be fully explored. OBJECTIVE AND METHODS: Over the course of two years, we worked as a consortium of 20+ academics in a participatory and consensus method to develop the first policy agenda for mitigating air pollution's impact on brain health and dementia, including an umbrella review and engaging 11 stakeholder organisations. RESULTS: We identified three policy domains and 14 priority areas. Research and Funding included: (1) embracing a complexities of place approach that (2) highlights vulnerable populations; (3) details the impact of ambient PM2.5 on brain health, including current and historical high-resolution exposure models; (4) emphasises the importance of indoor air pollution; (5) catalogues the multiple pathways to disease for brain health and dementia, including those most at risk; (6) embraces a life course perspective; and (7) radically rethinks funding. Education and Awareness included: (8) making this unrecognised public health issue known; (9) developing educational products; (10) attaching air pollution and brain health to existing strategies and campaigns; and (11) providing publicly available monitoring, assessment and screening tools. Policy Evaluation included: (12) conducting complex systems evaluation; (13) engaging in co-production; and (14) evaluating air quality policies for their brain health benefits. CONCLUSION: Given the pressing issues of brain health, dementia and air pollution, setting a policy agenda is crucial. Policy needs to be matched by scientific evidence and appropriate guidelines, including bespoke strategies to optimise impact and mitigate unintended consequences. The agenda provided here is the first step toward such a plan.

Association between anticholinergic burden and dementia in UK Biobank.

Background: Previous studies on the relationship between anticholinergic drugs and dementia have reported heterogeneous results. This variability could be due to different anticholinergic scales and differential effects of distinct classes of drugs. Methods: Using Cox proportional hazards models, we computed the association between annual anticholinergic burden (AChB) and the risk of dementia in UK Biobank with linked general practitioner prescription records between the years 2000 and 2015 (n = 171,775). Results: AChB according to most anticholinergic scales (standardized odds ratio range: 1.027-1.125) and the slope of the AChB trajectory (hazard ratio = 1.094; 95% confidence interval: 1.068-1.119) were predictive of dementia. However, the association between AChB and dementia held only for some classes of drugs, especially antidepressants, antiepileptics, and antidiuretics. Discussion: The heterogeneity in previous findings may partially be due to different effects for different classes of drugs. Future studies should establish differences in more detail and further examine the practicality of a general measure of AChB relating to the risk of dementia.

A comparison of blood and brain-derived ageing and inflammation-related DNA methylation signatures and their association with microglial burdens.

Inflammation and ageing-related DNA methylation patterns in the blood have been linked to a variety of morbidities, including cognitive decline and neurodegenerative disease. However, it is unclear how these blood-based patterns relate to patterns within the brain and how each associates with central cellular profiles. In this study, we profiled DNA methylation in both the blood and in five post mortem brain regions (BA17, BA20/21, BA24, BA46 and hippocampus) in 14 individuals from the Lothian Birth Cohort 1936. Microglial burdens were additionally quantified in the same brain regions. DNA methylation signatures of five epigenetic ageing biomarkers ('epigenetic clocks'), and two inflammatory biomarkers (methylation proxies for C-reactive protein and interleukin-6) were compared across tissues and regions. Divergent associations between the inflammation and ageing signatures in the blood and brain were identified, depending on region assessed. Four out of the five assessed epigenetic age acceleration measures were found to be highest in the hippocampus (ß range = 0.83-1.14, p ≤ 0.02). The inflammation-related DNA methylation signatures showed no clear variation across brain regions. Reactive microglial burdens were found to be highest in the hippocampus (ß = 1.32, p = 5 × 10-4 ); however, the only association identified between the blood- and brain-based methylation signatures and microglia was a significant positive association with acceleration of one epigenetic clock (termed DNAm PhenoAge) averaged over all five brain regions (ß = 0.40, p = 0.002). This work highlights a potential vulnerability of the hippocampus to epigenetic ageing and provides preliminary evidence of a relationship between DNA methylation signatures in the brain and differences in microglial burdens.

Mechanisms of motoric cognitive risk-Hypotheses based on a systematic review and meta-analysis of longitudinal cohort studies of older adults.

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; I2  = 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.