Cohort Profile: Dementia Risk Prediction Project (DRPP)

The Dementia Risk Prediction Project (DRPP) was established to bring together data from 16 longitudinal cohorts of diverse middle-aged and older adults to provide a resource for research of dementia and its vascular and lifestyle risk factors, and develop a dynamic dementia risk prediction model. Sixteen cohorts with participants from 49 of the 50 US states, France, Iceland, England and the Netherlands with baseline exams ranging from 1948 to 2006 were included. Participants were recruited across multiple sites with multiple in-person assessments of clinical, genetic and behavioural risk factors, follow-up of >10 years and ongoing Alzheimer’s disease and related dementias ascertainment. Collectively, there are 119 061 individuals with data available at baseline. The DRPP provides direct access to harmonized individual-level data for 95 134 individuals from 14 of the 16 cohorts. Median baseline age is 59 years (interquartile range: 49–70) with a maximum age at follow-up of >90 years. Frequency of follow-up varies by cohort, with exams occurring every 2–12 years; the number of in-person exams ranges from 2 to 32. To apply for permission to access our data on our secure portal, please visit our website at drpp.northwestern.edu. Dementia is a major public health problem; despite declines in the age-specific incidence, its prevalence will continue to increase due to ageing of populations.1–3 Worldwide, an estimated 55 million people are living with Alzheimer’s or other dementias and, as the population continues to age, this number is expected to rise to 78 million in 2030 and 139 million in 2050.4 The number of individuals living with dementia is increasing, leading to greater burden of morbidity, caregiving needs and healthcare utilization. Although we have made strides in reducing mortality and morbidity from other diseases such as cardiovascular disease, stroke and cancer, the proportion of deaths due to dementia has increased by >145% in the USA in the past 20 years5 and is presently the seventh leading cause of death among all diseases globally.4 Dementia encompasses a set of complex chronic disorders with neuropathology that is often ‘mixed’, with contributions from vascular and neurodegenerative pathologies. Specifically, >70% of Alzheimer’s disease and related dementias (ADRD) cases are estimated to have mixed vascular and Alzheimer’s disease (AD) pathology.6 Further, many ADRD risk factor profiles are stronger predictors in midlife than in late life. Therefore, the risk factor profiles are also complex and variable. Although non-modifiable risk factors such as age, sex, race/ethnicity and apolipoprotein E (APOE) genotype impact dementia risk, it has been estimated that 40% of all dementia cases could be prevented or delayed by targeting modifiable risk factors.7 Modifiable risk factors that contribute to the largest proportion of dementia cases include midlife hearing status, diabetes, midlife hypertension, midlife obesity, depression, physical inactivity, smoking, low education, excessive alcohol consumption, head injury and air pollution.7 For example, an analysis of 7878 Japanese American men in the Honolulu-Asia Aging Study (HAAS) found that untreated midlife hypertension alone contributes to 27% of dementia risk.8 In a review of English-language systematic reviews and meta-analyses, these modifiable risk factors combined contributed to 54.1% of the population attributable risk for dementia in the USA and 50.7% worldwide.9 Several studies have examined longitudinal trajectories as well as the visit-to-visit variability of risk factors in the long prodrome preceding ADRD diagnosis.10,11 Among them, trajectories of blood pressure, body mass index (BMI) and cholesterol have been studied extensively.10,12,13 Interestingly, most of those studies show an age-dependent pattern in the association between these risk factors and cognitive impairment.12 For example, in a paper using data from Whitehall II participants, different BMI trajectories were identified among people who ultimately developed ADRD as compared with those who did not.13 Similarly, collaborators in the HAAS and the Atherosclerosis Risk in Communities Study (ARIC) have both demonstrated that specific blood pressure trajectories in mid- to late life are related to incident dementia.14,15 Importantly, these mid-life risk factor trajectories are also related to estimated brain amyloid deposition, signalling that these same risk factors impact AD in addition to vascular forms of dementia.16 These findings and others like them highlight the importance of considering the life-course trajectory of vascular risk factors rather than current or cross-sectional blood pressure or weight to define one’s ADRD risk, especially in late life. Young and midlife risk exposures, interactions of various risk factors with each other and ageing all contribute to the risk of developing dementia. This level of complexity motivates comprehensive and dynamic risk assessment using well-characterized cohort studies with available data from multiple time points to develop rich, robust risk prediction models. Retrospective harmonization of a multiple of such studies facilitates sufficient statistical power, provides the ability for cross-validation or replication and increases heterogeneity of the pooled sample.17 None of the prior dementia risk models has incorporated longitudinal risk factor patterns.18 