Sarah Naomi James

University College London | UCL · Department of Primary Care and Population Health (PCPH)

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 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...

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...

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...

Background A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. Methods Participants, born in a single week in 1946 in mainland Britain, have ha...

There is an increasing body of evidence suggesting that vascular disease could contribute to cognitive decline and overt dementia. Of particular interest is atherosclerosis, as it is not only associated with dementia, but could be a potential mechanism through which cardiovascular disease directly impacts brain health. In this work, we evaluated th...

Objective To quantify the independent and interactive associations of amyloid-β (Aβ) and white matter hyperintensity volume (WMHV) – a marker of presumed cerebrovascular disease (CVD) – with rates of neurodegeneration, and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal membe...

Alzheimer’s Disease is more common in women than men. Menopause timing and type have been linked with cognition post‐menopause, but associations with dementia risk are unclear. Within the MRC National Survey of Health and Development (NSHD), childhood cognition predicts later‐life cognition and has largely explained menopause‐cognition associations...

Fixel‐based analysis (FBA) of diffusion MRI allows analysis of brain white matter (WM) tracts with greater specificity than voxel‐based approaches, including measures of microstructural fibre density (FD), macrostructural fibre cross section (FC), and representations of crossing fibres. We use FBA to explore early WM changes associated with amyloid...

Although APOE ε4 carriers are at substantially higher risk of developing Alzheimer’s disease than noncarriers1, controversial evidence suggests that APOE ε4 might confer some advantages, explaining the survival of this gene (antagonistic pleiotropy)2,3. In a population-based cohort born in one week in 1946 (assessed aged 69–71 years), we assessed d...

Longitudinal studies of the relationship between hyperglycemia and brain health are rare and there is limited information on sex differences in associations. We investigated whether glycosylated haemoglobin (HbA1c) measured at ages of 53, 60-64 and 69 years, and cumulative glycemic index (CGI), a measure of cumulative glycemic burden, were associat...

Background Grip strength is an indicator of physical function with potential predictive value for health in ageing populations. We assessed whether trends in grip strength from midlife predicted later-life brain health and cognition. Methods 446 participants in an ongoing British birth cohort study, the National Survey of Health and Development (N...

Objective To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study. Methods Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid...

Background In view of reported associations between high adiposity, particularly in midlife and late-life dementia risk, we aimed to determine associations between body mass index (BMI), and BMI changes across adulthood and brain structure and pathology at age 69–71 years. Methods Four hundred sixty-five dementia-free participants from Insight 46,...

Objective To assess associations between head injury (HI) with loss of consciousness (LOC), ageing and markers of later‐life cerebral pathology; and to explore whether those effects may help explain subtle cognitive deficits in dementia‐free individuals. Methods Participants (n = 502, age = 69–71) from the 1946 British Birth Cohort underwent cogni...

Background The insulin/insulin-like signalling (IIS) pathways, including Insulin-like Growth Factors (IGFs), varies with age. However, their association with late-life cognition and neuroimaging parameters is not well characterised. Methods Using data from the British 1946 birth cohort we investigated associations of IGF-I, -II and IGFBP-3 (measur...

We investigated whether subtle visuomotor deficits were detectable in familial and sporadic preclinical Alzheimer’s disease. A circle-tracing task – with direct and indirect visual feedback, and dual-task subtraction – was completed by 31 individuals at 50% risk of familial Alzheimer’s disease (19 presymptomatic mutation carriers; 12 non-carriers)...

KLOTHO*VS heterozygosity (KL*VSHET+) was recently shown to be associated with reduced risk of Alzheimer’s disease (AD) in APOE*4 carriers. Additional studies suggest that KL*VSHET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-an...

Alzheimer's disease has a preclinical stage when cerebral amyloid-β deposition occurs before symptoms emerge, and when amyloid-β-targeted therapies may have maximum benefits. Existing amyloid-β status measurement techniques, including amyloid PET and CSF testing, are difficult to deploy at scale, so blood biomarkers are increasingly considered for...

Accelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge...

Age is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained...

