Marcus Richards

• Medical Research Council (UKRI)

Higher HbA1c in mid-to-later life has been associated with smaller whole brain volume (WBV) in older women but not men. We explored whether this association was replicated using different markers of (a) glycaemic health (fasting glucose, insulin resistance (HOMA2-IR), and β-cell function (HOMA-%B) and (b) brain structure (white or grey matter volum...

Background Existing evidence on associations between exposure to air pollution and psychological distress from middle to older age is limited by consideration of short exposure periods, poor historical covariates, exposures and outcomes, and cross-sectional study designs. We aimed to examine this association over a 26-year period between ages 43 an...

BACKGROUND Alzheimer's disease‐related biomarkers detect pathology years before symptoms emerge, when disease‐modifying therapies might be most beneficial. Remote cognitive testing provides a means of assessing early cognitive changes. We explored the relationship between neurodegenerative biomarkers and cognition in cognitively normal individuals....

We assessed the association between leisure time physical activity patterns across 30 years of adulthood with a range of in vivo Alzheimer’s disease-related neurodegenerative markers and cognition, and their interplay, at age 70. Participants from the 1946 British birth cohort study prospectively reported leisure time physical activity five times b...

Background Autistic people appear less likely to benefit from currently-recommended mental health treatments. Intervention development and adaptation is hampered by a lack of knowledge regarding whether subgroups of autistic people differ in their response to interventions, and what characterises subgroups of autistic people who respond differently...

Background Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals...

Background Understanding when Aß positive cognitively normal individuals develop tau pathology has important implications for treatment with anti‐Aß therapies. We employed a changepoint regression approach to estimate time from Aß‐PET positivity to regionally elevated tau‐PET in a population‐based cohort of primarily cognitively unimpaired individu...

Background Cerebral Aβ accumulates decades before symptom onset in AD. Sampled iterative local approximation (SILA, Betthauser et al. 2022) is a technique for estimating time from Aβ positivity (Aβ+) using Aβ‐PET. Here we explore the influence of APOE‐ɛ4 carriership and sex on estimated age of Aβ+ (EAAβ) in primarily cognitively normal individuals...

Background Understanding when Aβ positive cognitively normal individuals develop tau pathology has important implications for treatment with anti‐Aβ therapies. We employed a changepoint regression approach to estimate time from Aβ‐PET positivity to regionally elevated tau‐PET in a population‐based cohort of primarily cognitively unimpaired individu...

Background In elite athletes, participation in sports associated with repetitive head injury exposure has been linked to an increased risk of neurodegeneration later in life. However, there has been limited study in more general populations. We aimed to investigate whether participation in such sports impacted outcomes relevant to brain health in a...

Background Prior research has highlighted that people living with dementia experiencing depression or anxiety can benefit from psychological therapies delivered in primary care. Yet, studies have mainly focused on common dementia types, leaving a gap in evidence for more atypical dementias, and especially those that are not memory‐led. This evaluat...

Background Psychological therapies are recommended for people living with dementia who experience depression or anxiety. However, people living with dementia often experience specific barriers to accessing services providing such interventions, notably due to the stigma associated with dementia. This study sought to understand pathways to entering...

Background Associations of common infections with Alzheimer’s disease have been reported, but potential mechanisms underlying these relationships are unclear. A hypothesised mechanism is amyloid‐beta (Aβ) aggregation as a defense mechanism in response to infection, with subsequent tau accumulation. However, no studies have assessed associations of...

Background Accelerated epigenetic ageing has been associated with various age‐related health outcomes, but its relevance for dementia risk prediction is unclear. We investigated whether accelerated midlife epigenetic age associates with poor later‐life brain health. Methods Participants were 230 individuals from Insight 46, drawn from the 1946 Bri...

Background With an aging population, it is essential to identify subtle features of brain pathology – both neurodegenerative and vascular – at an early stage, which may predict risk of future decline. We used diffusion MRI (dMRI) to assess grey matter cortical microstructure and investigate associations with 1) Alzheimer’s disease (AD) pathology an...

Background Cognitive assessments are essential for detecting and monitoring cognitive changes in neurological populations. Compared to standard pen‐and‐paper tests, online cognitive tasks offer a more accessible, scalable, repeatable and cost‐effective approach to assessment. Cognitron is an online cognitive assessment platform with previously demo...

Background Sleep and circadian disruption are associated with increased dementia risk, yet the mechanism remains poorly understood. We examined the relationship between night/shift working in the fourth decade and late‐life brain health. We explored whether significant relationships were mediated by life course factors including cardiovascular risk...