Longitudinal risk factor patterns, as discussed above, are highly associated with the risk of dementia later in life independently of baseline risk factor levels.10,12,13 It is likely that using risk factor trajectories will improve our ability to identify individuals at high risk of future ADRD and discriminate between high-risk and low-risk individuals to direct resources and preventive interventions at individuals who would benefit most within our resource-constrained healthcare systems. The Dementia Risk Prediction Project (DRPP) was thus formed to create a rigorously harmonized data set for developing and validating an accurate and personalized, dynamic dementia risk prediction model that incorporates longitudinal risk factor measurements and easily updates as new measurements are accrued. Additionally, the DRPP data will also be made accessible to approved researchers to collaborate and conduct research that may not be possible in smaller, individual cohorts. The DRPP is a pooled consortium initially founded with individual-level data from 16 well-characterized prospective, natural history cohorts of diverse middle-aged and older adults (Table 1). Cohorts were included if they performed multiple in-person assessments of vascular risk factors and had a follow-up of >10 years and ongoing ADRD ascertainment. Table 1 briefly describes each the main research focus, location, size, baseline exam year and length of follow-up of each cohort. Characteristics of the 14 derivation studies and 2 validation studies Includes individuals aged ≥18 years. External validation study. The DRPP includes four European cohorts, each based in different countries. The Three-City Study (3C) includes individuals from three French cities: Bordeaux, Dijon and Montpellier; 61% of baseline participants were female.19 The Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) is a single-centre study of older men and women (58% female at baseline) in Iceland.20 The Rotterdam Study (RS) is an ongoing population-based study in the city of Rotterdam, the Netherlands, that recruited participants aged ≥45 years into three cohorts (RS-I, RS-II, RS-III).21 The Whitehall II study is an ongoing longitudinal study of British civil servants based in London at recruitment to the study; at baseline, the study population was 89% White and 33% female.22 The remaining 12 cohorts are based in the USA, some are single-centre and others are larger, multicentre studies. The ARIC is based in North Carolina, Mississippi, Minnesota and Maryland; participants aged 45–65 years (55% female and 27% non-White) were recruited at the first visit between 1987 and 1989 and it is ongoing.23 The Cardiovascular Health Study (CHS) is based in California, Maryland, North Carolina and Pennsylvania, and consisted of 58% women, 16% African American and 31% with cardiovascular disease (CVD) at baseline.24 The HAAS is based in Hawaii and includes older Japanese American men.25 The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicentre study based in New York, Maryland, Illinois, California, Minnesota and North Carolina; at baseline, the study population was 38% White, 28% African American, 23% Hispanic and 11% Asian.26 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) includes participants from all 48 contiguous states; 55% are women, 41% are Black and 56% are from the Stroke Belt region.27 The Sacramento Area Latino Study on Aging (SALSA) recruited a representative sample of individuals of predominantly Mexican heritage residing in Sacramento, California.28 The final six US cohorts include the original Framingham Heart Study (FHS)29 and five of its offshoots [Offspring (FOS), New Offspring Spouse (NOS), Generation 3 (Gen 3), Omni and Omni 2], all based in Framingham, Massachusetts and its surrounding towns. The FHS recruited the original participants for the baseline exam in 1948. The FOS started in 1971 and includes the offspring of the original cohort and their spouses. The NOS included the spouse of members of the FOS by 2003 if they were never included prior and if at least two of their children participated in the Gen 3, a third generation of participants recruited in 2002. In 1994 and 2003, two new cohorts (Omni and Omni 2) were included to reflect the increasing diversity of the Framingham community.30 Variables in 14 of the 16 cohorts were harmonized internally by DRPP analysts and the remaining two (RS and 3C) are external cohorts to be used for validation of risk prediction models. Individual-level data are not available for the external cohorts, but the variables have been harmonized to variable definitions of DRPP by local teams and validation analyses will be run in parallel to the core DRPP data at these two external sites. Together in DRPP, the consortium cohort represents 119 061 individuals with baseline data from 49 of 50 US states, France, Iceland, England and the Netherlands. Of these, 86 646 individuals have at least one global cognitive assessment score [DRPP used Mini-Mental State Examination, Cognitive Abilities Screening Instrument, Modified Mini-Mental State Examination (3MSE) and Montreal Cognitive Assessment to harmonize a single global cognitive assessment; more details can be found in the Supplementary Methods S1, available as Supplementary data at IJE online]. The median baseline age was 59 years (IQR: 49–70) with a maximum age at follow-up of >90 years. Baseline data were collected over multiple decades, generations and epochs ranging