Cigarette smoking is implicated as a risk factor for dementia, but the underlying mechanisms are poorly understood. In a population‐based sample free of dementia, we examine associations between smoking patterns over the life course and imaging markers associated with dementia. Dementia‐free participants from Insight 46 (n=458, 49% female, age 69‐7...

Mid‐life hypertension is an established risk factor for late‐life cognitive impairment. Whilst previous studies demonstrate mid‐life hypertension is associated with larger white matter (WM) hyperintensity volumes, Differences in normal appearing white matter (NAWM) microstructure may provide an earlier indication of WM injury. In a population‐based...

While APOE‐ε4 carriers are at higher risk of Alzheimer’s disease (AD), there is evidence that APOE‐ε4 may have some beneficial effects across the life‐span, including on cognition. It is unclear how such effects may relate to subtle memory decline during the preclinical phase of AD. Two previous studies reported that APOE‐ε4 carriers recalled objec...

The two commonest contributors to late‐life cognitive impairment are Alzheimer’s (AD) and cerebrovascular disease; these two conditions almost invariably overlap. Understanding the determinants of the pathologies that underpin these conditions and how they interact to influence late‐life brain health is vital for rational risk prevention and for cl...

Word‐finding difficulties are a common early feature of Alzheimer’s disease (AD) and may be detectable during the preclinical stage. However, the relationship between changes in naming ability and accumulation of β‐amyloid pathology is not fully understood, and questions remain about the role of factors such as sex and education. Participants in In...

Alzheimer’s (AD) and cerebrovascular disease are common causes of cognitive impairment in later life and often co‐exist. Understanding how AD and vascular pathologies act independently or together to influence neurodegeneration in later life is important for the development of effective treatments and clinical trial design. 219 cognitively normal p...

We examined cross‐sectional associations between plasma phospho‐tau181 (p‐tau181) and amyloid PET, MRI and cognitive outcomes in Insight 46, a sub‐study of the British 1946 birth cohort. At age 69‐71, participants underwent blood sampling, neurocognitive assessment, and 3T‐MRI with simultaneous 18F‐florbetapir‐PET (yielding amyloid status binarized...

Objective To explore the value of olfactory identification deficits as a predictor of cerebral β-amyloid status and other markers of brain health in cognitively normal adults aged ~ 70 years.Methods Cross-sectional observational cohort study. 389 largely healthy and cognitively normal older adults were recruited from the MRC National Survey of Heal...

Background The insulin/insulin-like signalling (IIS) pathways, including Insulin-like Growth Factors (IGFs), varies with age. However, their association with late-life cognition and neuroimaging parameters is not well characterised. Methods Using data from the British 1946 birth cohort we investigated associations of IGF-I, -II and IGFBP-3 (measur...

The commonest causes of dementia are Alzheimer's disease and vascular cognitive impairment. Although these conditions have been viewed as distinct entities, there is increasing evidence that neurodegenerative and vascular pathologies interact or overlap to cause cognitive decline, and that at least in some cases individuals at risk of cognitive dec...

Introduction: We investigated whether life-course factors and neuroimaging biomarkers of Alzheimer's disease pathology predict reaction time (RT) performance in older adults. Methods: Insight 46 study participants, all born in the same week in 1946 (n = 501; ages at assessment = 69 to 71 years), completed a 2-choice RT task and amyloid beta (Aβ)...

Introduction: Cortical thickness has been proposed as a biomarker of Alzheimer's disease (AD)- related neurodegeneration, but the nature of its relationship with amyloid beta (Aβ) deposition and white matter hyperintensity volume (WMHV) in cognitively normal adults is unclear. Methods: We investigated the influences of Aβ status (negative/positi...

Importance Midlife vascular risk burden is associated with late-life dementia. Less is known about if and how risk exposure in early adulthood influences late-life brain health. Objective To determine the associations between vascular risk in early adulthood, midlife, and late life with late-life brain structure and pathology using measures of whi...

Background The human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of...

Aims/hypothesis Type 2 diabetes, hyperglycaemia and insulin resistance are associated with cognitive impairment and dementia, but causal inference studies using Mendelian randomisation do not confirm this. We hypothesised that early-life cognition and social/educational advantage may confound the relationship. Methods From the population-based Bri...

Objective: To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development. Methods: A total of 502 indivi...