Background Dementia‐related biomarkers can detect pathology years before clinical diagnostic criteria are met. Understanding the relationship between biomarkers and early cognitive changes is crucial as disease‐modifying therapies may have maximum benefits when delivered early. We aimed to demonstrate the utility of remote computerised cognitive te...

Increasing evidence links circadian and sleep disruptions with depression, though whether they are causally related remains unclear. This study used Mendelian randomization (MR) with exposures instrumented using genome-wide genetic variants and data from the UK Biobank (n=408 480; mean age=56.9 years) to explore causal associations between circadia...

While the associations of mid-life cardiovascular risk factors with late-life white matter lesions (WMH) and cognitive decline have been established, the role of cerebral haemodynamics is unclear. We investigated the relation of late-life (69–71 years) arterial spin labelling (ASL) MRI-derived cerebral blood flow (CBF) with life-course cardiovascul...

INTRODUCTION People with dementia may benefit from psychological therapies for depression or anxiety, but evidence of their effectiveness in atypical dementia is limited. METHODS Using electronic health‐care records of > 2 million people who attended psychological therapy services in England between 2012 and 2019, we examined pre–post therapy symp...

Background: Little is known about the effect of persistent financial adversity across adulthood on cognitive ageing, and whether these impacts vary based on sex, childhood socioeconomic circumstances (SEC) and genetic risk. Methods: Using data from the 1946 Birth cohort study (N=2,759), with extensive data spanning over 70 years, as well as an embe...

Accelerated long-term forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (e.g. minutes) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease pathology, and how...

BACKGROUND: Alzheimer's disease-related biomarkers detect pathology years before symptoms emerge, when disease-modifying therapies might be most beneficial. Remote cognitive testing provides a means of assessing early changes. We explored the relationship between neurodegenerative biomarkers and cognition in cognitively normal individuals. METHODS:...

INTRODUCTION: Online assessments are scalable and cost-effective for detecting cognitive changes, especially in elderly cohorts with limited mobility and higher vulnerability to neurological conditions. However, determining the uptake, adherence, and usability of these assessments in older adults, who may have less experience with mobile devices is...

Background and objectives: The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females...

Purpose This study examines how different forms of social isolation, such as living alone, lack of community engagement, and unemployment, are associated with mental health in mid-life (ages 42-46), a life stage often overlooked when examining the impacts of social isolation. Methods Using longitudinal data (1999-2016) from two British birth cohor...

INTRODUCTION Limited observational windows lead to conflicting results in studies examining educational differences in Alzheimer's disease and related dementias (ADRD) risk, due to observational window bias relative to onset of accelerated cognitive decline. This study tested a novel model to address observational window bias and tested for the pre...

Anticholinergic medication use is associated with cognitive decline and incident dementia. Our study, a prospective birth cohort analysis, aimed to determine if repeated exposure to anticholinergic medications was associated with greater decline, and whether decline was reversed with medication reduction. From the Medical Research Council (MRC) Nat...

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...

Background Autistic people are disproportionately likely to experience premature mortality and most mental and physical health conditions. We measured the incidence of diagnosed conditions accounting for the most disability-adjusted life years in the UK population according to the Global Burden of Disease study (anxiety, depression, self-harm, harm...

Background The emotional impact of the coronavirus disease 2019 (COVID-19) pandemic on people with dementia has been quantified. However, little is known about the impact of change in home-care use owing to the pandemic. Objective To determine the longitudinal association between dementia, change in home-care use, and depressive symptoms during th...

Background Hearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer’s disease and cerebrovascular disease influence these relationships, is unclear. Methods Data from 287 adults born i...

Background Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). Methods Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent R...

Background Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. Aim We investigated associations between carotid atherosclerosis...

APOE genotype is the strongest genetic risk factor for late onset Alzheimer's disease, with the ϵ2 and ϵ4 alleles decreasing and increasing risk relative to the ϵ3 allele, respectively. Although evidence has been conflicting, several common infections have been associated with Alzheimer's disease risk, and interactions by APOE ϵ4 carriage have also...

Background Psychological therapies can be effective in reducing symptoms of depression and anxiety in people living with dementia (PLWD). However, factors associated with better therapy outcomes in PLWD are currently unknown. Aims To investigate whether dementia-specific and non-dementia-specific factors are associated with therapy outcomes in PLW...

Objective:Social health (SH) markers, including marital status, contact frequency, network size, and social support, have been linked with increased cognitive capability. However, the underlying mechanisms remain poorly understood. We aim to investigate whether depression symptoms and inflammatory biomarkers mediate associations between SH and cogn...