from 1948 to 2006. This cohort includes 20 188 (21%) individuals who identify as Black, 5348 (6%) Asian, 3746 (4%) Hispanic, 182 (0.2%) Other and 65 567 (69%) White. The two validation cohorts did not collect race and ethnicity data and are therefore not included here. Each individual study has its own follow-up time and exam schedule, and these vary significantly (Figure 1). The DRPP includes data from 1948 through to 2020, with >1 million person-years of follow-up time. The number of exams ranges from two in the AGES-Reykjavik and REGARDS to 32 in the original FHS cohort. Exams were, in most cases, separated by a year or two but, in others, by as many as 12 years. Some cohorts included phone calls between in-person examinations for additional outcome surveillance and cognitive testing. Timing and frequency of risk factor measurement, by cohort. AGES, Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC, Atherosclerosis Risk in Community; APOE, apolipoprotein E; BMI, body mass index; BP, blood pressure; CHS, Cardiovascular Health Study; F/U, follow-up; FHS, Framingham Heart Study; FOS, Framingham Offspring Study; NOS, Framingham New Offspring Spouse; FHS-Gen3, Framingham Heart Study Generation 3; FHS-Omni, Framingham Heart Study Omni; FHS-Omni 2, Framingham Heart Study Omni 2; HAAS, Honolulu Heart Program/Honolulu-Asia aging Study; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SALSA, Sacramento Area Latino Study on Aging; 3C, The Three-City Study; RS, Rotterdam Study; Yr, year. Note: Study exams use the same language as in their original cohort. Unless stated otherwise, Exam 1 or Phase 1 for each cohort is its baseline visit. RS lists visits as Study-Cohort-visit number (ex. RS-I-2 for Rotterdam Study Cohort 1, Visit 2) These cohorts collected data at multiple in-person assessments in various domains including demographics (age, gender, race/ethnicity, educational attainment), clinical risk factors (blood pressure, cholesterol, glucose, HbA1C, use of medications), genetic (APOE) and behavioural risk factors (diet, smoking, alcohol use, physical activity) and ongoing dementia, stroke and cardiovascular event ascertainment. Further information regarding the methods that were used to measure and ascertain these variables in each cohort can be found in Supplementary Tables S1–S9 (available as Supplementary data at IJE online). Of the variables collected by each cohort, 42 common variables have been harmonized by the DRPP. Thirteen of the 16 cohorts assessed incident dementia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria [many with AD specifically according to National Institute of Neurological Disorders and Stroke–Alzheimer Disease and Related Disorders (NINCDS-ADRDA) criteria], which include cognitive testing, clinical assessment and interviewing.31 Three of the cohorts rely on the International Classification of Diseases, Tenth Revision (ICD-10) codes. Because ICD-10 codes are likely to represent under-ascertainment of the outcome, we will conduct sensitivity analyses with and without these three cohorts to test the robustness of our models to case ascertainment methods. Cohort-specific dementia definitions can be found in Supplementary Table S10 (available as Supplementary data at IJE online). DRPP data were harmonized over a 2-year period (September 2020 to June 2022) following the Maelstrom guidelines for retrospective data harmonization.17 Fortier et al. describe a process, similar to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)32 or Meta-analyses of Observational Studies in Epidemiology (MOOSE)33 statements, which codify and guide successful data harmonization.17 During the grant application period, our team defined the research questions, objectives and protocol; assembled information; and selected studies that fit our inclusion criteria (listed above). After engaging all 16 cohorts, we identified the variables needed and requested corresponding data sets with the most detail possible. The level of detail varied from data dictionaries to exact exam questions. Data were inventoried and their harmonization potential was evaluated based on data collection methods and compatibility with data from other cohorts. In some cases, additional data and information were requested to pooled The DRPP includes incident cases of dementia, incident cases of disease and incident cases of To the DRPP has harmonized 42 variables using methods to the data available Table available as Supplementary data at IJE online). The consortium demographics are in Table the harmonization process, we examined by age for variables (Figure 2 cholesterol over by of disease over time each chronic disease and (Figure 3 hypertension by and event by age and cohort (Figure the dementia person-years by age and These are with prior cholesterol by age by for 14 derivation studies AGES, Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC, Atherosclerosis Risk in Community; CHS, Cardiovascular Health Study; FHS, Framingham Heart Study; HAAS, Honolulu Heart Program/Honolulu-Asia aging Study; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SALSA, Sacramento Area Latino Study on Aging by cohort. is based on American Heart of BP, and BP, and 1, 2, for 14 derivation studies AGES, Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC, Atherosclerosis Risk in Community; BP, blood pressure; CHS, Cardiovascular Health Study; FHS, Framingham Heart Study; HAAS, Honolulu Heart Program/Honolulu-Asia aging