Background Cognitive function may serve as an early indicator of prodromal Alzheimer’s disease (AD). We examined how cognitive measures over the life course are associated with the AD-related biomarkers of amyloid (Aβ) status and whole brain volume in a population-based sample free of dementia and other major neurological disorders. Methods Data w...

Background: Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated w...

Background: Little is known about the link between affective symptoms and cognitive function across the life course. This study aims to investigate whether affective symptoms in adolescence and adulthood predict trajectories of cognitive function from middle to late-adulthood. Methods: Data from the MRC National Survey of Health and Development...

Objective To summarise the incidental findings detected on brain imaging and blood tests during the first wave of data collection for the Insight 46 study. Design Prospective observational sub-study of a birth cohort. Setting Single-day assessment at a research centre in London, UK. Participants 502 individuals were recruited from the MRC Nation...

Background Preterm birth is associated with an increased risk for cognitive-neurophysiological impairments and attention-deficit/hyperactivity disorder (ADHD). Whether the associations are due to the preterm birth insult per se , or due to other risk factors that characterise families with preterm-born children, is largely unknown. Methods We empl...

Preterm birth is associated with heightened risk for attention-deficit/hyperactivity disorder (ADHD)-like symptoms and neurocognitive impairments, including impairments in performance monitoring. Here, we investigate the cognitive and neurophysiological processes from a performance-monitoring task in preterm-born adolescents and examine whether the...

Additional analyses. Appendix A–Excluding preterm-born individuals with a research diagnosis of ADHD from the analysis. Appendix B–Analysis controlling for IQ. Appendix C–Analysis of the males only. Appendix D–Analysis of the age-matched subsample. (DOCX)

Objectives The life course determinants of midlife and later life cognitive function have been studied using longitudinal population-based cohort data, but far less is known about whether the pattern of these pathways is similar or distinct for clinically relevant cognitive state. We investigated this for Addenbrooke’s Cognitive Examination third e...

Background Affective disorders are associated with poorer cognition in older adults; however, whether this association can already be observed in mid-life remains unclear. Aims To investigate the effects of affective symptoms over a period of 30 years on mid-life cognitive function. First, we explored whether timing (sensitive period) or persisten...

A recent study (James et al. 2016) found that attention-deficit/hyperactivity disorder (ADHD) was associated with hypo-arousal, indexed by low electrodermal activity, during a low-demand reaction-time task, which normalized in a fast-incentive condition. We now investigate if (1) autonomic arousal in individuals with ADHD changes over a long testin...

Background: Physical activity interventions are increasingly recognised to help reduce depressive symptoms; however, fatigue and perception of increased energy expenditure, often associated with depression, may be barriers to compliance. Whether this association differs between different ethnicities is unknown. This analysis investigates associatio...

Objective Identifying and recruiting people with early pre-symptomatic Alzheimer’s disease to neuroimaging research studies is increasingly important. The extent to which results of these studies can be generalised depends on the recruitment and representativeness of the participants involved. We now report the recruitment and participation pattern...

Background: Affective problems increase the risk of dementia and cognitive impairment, yet the life course dimension of this association is not clearly understood. We aimed to investigate how affective problems across the life course relate to later-life cognitive state. Methods: Data from 1269 participants from the Medical Research Council Nati...

Preterm birth has been associated with an increased risk for ADHD-like behavioural symptoms and cognitive impairments. However, direct comparisons across ADHD and preterm-born samples on neurophysiological measures are limited. The aim of this analysis was to test whether quantitative EEG (QEEG) measures identify differences or similarities in pret...

Background Whilst preterm-born individuals have an increased risk of developing attention-deficit/hyperactivity disorder (ADHD), and are reported to have ADHD-like attention and arousal impairments, direct group comparisons are scarce. Methods We directly compared preterm-born adolescents ( n = 186) to term-born adolescents with ADHD ( n = 69), an...

Objective: This study investigates whether impairments associated with persistent ADHD-impaired attention allocation (P3 amplitude), peripheral hypoarousal (skin conductance level [SCL]), and adjustment in preparatory state (contingent negative variation [CNV])-reflect enduring deficits unrelated to ADHD outcome or are markers of ADHD remission....