Objective:The recognition of dementia as a multifactorial disorder encourages the exploration of new pathways to understand its origins. Social health might play a role in cognitive decline and dementia, but conceptual clarity is lacking and this hinders investigation of associations and mechanisms. Social health might provide a new perspective on...

Background Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person’s risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46—a multi-phase longitudina...

INTRODUCTION We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population‐based studies. METHODS We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and ou...

Background Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potent...

Background Sleep disturbance is associated with an increased risk of developing Alzheimer’s disease, yet the relationship between sleep metrics and brain pathology remains poorly understood. Complementing ‘traditional’ metrics such as total sleep time (TST) and sleep efficiency (SE), the midpoint of sleep, interdaily stability and intradaily variab...

Background In Alzheimer’s disease, early amyloid‐β and tau deposition may have differential downstream effects on synaptic function and neuronal loss in a stage‐dependent manner. Amyloid‐related synaptic changes are thought to precede tau accumulation, which starts in the medial temporal lobe before propagating and leading to neurodegeneration. We...

Background We assess if, and at which ages during 30 years of adulthood, undertaking leisure time physical activity (LTPA) is associated with brain health at age 70, and to what extent brain health metrics explain the positive association between LTPA and later‐life cognition. Method Participants from the British 1946 birth cohort prospectively re...

Background We investigated imaging biomarkers of Aβ and neurodegeneration in relation to tau‐PET Braak stage in a preclinical birth cohort. Method Cognitively normal individuals enrolled in Insight 46, the neuroimaging sub‐study of the MRC National Survey of Health and Development (1946 British birth cohort), were scanned on combined PET/MR with [...

Background Earlier menopause age associates with poorer cognitive performance post‐menopause, but links with dementia risk are mixed and the potential mechanisms underlying such associations are unclear. Few studies have examined the relationship between menopause age and later‐life brain health. Method Our study included 126 women from Insight 46...

Background Social health (SH) markers, including marital status, contact frequency, network size, and social support, have been linked with increased cognitive capability. However, the underlying mechanisms remain poorly understood. We aim to investigate whether depression symptoms and inflammatory biomarkers mediate associations between SH and cog...

Background Primary care psychological therapy services can be effective in reducing symptoms of depression and anxiety in people living with dementia (PLWD) and are recommended in national guidelines (e.g., NICE, UK). However, it is currently unknown which factors are associated with better psychological therapy outcomes in PLWD. Method National l...

Background Evidence for a role of common infections in neurodegenerative and cerebrovascular diseases is conflicting, and the extent to which pathogen exposure associates with subclinical imaging markers of these diseases is unclear. We aimed to investigate associations between a panel of serological measures characterising exposure to common patho...

Background Many studies of memory in older adults report a sex difference, usually with female participants scoring slightly better than males. These sex differences may be partially due to the content of the tests, with some content being more memorable to males or females (https://doi.org/10.1093/ARCLIN/ACAC102). We investigated whether male and...

Background Cognitive decline in older age has significant health, economic and social consequences and there is evidence that financial adversity might play a role. Financial adversity, for many, is not an acute but a chronic stressor. However, little is known about the effect of persistence exposure to financial adversity across the lifecourse on...

Background In older adults, exposure to area disadvantage is associated with poorer cognitive performance, smaller whole brain and hippocampal volumes and cardiovascular risk. However, there is little research on the timing, accumulation and change in exposure to area disadvantage. This study aimed to investigate whether exposure to area disadvanta...

Background Depression and anxiety are well recognised as risk factors for dementia and poorer cognitive outcomes. However, considerably less is known about the relationship between quality of life and cognitive function over time. Quality of life is not simply the absence of mental health problems, but instead is a related but distinct construct. I...

Background White matter hyperintensity volume (WMHV) is a presumed marker of cerebrovascular disease associated with ageing, Alzheimer’s disease (AD) and vascular dementia. Higher baseline WMHV is associated with increased brain atrophy rate, with disproportionate effects in the hippocampus – a region affected early in AD. Understanding the relatio...

Background Accelerated Long‐term Forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease path...

Background We investigated imaging biomarkers of Aß and neurodegeneration in relation to tau‐PET Braak stage in a preclinical birth cohort. Method Cognitively normal individuals enrolled in Insight 46, the neuroimaging sub‐study of the MRC National Survey of Health and Development (1946 British birth cohort), were scanned on combined PET/MR with [...

