An overview of cohort studies in brain science research

Abstract

Driven by the development of evidence-based medicine, cohort studies provide reliable and scientific evidence for brain health and neurological disorders. This review provides a concise introduction to several internationally renowned classical cohorts, highlighting their notable contributions to brain health research. Additionally, it provides a brief introduction to disease-specific cohorts in the field of brain science along with their research outcomes. Moreover, the review examines Chinese cohorts related to brain health and discusses the significant findings from the related studies. Increased interdisciplinary cooperation and cohort data sharing are expected to generate new ideas and scientific standards for the early diagnosis of neurological diseases and personalized prevention and treatment strategies in the future, thereby effectively improving brain health.

In 1992, the Journal of the American Medical Association published a paper titled “Evidence-Based Medicine. A New Approach to Teaching the Practice of Evidence-Based Medicine” [1]. The article marked the advent of evidencebased medicine. Driven by evidence-based medicine, medical research methods have been continuously improved and refined. Cohort research—along with systematic reviews, meta-analyses, randomized controlled trials, case-control studies, and other research methods—has become a fundamental observational design in medical research [2].

A cohort study, also known as a prospective study, longitudinal study, or follow-up study, follows a group of people with the same characteristics or exposure over an extended period. Cohort studies are effective in helping to understand the causes of diseases, contributing to early screening and early diagnosis, and providing new ideas and a scientific basis for developing accurate measures for use in disease prevention and control. This review provides a brief introduction to internationally recognized classical cohorts, disease-specific cohorts focusing on neuroscience, and Chinese cohorts. There is a growing trend in the publication of cohort studies in academic journals.

1 Internationally renowned classical cohorts and their contributions to brain health

1.1 Framingham Heart Study (FHS)

The FHS is a landmark cohort study, which was established in 1948 to improve the understanding of coronary heart disease in the USA (http://www.framinghamheartstudy.org/). The FHS is a deeply phenotyped cohort study with a sustained focus on epidemiological methods and technological advances to facilitate scientific discoveries. Research based on the FHS goes far after 70, and its focus has expanded to the brain and down to the molecular level (Fig. 1) [3]. The FHS now possesses a rich, longitudinal, transgenerational database, in addition to cell and genetic sequences and imaging scans of the heart, brain, bone, and liver. The FHS has evolved into a successful, multigenerational study that analyzes family patterns of cardiovascular and other diseases. FHS researchers also collaborate with scientists in the US and around the world to study brain diseases such as aging, stroke, and Alzheimer’s disease (AD). A paper in 2019 summarized the many landmark research findings on brain diseases using FHS data over the past 70 years [3]. For example, in 1970, high blood pressure was found to increase the risk of stroke and atrial fibrillation was found to increase the risk of stroke five-fold. In 2010, the FHS reported that sleep apnea increased the risk of stroke, and in 2009, it found that elevated leptin levels reduced the risk of AD [3]. Two recent studies from the FHS explored the causes of AD. One study found that obesity influenced the expression of Alzheimer’s disease-related genes [4]. The other recent study suggested that long-term blood pressure patterns in midlife predict the risk of dementia in later life [5]. We can expect a growing number of research findings related to brain health using the FHS cohort data to be published in the future.

Fig. 1

Timeline of the Framingham Heart Study [3]

1.2 UK Biobank (UKB)

The UKB (https://www.ukbiobank.ac.uk/) is one of the most widely renowned cohort studies, consisting of a large-scale biomedical database and research resource, as an opening biobank. Since its establishment in 2006, the UKB has evolved into a comprehensive biomedical database and research resource encompassing genetic, lifestyle, and health information, along with biological samples from half a million participants in the United Kingdom. The UKB has made a substantial investment of $3.7 billion, with an investment and research output comparable to that of a national laboratory. More than 30,000 research teams from around the world have used the UKB data, generating more than 10,000 scientific papers. The number of Chinese researchers using UKB data ranked third in the world. Recently, an article by Professor Yu Jintai from Fudan University was published in the top journal Nature Aging. Based on the UKB database, Professor Yu’s study successfully identified plasma proteomic profiles that can predict the risk of future dementia in healthy adults 15 years earlier than current methods [6]. Taken together, the UKB is facilitating a better understanding of the prevention, diagnosis, and treatment of a wide range of serious and life-threatening illnesses, including brain diseases.

