Archana Singh-Manoux

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• PhD
• Professor at French Institute of Health and Medical Research

Importance Epidemiological studies suggest that lifestyle factors are associated with risk of dementia. However, few studies have examined the association of diet and waist to hip ratio (WHR) with hippocampus connectivity and cognitive health. Objective To ascertain how longitudinal changes in diet quality and WHR during midlife are associated wit...

Background Data from high‐income countries (HICs) suggest a decline in age‐specific incidence rates of dementia. However, this has happened primarily in HICs, with low‐ and middle‐ income countries (LMICs) facing two main challenges: a higher burden of risk factors and, in general, a faster ageing population. Most people with dementia live in LMICs...

Background The progressive nature of dementia and the complex needs means that people living with dementia require tailored approaches to address their changing care needs over time. These include physical multimorbidity, psychological, behavioural, and cognitive symptoms and possible risks arising from these and helping family caregivers. However,...

Background The 2020 Lancet Commission on dementia prevention, intervention and care estimated that up to 40% of dementia cases could be prevented by tackling 12 potentially modifiable risk factors, namely less education, hearing loss, hypertension, physical inactivity, diabetes, social isolation, excessive alcohol consumption, air pollution, smokin...

Background Our authors from around the world met to summarise the available knowledge, decide which potentially modifiable risk factors for dementia have compelling evidence and create the most comprehensive analysis to date for potentially modifiable risk factors to inform policy, give individuals the opportunity to control their risks and generat...

Background Cerebrovascular reactivity (CVR) is implicated in the progression of dementia, though the underlying mechanisms is not understood. This study examines the relationships between CVR and brain structure and cognitive decline, moderated by mid‐life dementia risk. Method 163 participants from the Whitehall‐II cohort underwent neuropsycholog...

Objective We hypothesise that subclinical myocardial injury during midlife, indexed by increases in cardiac troponin I, is associated with accelerated cognitive decline, smaller structural brain volume, and higher risk of dementia. Design Longitudinal cohort study Setting Civil service departments in London (Whitehall II study) Participants 5985 pa...

Background The trajectories of anthropometric and body composition measures (important predictors of diabetes) are rarely explored before diabetes diagnosis. Our study aimed to compare trajectories of fat mass (FM), fat-free mass (FFM), body mass index (BMI), and waist circumference (WC) preceding type 2 diabetes mellitus (T2DM) to aging trajectori...

Introduction: Early-onset dementia (EOD) is defined as dementia diagnosed before age 65. While much is known about late-onset dementia (LOD), research on EOD is scarce. The Dementia Risk Pooling Project (DRPP) harmonized data from nine community-based prospective studies, including under-represented racial/ethnic groups. We hypothesized that EOD in...

Introduction: Apolipoprotein E ( APOE ) is a glycoprotein that mediates and regulates lipid transport and uptake. The APOE e4 allele is associated with increased risk of mortality and Alzheimer’s Disease and related dementias. It has been suggested that the APOE e2 allele is associated with increased survival and serves as a protective factor for c...

Introduction: Dementia cases in the US are projected to nearly double from 5.3 million in 2019 to 10.5 million by 2050. Research has suggested that 41% of US dementia cases may be prevented by eliminating several specific modifiable risk factors. Still, few studies examine risk factor variation between midlife and late-life. Previous studies have a...

Background The contribution of modifiable risk factors to social inequalities in dementia, observed in longitudinal studies, remains unclear. We aimed to quantify the role of cardiovascular health factors, assessed using Life's Essential 8 (LE8) score, in mediating social inequalities in incidence of dementia and, for comparison, in incidence of st...

Background Several risk prediction equations exist for the incidence of Alzheimer’s Disease and related dementias (ADRD); however, current equations are based on studies of older individuals, with limited follow‐up time and covariates, and have generally not performed well in external validation. The aim of this study is to develop a novel dementia...

Background Cerebrovascular biomarkers such as cerebrovascular reactivity (CVR) have previously been associated with episodic memory. However, the relationship between memory and regional CVR within the hippocampus is not well studied. Moreover, whether this association is affected by hippocampal volume remains to be investigated. This study investi...

Background Machine learning models have been used to create accurate prediction models for dementia. However, many suffer from overfitting and external validation often results in decreased performance. Pooling data from various sources for model training can improve the generalizability of prediction models. We show here a prediction model for dem...

Background The sources of inter‐ and intra‐individual variability in age‐related cognitive decline remain poorly understood. We examined the association between 20‐year trajectories of cognitive decline and multimodal brain structure and morphology in older age. Method We used the Whitehall II Study, an extensively characterised cohort with 3T bra...