Background Cardiovascular and cerebrovascular pathology may accelerate brain aging and cognitive decline. Structural cerebrovascular imaging biomarkers, such as white matter hyperintensities, reflect mostly irreversible accumulated damage. In contrast, cerebral blood flow (CBF), measured with arterial spin labelling (ASL) perfusion MRI, is a potent...

Objective To investigate the accumulation of adversities (duration of exposure to any, economic, psychosocial) across the lifecourse (birth to 63 years) on cognitive function in older age, and the mediating role of mental health. Design National birth cohort study. Setting Great Britain. Participants 5362 singleton births within marriage in Engl...

Background and Objectives Unprecedented social restrictions during the COVID-19 pandemic have provided a new lens for considering the inter-relationship between social isolation and loneliness in later life. We present these inter-relationships before and during the COVID-19 restrictions and investigate to what extent demographic, socio-economic, a...

Background Social health markers, including marital status, contact frequency, network size, and social support, have shown associations with cognition. However, the underlying mechanisms remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. Metho...

Background Previous research has shown that people who have been diagnosed autistic are more likely to die prematurely than the general population. However, statistics on premature mortality in autistic people have often been misinterpreted. In this study we aimed to estimate the life expectancy and years of life lost experienced by autistic people...

We investigate associations between normal-appearing white matter microstructural integrity in cognitively normal ∼70-year-olds and concurrently measured brain health and cognition, demographics, genetics and life course cardiovascular health. Participants born in the same week in March 1946 (British 1946 birth cohort) underwent PET-MRI around age...

There is growing evidence of the impact of informal caregiving on adolescent mental health, and its role is often hidden unintentionally or intentionally, which may hamper early identification and support for young informal caregivers. However, the quantitative evidence regarding household factors relating to informal caregiving has mostly been bas...

Introduction: In this study we examine whether social health markers measured at baseline are associated with differences in cognitive capability and in the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. Methods: We applied an integrated data analysis approach to 16,858 participants...

Introduction: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. Methods: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and o...

Background: There is evidence for a cumulative effect of adversities on mental health, however, less is known on the accumulating duration of exposure to adversity across the lifecourse on mental health in older adults. Methods: Using data from the 1946 British birth cohort study (N = 2745), we examined associations between the accumulation of a...

Background: Public restriction and school closure policies during the pandemic may have long-term effects on adolescents' mental health, and adolescents' feelings and needs may change as the pandemic progresses. This study was conducted to explore the network structure and differences in emotional and behavioral problems (EBPs), loneliness, and su...

Background and Objectives: Unprecedented social restrictions during the COVID-19 pandemic have provided a new lens for considering the inter-relationship between social isolation and loneliness in later life. We present these inter-relationships before and during the COVID-19 restrictions and investigate to what extent demographic, socio-economic,...

Background Determining Aβ‐PET status is crucial for Alzheimer’s disease trials. Standard uptake value ratio (SUVR) using a reference region is a common semi‐quantitative technique. Sex differences in regional blood flow and white matter (WM) could impact SUVR differentially depending on the reference region. It is important to understand how method...

Background Peripheral hearing impairment has been proposed as a risk factor for dementia. However, the relationship between hearing ability, neurodegeneration and cognitive decline, and the extent to which pathological processes associated with increased risk of specific causes of dementia, such as β‐amyloid and small vessel disease, influence thes...

Background Subjective Cognitive Decline (SCD) may represent the onset of cognitive decline before impairment on standard cognitive tests occurs (Jessen et al., 2014). Previous cross‐sectional studies were shown to have limited ability to capture objective differences in cognitive performance between groups with and without SCD (Cacciamani et al., 2...

Aims: People with depression are up to 72% more at risk to develop cardiovascular disease (CVD) in their lifetime. Evidence-based psychotherapies are first-line interventions for the treatment of depression and are delivered nationally in England through the National Health Service via the Improving Access to Psychological Therapy (IAPT) primary c...

Background Growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-te...

Background: Autism has long been viewed as a paediatric condition, meaning that many autistic adults missed out on a diagnosis as children when autism was little known. We estimated numbers of diagnosed and undiagnosed autistic people in England, and examined how diagnostic rates differed by socio-demographic factors. Methods: This population-ba...

Objectives: Associations between age at menopause and cognition post-menopause are examined to determine whether relationships are stronger for certain cognitive domains. Study design: Women from the Medical Research Council National Survey of Health and Development and its neuroscience sub-study, Insight 46, were included if they had known age...