1.3 National Health and Nutrition Examination Survey (NHANES)

The NHANES is an important US cohort study that collects information on participants’ health and nutrition, including physiological measurements, health questionnaires, laboratory tests, and nutrition surveys. The data have been updated every two years since the 1980s. The data are freely accessible and researchers can download data directly on demand. According to incomplete statistics, in the past decade, a total of 10,530 papers related to the NHANES have been published, many of which have explored brain health, such as stroke, cognitive impairment, depression, and anxiety [7-9 ].

1.4 All of Us Research Program (AoURP)

The AoURP is a newly established national large cohort study (https://allofus.nnlm.gov/). It began all over the United States in 2018 with plans to enroll 1 million core participants by 2024 with follow-ups over several decades. Data from the AoURP include the genetic, social, and environmental factors that influence health and disease. The AoURP data provide researchers with a comprehensive health landscape to better understand individual health and disease progression, including brain diseases such as depression and dementia. The program adopts the strategy of simultaneous construction and application, and some data are openly shared. Using the AoURP’s cloud-based platform Researcher Workbench, registered researchers have access to powerful, in-depth data for conducting research [10].

2 International disease-specific cohorts in neurological diseases

In the neuroscience and medicine field, remarkable progress has been made in the study of neurological disease cohorts and brain health (Table 1). These studies aim to gain insights into the pathogenesis of neurological diseases, explore effective prevention and treatment strategies, and promote brain health. International research institutions have collected large amounts of clinical data, imaging data, and biological samples by establishing large-scale neurological disease cohorts, as shown in Figure 2. These cohorts cover a variety of neurological disorders, such as AD, Parkinson’s disease, and stroke. Analysis of these data allows researchers to reveal the incidence of a disease, the rate of progression, and influencing factors, thus providing a scientific basis for the development of personalized treatment plans.

Table 1

International disease-specific cohorts focused on AD and other neurological diseases

	Name	Country/region	Brief Introduction
1	NACC	America	National Alzheimer’s Coordinating Center (NACC) was established by the National Institute on Aging in 1999. NACC provides a valuable resource for both exploratory and explanatory AD research. NACC data are freely available to all researchers.
2	ADNI	America	Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a longitudinal, multi-center study to develop clinical, imaging, genetic, and biochemical biomarkers for early detection and tracking of AD.
3	AIBL	Australia	The Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL) aims to recruit 1000 individuals aged over 60 to assist with prospective research into AD.
4	EPAD	Europe	European Prevention of Alzheimerʹs Dementia Consortium (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of AD.
5	OASIS	America	Open Access Series of Imaging Studies (OASIS) aims to make brain neuroimaging datasets freely available to the scientific community, and to promote future discoveries in basic and clinical neuroscience.

Fig. 2

Study design and timelines of ADNI (https://adni.loni.usc.edu/)

An increasing number of studies in the field of brain health are being conducted with cohorts. A team from Harvard analyzed two prospective US cohorts, namely the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study, and found that a daily consumption of at least 7 g/d grams of olive oil was associated with a significant 28% reduction in the risk of dementia-related death [11]. The differential diagnosis of dementia remains a challenge. In July 2024, researchers proposed an artificial intelligence (AI) model framework for dementia screening, using data from nine independent cohorts, such as NACC, ADNI, FHS, AIBL and OASIS [12]. To identify the etiologies contributing to dementia in individuals, the researchers analyzed a broad array of data from the nine cohorts, including demographic information, personal and family medical history, medication use, neuropsychological assessments, and multimodal neuroimaging. The AI model framework has the potential to be integrated as a dementia screening tool [12].

3 Chinese cohorts and brain health study

The number of Chinese cohorts is on the rise. With its large population base, rich ethnic diversity, significant regional variations, and complex disease spectrum, China possesses unique requirements and advantages for conducting cohort research. Examples include the China Aging and Neurodegenerative Initiative (CANDI), China Study of Cognition and Aging (COAST), China Kadoorie Biobank (CKB), Neurological Disease Specific Cohort Study (Chinese Center for Disease Control), Taizhou Longitudinal Study (TZL, Fudan University), China Health and Retirement Longitudinal Study (CHARLS, Peking University), the Chinese Longitudinal Healthy Longevity Survey (CLHLS, Fudan University), and the China Birth Cohort (CNBC, Najing Medical University). The following three Chinese cohorts are being used to study brain health.