Background: Epidemiological studies suggest lifestyle factors may reduce the risk of dementia. However, few studies have examined the association of diet and waist-to-hip ratio with hippocampus connectivity. Methods: In the Whitehall II Imaging Sub-study, we examined longitudinal changes in diet quality in 512 participants and waist-to-hip ratio in...

INTRODUCTION We first examined the role of age at cardiovascular disease (CVD) onset for incident dementia, and then examined whether lifestyle factors at guideline‐recommended levels in individuals with CVD mitigates dementia risk. METHODS We used population‐based data (Whitehall II: n = 10,308/baseline 1985–1988/examinations every 4–5 years). Li...

Background Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia. Methods Obesity (body mass index ≥ 30 kg/m 2) and poor metabolic health (≥ 2 of elevated seru...

Background: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. Methods: In 3 European cohorts (NutriNet-...

Background: Current dementia risk scores have had limited success in consistently identifying at-risk individuals across different ages and geographical locations. Objective: We aimed to develop and validate a novel dementia risk score for a midlife UK population, using two cohorts: the UK Biobank, and UK Whitehall II study. Methods: We divide...

Background High-sensitivity cardiac troponin testing is a promising tool for cardiovascular risk prediction, but whether serial testing can dynamically predict risk is uncertain. We evaluated the trajectory of cardiac troponin I in the years prior to a cardiovascular event in the general population, and determine whether serial measurements could t...

Importance: The clinical value of current multifactorial algorithms for individualized assessment of dementia risk remains unclear. Objective: To evaluate the clinical value associated with 4 widely used dementia risk scores in estimating 10-year dementia risk. Design, setting, and participants: This prospective population-based UK Biobank coh...

Introduction: The association of lipids with dementia remains a subject of debate. Using data from 7,672 participants of the Whitehall II prospective cohort study, we examined whether timing of exposure, length of follow-up, or sex modifies this association. Methods: Twelve markers of lipid levels were measured from fasting blood and eight among...

The increasing number of people with dementia globally illustrates the urgent need to reduce dementia's scale and impact. Lifetime social participation may affect dementia risk by increasing cognitive reserve, and through brain maintenance by reducing stress and improving cerebrovascular health. It may therefore have important implications for indi...

Background Alzheimer’s disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us...

Background: The extent to which education explains variations in sex differences in cognitive function between countries at different levels of economic development is unknown. We examined the role of education in sex differences in four cognitive domains in high- and middle-income countries. Methods: Analyses were based on 70,846 participants,...

Background: Research on frailty, a major contributor to heterogeneity in health, is undertaken on older adults although the processes leading to frailty are likely to begin earlier in the life course. Using repeat data spanning 25 years, we examined changes in physical and mental functioning before the onset of frailty, defined using Fried's frail...

Recent data suggest a temporal trend in decline in functional limitations in older adults but whether this trend extends to the period after the 8th decade of life remains unclear. We examined change in prevalence of limitations in activities and instrumental activities of daily living (ADL and IADL) between 2008 and 2015 among adults of 60–94 year...

Background Sleep duration has been shown to be associated with individual chronic diseases but its association with multimorbidity, common in older adults, remains poorly understood. We examined whether sleep duration is associated with incidence of a first chronic disease, subsequent multimorbidity and mortality using data spanning 25 years. Meth...

Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing...

Background There is consistent evidence of social inequalities in dementia but the mechanisms underlying this association remain unclear. We examined the role of smoking in midlife in socioeconomic differences in dementia at older ages. Methods Analyses were based on 9951 (67% men) participants, median age 44.3 [IQR=39.6, 50.3] years at baseline i...

Background Age is the strongest risk factor for dementia and there is considerable interest in identifying scalable, blood-based biomarkers in predicting dementia. We examined the role of midlife serum metabolites using a machine learning approach and determined whether the selected metabolites improved prediction accuracy beyond the effect of age....

Background: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher r...

This cross-sectional study analyzes 10-year trends in sales of Alzheimer disease drugs in France compared with trends in the UK, Spain, and Germany.

Background Heavy alcohol consumption increases the risk of several chronic diseases. In this multicohort study, we estimated the number of life-years without major chronic diseases according to different characteristics of alcohol use. Methods In primary analysis, we pooled individual-level data from up to 129,942 adults across 12 cohort studies w...

Objective: Previous research suggests an inconsistent association between Metabolic syndrome (MetS) and incident dementia. We examined the role of number of MetS components and age at their assessment for incident dementia. Research design and methods: MetS components (fasting glucose, triglycerides, waist circumference, blood pressure, and HDL ch...

Objective: To elaborate a new algorithm to establish a standardized method to define cuff-offs for CSF biomarkers of Alzheimer's disease (AD) by validating the algorithm against CSF classification derived from PET imaging. Methods: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cut-offs for CSF amyloid-β...