Background Identifying blood-based signatures of brain health and preclinical pathology may offer insights into early disease mechanisms and highlight avenues for intervention. Here, we systematically profiled associations between blood metabolites and whole-brain volume, hippocampal volume, and amyloid-β status among participants of Insight 46—the...

Background To assess how timing, frequency and maintenance of being physically active, spanning over 30 years in adulthood, is associated with later-life cognitive function. Methods Participants (n=1417, 53% female) were from the prospective longitudinal cohort study, 1946 British birth cohort. Participation in leisure time physical activity was r...

Purpose Existing evidence on the mental health consequences of disadvantaged areas uses cross-sectional or longitudinal studies with short observation periods. The objective of this research was to investigate this association over a 69-year period. Methods Data were obtained from the MRC National Survey of Health and Development (NSHD; the Britis...

Despite growing concerns in the UK about social isolation, there remains a lack of evidence on the extent and time trends of social isolation from longitudinal, population-based studies. There is also little research that assesses the multiple domains of social isolation across the lifecourse and between generations in a holistic way accounting for...

We aim to assess how the timing of being physically active in adulthood is associated with later‐life cognitive function; and estimate to what extent these effects are explained by pathways including earlier life influences, cardiovascular and mental health. Data from participants (n = 1417, 53% female) in the British 1946 birth cohort were include...

Consistent patterns of reduced cortical thickness (so‐called signature regions) have been identified in early Alzheimer’s disease (AD), including in the pre‐dementia stages, but studies investigating the pathological underpinnings and cognitive consequences of longitudinal changes in these regions have been limited. 337 cognitively normal participa...

Objective The recognition of dementia as a multifactorial disorder encourages the exploration of new pathways to understand its origins. Social health might play a role in cognitive decline and dementia, but conceptual clarity is lacking and this hinders investigation of associations and mechanisms. The objective is to develop a conceptual framewor...

Background Meta-analyses support an association between anxiety in older adulthood and dementia. The aim of this study was to use routinely collected health data to test whether treatment of anxiety disorders through psychological intervention is associated with a lower incidence of dementia. Methods In this prospective cohort study, data from nat...

Introduction: Although APOE ε 4 allele carriage confers a risk of coronary disease, its persistence in human populations might be explained by certain survival advantages (antagonistic pleiotropy) . Hypothesis: Combining data from two British cohorts– the 1946 National Survey of Health and Development (NSHD) and Southall and Brent Revised (SABRE)–w...

We had previously identified visual impairment increasing risk of incident dementia. While a bi-directional vision-cognition association has subsequently been proposed, no study has specifically examined the longitudinal association between dementia and incidence of clinically defined visual impairment. In this territory-wide community cohort study...

Background Carriage of the ancestral APOE ε4 allele confers a risk of developing Alzheimer's and coronary artery disease, but its persistence in human populations also suggests some potential survival advantages. To date it remains unclear whether APOE ε4 carriage independently associates with a better or worse long-term cardiac phenotype. Purpose...

Aim To synthesise evidence regarding the association between positive psychological constructs (PPCs) and cognitive function in adults aged 50+. Methods Literature searches: Medline, PsycINFO, and Scopus (inception to February 2022). Studies were included if they reported on the association between at least one PPC and one objective measure of cog...

Background Depression and anxiety are common and deleterious in people living with dementia (PLWD). It is currently unknown whether routinely provided psychological therapy can help reduce these symptoms in PLWD. This study aimed to investigate improvements in depression and anxiety symptoms over the course of therapy offered in primary care psycho...

Few studies can address how adulthood cognitive trajectories relate to brain health in 70-year-olds. Participants (n=468, 49% female) from the 1946 British birth cohort underwent 18F-Florbetapir PET/MRI. Cognitive function was measured in childhood (age 8 years) and across adulthood (ages 43, 53, 60-64 and 69 years) and was examined in relation to...

Valid and reliable life-course and cross-cohort comparisons of psychological distress are limited by differences in measures used. We aimed to examine adulthood distribution of symptoms and cross-cohort trends by equating the scales of psychological-distress measures administered in the 1946, 1958, and 1970 British birth cohorts. We used data from...

We examined associations between structural and functional aspects of social health, and subsequent trajectories of cognitive capability (memory, executive functioning, and processing speed). Using data from 16,858 participants (mean age 65.8 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Stu...

Background Using the British 1946 birth cohort we previously estimated life course paths to the Addenbrooke’s Cognitive Examination (ACE-III). Objective We now compared those whose ACE-III scores were expected, worse and better than predicted from the path model on a range of independent variables including clinical ratings of cognitive impairment...