Study; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SALSA, Sacramento Area Latino Study on Aging Dementia by age at baseline and for derivation studies REGARDS dementia data are AGES, Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC, Atherosclerosis Risk in Community; CHS, Cardiovascular Health Study; FHS, Framingham Heart Study; HAAS, Honolulu Heart Program/Honolulu-Asia aging Study; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; SALSA, Sacramento Area Latino Study on Aging Baseline by cohort AGES, Age, Gene/Environment Susceptibility-Reykjavik Study; ARIC, Atherosclerosis Risk in Community; CHS, Cardiovascular Health Study; FHS, Framingham Heart Study; FOS, Framingham Offspring Study; NOS, Framingham New Offspring Spouse; FHS-Gen3, Framingham Heart Study Generation 3; FHS-Omni, Framingham Heart Study Omni; Framingham Heart Study Omni 2; HAAS, Honolulu Heart Program/Honolulu-Asia aging Study; MESA, Multi-Ethnic Study of Atherosclerosis; REGARDS, Reasons for Geographic and Racial Differences in Stroke; RS, Rotterdam Study; SALSA, Sacramento Area Latino Study on Aging; 3C, The Three-City After validation and of models based on baseline we to develop dynamic longitudinal risk prediction models using statistical and that will risk factor trajectories to identify individuals at high risk of The of the DRPP is with and in It includes available to as well as the harmonization of external cohort Additionally, the DRPP has pooled and harmonized a of data on incident dementia and dementia risk factors multiple domains that have been made available on a for other approved collaborators to The consortium includes multiple studies of a diverse of individuals a of race/ethnicity, and DRPP includes >1 million person-years of with individuals behavioural and clinical data at multiple time points across the life of the dementia risk prediction to this has been in the diversity and inclusion of in DRPP are an The cohorts that are included in the DRPP also a of methods and of These period and cohort our risk prediction to be and not to a single cohort or sample External validation is a in risk prediction models in to and and the of two external validation cohorts with harmonized data is with all there is a potential for for behavioural such as physical or lifestyle variables such as with to harmonize these data at the were such as for they were selected based on their association with ADRD and brain above, the heterogeneity in ascertainment of dementia between studies is an that be in each The DRPP and analyses of these data as well as the addition of new cohorts to our can apply for use of the DRPP data or review the data at drpp.northwestern.edu. collaborators will have access to a data set on the specifically for the individuals to access data on a secure at to statistical analysis using a of and to on the same individual-level data are and be or in After analyses are on the DRPP is by the DRPP team to that individual-level data our and is it to the For more information or to a please visit our website or study The DRPP has been approved by the at In the individual cohorts have been approved by their local and from a of the Supplementary data are available at IJE collection of data from individual cohorts and the inventoried individual-level of and the harmonized variables and the harmonization of external cohort inventoried individual-level data and harmonized the lifestyle of the inclusion and harmonization of cognitive harmonized cognitive on data and on harmonization access to and on the on the Whitehall II on the on the on the on the FHS data and with data harmonization and harmonization and harmonized the RS data and on data data for the on and the HAAS and risk prediction and statistical on the on the on the data and on the on the REGARDS and with data on the and ARIC and with data on the on the statistical of the harmonization and the harmonization the of the study. review of the The Dementia Risk Prediction Project (DRPP) is by the National Institute for Disorders and Stroke from the National of National Institute of Aging from the National of Health National Institute of Neurological Disorders and Stroke and the National of Health National Institute on Aging 1 was by the National Institute on Aging and was by grant from the National Institute on Aging and from from and and and are by the Alzheimer’s Disease and from The and for and is by an from the as for Alzheimer’s Disease and by an from the as the of and and This was by the National Heart and Institute Heart Study and of and from the National Institute on Aging the National Institute of Neurological Disorders and Stroke The Atherosclerosis Risk in Communities study has been in or in with from the National and National of of Health and The the and participants of the ARIC study for their research was by and and from the National and Institute with additional from the National Institute of Neurological Disorders and Stroke was by from the National Institute on Aging of and can be found at The Multi-Ethnic Study of Atherosclerosis (MESA) was by and from the National and and by and from the National for The the other the and the participants of the study for their of and can be found at This paper has been and approved by the and The is the of the and not represent the of the National of would like to all study participants, as well as the following data and analysts at each cohort for their and and None

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