Afin de comprendre le rôle de l’alimentation sur les trajectoires de déclin cognitif et le risque de démences, des méthodes d’épidémiologie nutritionnelle, visant à appréhender l’alimentation dans son entier, ont été appliquées au champ de la neuropsychiatrie depuis une dizaine d’années. Les résultats de ces études épidémiologiques suggèrent un lie...

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonan...

Immune system and blood brain barrier (BBB) dysfunction are implicated in the development of Alzheimers disease and other dementias, but their causal role remains unknown. We performed Mendelian randomization (MR) for 43,643 immune system and BBB-related biomarkers and identified 126 potential causal risk factors for dementias. A phenome-wide analy...

Background Aortic pulse wave velocity is a noninvasive measure of aortic stiffness and arterial aging. Its current value in cardiovascular risk estimation practice is unknown. We aimed to establish whether aortic pulse wave velocity identified individuals with higher risk of incident major adverse cardiovascular events and improved performance of t...

Objective To examine the association of midlife and late life multimorbidity, including severity of multimorbidity, with incident dementia. Design Prospective cohort study. Setting Civil service departments in London (Whitehall II study, study inception in 1985-88). Participants 10 095 participants, aged 35 to 55 at baseline. Main outcome measu...

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis a...

This cohort study examines major surgical admissions and quality of life.

Background: Cognitive dysfunction is common in haemodialysis patients but whether poor kidney function in the general population is also associated with higher risk of dementia remains unclear. Objective: To examine the association of kidney function with incident dementia in community dwelling older adults. Design: Whitehall II prospective study...

Background Globally, up to 40% of dementia cases may be prevented if several key risk factors, such as low education and obesity, are targeted. This has motivated interest into the development of risk scores that aim to quantify an individual’s risk of developing dementia within a given time frame. However, translation to a clinical setting has bee...

Background Women are more likely to have functional limitations (ie, limitations in activities of daily living) than men, partly due to sex differences in socioeconomic factors. How changes in sex differences in socioeconomic factors in successive birth cohorts have affected functional limitations is unclear. We aimed to examine sex differences in...

Background Women are more likely to have functional limitations than are men, partly because of greater socioeconomic disadvantage. However, how sex differences vary by severity of functional limitations remains unclear. We examined sex differences in functional limitations, with attention to socioeconomic factors and severity of limitations. Meth...

Background Women are more likely to have functional limitations than men, partly due to socioeconomic disadvantage. As much of this research is based on dichotomised measures of limitation, how sex differences vary by level of limitations remains unclear. The aim of our study was to examine sex differences in functional limitations in people born b...

We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96, SD = 5.18, 79% men). We used line...

Objective: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, accordin...

In Reply Dr Gao and colleagues raise 3 concerns regarding the conclusions of our article.¹ First, they want us to consider hearing and visual complications of diabetes. Our study examined the role of age at onset of diabetes in determining risk of dementia rather than the complications of diabetes. Gao and colleagues refer to 2 recent articles show...

Background Globally, some 50 million people had Alzheimer’s disease and related dementias in 2018. China accounts for approximately a quarter of cases. It is estimated that the cost of dementia in China was approximately USD 50 billion in 2010. China’s rapid ageing process is occurring at an earlier stage of economic development than other countrie...

Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. Design Multicohort study with three sets of analyses. Setting United Kingdom, Europe, and the United States. Participants Three associations were examined: cognitive stimulation and dem...

Objectives To examine multiple objective and self-reported measures of motor function for their associations with mortality. Design Prospective cohort study. Setting UK based Whitehall II cohort study, which recruited participants aged 35-55 years in 1985-88; motor function component was added at the 2007-09 wave. Participants 6194 participants...

Introduction: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20-year follow-ups. Methods: In the White...

Background The positive direct relation between stress and the development of cardiovascular disease has increasingly been recognized. However, the link between hypothalamic-pituitary-adrenal (HPA) dysregulation and subclinical cardiovascular disease has not been studied longitudinally. We investigated the relation of diurnal salivary cortisol, as...

Background: Globally, up to 40% of dementia cases may be prevented if several key risk factors, such as low education and obesity, are targeted. This has motivated interest into the development of risk scores that aim to quantify an individual’s risk of developing dementia within a given time frame. However, translation to a clinical setting has be...

Background Evaluation of cardiovascular disease risk in primary care, which is recommended every 5 years in middle-aged and older adults (typical age range 40–75 years), is based on risk scores, such as the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) and American College of Cardiology/American Heart Association Athero...

Background Studies generally use cognitive assessment done at one timepoint to define cognitive impairment in order to examine conversion to dementia. Our objective was to examine the predictive accuracy and conversion rate of seven alternate definitions of cognitive impairment for dementia. Methods In this prospective study, we included participa...

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in im...