3.1 China Aging and Neurodegenerative Initiative (CANDI) study

Given the substantial variations in ethnicity, genetic background, lifestyle, and many other factors, it is particularly important for researchers to be able to access local data when conducting dementia cohort studies in the Chinese population. The CANDI was officially launched in 2018. Following international platform construction standards, the project aims to recruit approximately 500 participants in the clinical cohort of the First Affiliated Hospital of China University of Science and Technology, including cognitively healthy individuals and patients with mild cognitive impairment, AD, and non-AD dementia, and carry out longitudinal follow-ups. Adhering to the amyloid/tau/neurodegeneration (A/T/N) research framework, the study carried out multidimensional cognitive assessments and multi-modal neuromolecular imaging data collection. A standardized sample bank was established to store samples of patients’ blood, cerebrospinal fluid, urine, stool, and others. The analysis of core AD markers in blood and cerebrospinal fluid, including β-amyloid 40 (Aβ40), Aβ42, tau protein, and phosphorylated tau protein (P-tau 181) was carried out. This CANDI cohort study has established an effective approach for the early screening, diagnosis, and treatment of aging and neurodegenerative diseases in the Chinese population. The results have confirmed various blood biomarkers, especially pTau and GFAP, as non-invasive methods for detecting and screening early-stage AD [13]. Another study using the CANDI cohort demonstrated that a combined “A/T/N” system of AD biomarkers revealed by machine learning precisely predicted the onset of AD [14].

3.2 The China Cognition and Ageing Study (COAST)

The COAST is a nationwide, population-based cohort study on dementia in China (ClinicalTrials.gov identifier: NCT03653156). The study included individuals from 12 provinces from the north, south, and west of China, representing the geographical characteristics, degree of urbanization, economic status, dietary patterns, and cultural and social differences in the nation. The participants underwent cerebrospinal fluid tests, cognitive assessments, and brain imaging every two to three years. Many studies using the COAST cohort have been published. For example, one study demonstrated an association between healthy lifestyle factors and reduced rmemory decline in cognitively normal older adults, even those who were genetically susceptible to memory decline [15]. Recently, the New England Journal of Medicine published the results of a 20-year follow-up of a cohort of 10,000 individuals, which showed that the change of CSF biomarkers can predict the onset of AD 18 years in advance [16]. The COAST study provides valuable insights into biomarker changes prior to cognitive disease and highlights the importance of cohort studies in understanding disease progression and risk factors.

3.3 China Kadoorie Biobank (CKB)

The CKB is a cohort study of >512,000 adults recruited from 10 provinces across China over the past 20 years. The CKB cohort study is a large prospective international collaborative study on chronic diseases conducted by the Chinese Center for Disease Control and Prevention, the Chinese Academy of Medical Sciences, Peking University, and the University of Oxford, UK. Professor Liming Li, an epidemiologist at Peking University, leads the team. The CKB cohort study aims to establish a natural population cohort in China and an adult health database using biological samples to provide a scientific basis for the formulation of chronic disease prevention and control strategies specifically tailored to the Chinese population. The genotyping and population characteristics demonstrate the breadth, depth, and quality of the CKB data [17]. The CKB cohort study has produced fruitful research findings on brain diseases, demonstrating the scientific value of this biobank. Stroke is a leading cause of death and disability worldwide. Among the population-based CKB cohort study, the risk of recurrence or death within 5 years was found to be high after a first stroke, suggesting the need for urgent improvements in the secondary prevention of stroke in China [18]. Another study from the CKB demonstrated a significant association between lactation duration and the risk of stroke, particularly ischemic stroke, underscoring the importance of promoting breastfeeding as a targeted preventive strategy [19]. A recent study using the CKB data suggested a causal association between snoring and stroke [20].

The development of cohort studies and technology stemming from scientific research findings can facilitate a better understanding of disease etiology, further contribute to early screening and diagnosis, and provide new ideas and a scientific basis for precise and personalized prevention and treatment strategies. In the future, we can expect more interdisciplinary collaboration and data sharing to advance brain health and neuroscience.