Importance: Trends in type 2 diabetes show an increase in prevalence along with younger age of onset. While vascular complications of early-onset type 2 diabetes are known, the associations with dementia remains unclear. Objective: To determine whether younger age at diabetes onset is more strongly associated with incidence of dementia. Design,...

Sleep dysregulation is a feature of dementia but it remains unclear whether sleep duration prior to old age is associated with dementia incidence. Using data from 7959 participants of the Whitehall II study, we examined the association between sleep duration and incidence of dementia (521 diagnosed cases) using a 25-year follow-up. Here we report h...

We characterize the associations of total cerebral small vessel disease (SVD) burden with brain structure, trajectories of vascular risk factors, and cognitive functions in mid-to-late life. Participants were 623 community-dwelling adults from the Whitehall II Imaging Sub-study with multi-modal MRI (mean age 69.96 SD=5.18, 79% men). We used linear...

Background/objectives The mediating role of eating behaviors in genetic susceptibility to weight gain during mid-adult life is not fully understood. This longitudinal study aims to help us understand contributions of genetic susceptibility and appetite to weight gain. Subjects/methods We followed the body-mass index (BMI) trajectories of 2464 adul...

Background It is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart–brain associat...

Serum transthyretin (TTR) may be an early biomarker for Alzheimer’s disease and related disorders (ADRD). We investigated associations of TTR measured at baseline with cognitive decline and incident ADRD and whether TTR trajectories differ between ADRD cases and non-cases, over 22 years before diagnosis. A total of 6024 adults aged 45–69 in 1997–19...

INTRODUCTION: Current prognostic models of dementia have had limited success in consistently identifying at-risk individuals. We aimed to develop and validate a novel dementia risk score (DRS) using the UK Biobank cohort.METHODS: After randomly dividing the sample into a training (n=166,487, 80%) and test set (n=41,621, 20%), logistic LASSO regress...

A Correction to this paper has been published: https://doi.org/10.1038/s41366-021-00770-0

White matter hyperintensities (WMHs) on T2-weighted images are radiological signs of cerebral small vessel disease. As their total volume is variably associated with cognition, a new approach that integrates multiple radiological criteria is warranted. Location may matter, as periventricular WMHs have been shown to be associated with cognitive impa...

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain microstructure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic re...

Background Previous studies have shown an excess risk of Alzheimer's disease and related dementias among women. Education is thought to have a causal association with dementia onset. We aimed to investigate the role of education in influencing sex differences in cognitive ageing. Methods We analysed data from two prospective cohort studies in the...

Introduction The increasing evidence of SARS‐CoV‐2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia. Methods The Alzheimer's Association and representatives from more than 30 countries—with technical guidance from the World Health...

Introduction: The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia. Methods: The Alzheimer's Association and representatives from more than 30 countries-with technical guidance from the World Healt...

Background Approximately 25% of the general population carries at least one ε4 allele of the Apolipoprotein E ( APOE ε4), the strongest genetic risk factor for late onset Alzheimer’s disease. Beyond its association with late-onset dementia, the association between APOE ε4 and change in cognition over the adult life course remains uncertain. This st...

Background Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain str...

The concept of brain maintenance refers to the preservation of brain integrity in older age, while cognitive reserve refers to the capacity to maintain cognition in the presence of neurodegeneration or aging‐related brain changes. While both mechanisms are thought to contribute to individual differences in cognitive function among older adults, the...

Introduction: Conventional risk factors targeted by prevention (e.g., low education, smoking, and obesity) are associated with a 1.2- to 2-fold increased risk of dementia. It is unclear whether having a physical disease is an equally important risk factor for dementia. Methods: In this exploratory multicohort study of 283,414 community-dwelling...

Background Several studies have reported that participating more frequently in leisure activities protects against dementia, possibly by building cognitive reserve or through better vascular health. However, these studies have been highly susceptible to reverse causation bias due to short follow‐up duration. We therefore aimed to examine the associ...

Background Depressive symptoms are related to an increased risk of cognitive decline. Trajectories of depressive symptoms over the lifespan vary between people, but it is unclear whether these differences may exhibit dissociable structural changes in brain white matter and cognitive changes, including reduced executive function. Method In order to...

Background Aortic stiffness, assessed by carotid‐femoral pulse wave velocity (PWV), is closely linked with hypertension, heart disease and stroke. Recent research has suggested that rapid aortic stiffening may also be a risk factor for cognitive decline and dementia. However, the age of onset of this risk and its underlying brain physiology is unkn...

The role of circulating proteins in Alzheimer’s disease and related dementias is unknown. Using a follow-up of two decades, 4953 plasma proteins, and discovery (Whitehall II) and replication cohort (ARIC), we examined plasma proteins associated with cognitive decline rate and dementia. After replication and adjustment for known dementia risk factor...

Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and res...