Study design and participants
This was a population-based cohort study. Data were derived from the Shandong Yanggu Study of Aging and Dementia (SYS-AD), which targeted people aged 60 years and above in the rural area of Yanlou Town, Yanggu County, western Shandong Province, China.15 In August 2014–September 2015, a total of 3277 participants took part in the baseline examinations; of these, 278 participants were diagnosed with dementia (n = 206) or had insufficient information for the diagnosis of dementia (n = 72). The follow-up examination was performed in March-September 2018, as a part of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) project.16 Out of the 2999 dementia-free participants identified at baseline, 872 were excluded due to missing measures of cognitive reserve at baseline (n = 167), death (n = 229), loss to the follow-up examination (n = 528), or insufficient information for the diagnosis of dementia at follow-up (n = 14). Thus, a total of 2127 participants (70.9% of all eligible participants) who were free of dementia at baseline completed the follow-up examination (analytical sample 1). In addition, a total of 1635 participants were free of MCI at baseline and undertook the follow-up examination (analytical sample 2). Figure 1 shows the flowchart of study participants.
(Insert Fig. 1 here)
Data collection and assessments at baseline
At baseline, we collected data through face-to-face interviews, clinical examinations, and laboratory tests. Data included social demographics (e.g., age, sex, education, occupation, and marital status), lifestyles (e.g., smoking, alcohol drinking, physical activity, and social activity), cardiometabolic health conditions (e.g., hypertension, diabetes, hyperlipidemia, coronary artery disease, and stroke), neuropsychological tests, and social support. We categorized early-life educational levels as illiterate (no formal schooling), elementary school (1–5 years), and middle school or above (≥ 6 years). We dichotomized adulthood occupation as farming vs. non-farming, and marital status as married vs. single, divorced, or widowed. Smoking and alcohol consumption were categorized into ever vs. never smoking or drinking alcohol. We defined the frequency of physical activity in late life as at least weekly vs. less than weekly, and frequency of social activity in late life as never or occasional vs. frequent participation according to self-reported information. Social support (e.g., living alone or with family members and support from family members, neighbors, or colleagues) was assessed using the Social Support Rating Scale that was validated among Chinese population, and then dichotomized into low social support (below the mean Social Support Rating Scale score) vs. high social support, as previous reported.17 We used the structural equation models to generate the lifelong composite CR score by taking into account early-life educational attainment, adulthood occupation and marital status, and late-life physical activity, social activity, and social support, among all participants with all individual CR proxies in the SYS-AD study (n = 3060) (Fig. 2). Accordingly, we categorized lifelong composite CR capacity into low, medium, and high levels according to tertiles of the score.
(Insert Fig. 2 here)
Hypertension was defined as self-reported history or systolic pressure ≥ 140 mm Hg or diastolic pressure ≥ 90 mm Hg.16 Diabetes was defined according to self-reported history of diabetes diagnosed by a physician, fasting serum glucose ≥ 7.0 mmol/L, or current use of hypoglycemic medication.16 Hyperlipidemia was defined as the total cholesterol level ≥ 6.2 mmol/L, triglyceride ≥ 2.3 mmol/L, low-density lipoprotein cholesterol ≥ 4.1 mmol/L, high-density lipoprotein cholesterol < 1.0 mmol/L, or having a self-reported history of hyperlipidemia.15 We defined stroke and coronary heart disease according to self-reported history of the disease diagnosed by physicians during the annual health check-ups.15
Data collection and APOE genotyping at follow-up
At follow-up, we collected data on neuropsychological status, clinical conditions, and APOE genotypes, as previously reported.16 The trained staff collected venous blood samples, extracted genomic deoxyribonucleic acid from venous blood leukocytes, and then quantified deoxyribonucleic acid using Nanodrop 3300 spectrometry. The sequencing libraries were generated using MultipSeqCustom Panel (iGeneTech, Beijing, China) following standard procedures. Genotyping was conducted by an operator who was blinded to all clinical data. The distribution of APOE genotypes conformed to the Hardy-Weinberg equilibrium (P > 0.05).
Diagnosis of dementia and mild cognitive impairment
At both baseline and follow-up examinations, dementia was diagnosed following the criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,18 in which a 3-step diagnostic procedure was followed, as previously reported.15 Briefly, in step 1, the trained medical staff performed the first face-to-face interview, clinical examination, and laboratory tests following a structured questionnaire. In step 2, the neurologists specialized in dementia care (L.C., T.H., S.T., X.H., and Q.Z.) reviewed all the records from step 1 to screen participants who were suspected to have dementia or who had insufficient information for a judgement of dementia for further assessments. Finally, the neurologists conducted the second in-person or telephone interviews with participants who were selected in step 2 or with informants, and the diagnosis was made based on all assessments.
Alzheimer’s disease (AD) was diagnosed according to the National Institute on Aging-Alzheimer's Association criteria for probable AD.19 The diagnosis of vascular dementia was made according to the criteria of the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherche et l'Enseignement en Neurosciences for probable vascular dementia,20 which was based on the self-reported, clinical, or neuroimaging evidence of stroke, as well as the presence of a clear temporal relation between stroke and the onset of dementia. Dementia cases who could not be classified as either AD or vascular dementia were considered to have other types of dementia.
Among participants who were free of dementia both at baseline and follow-up, MCI was clinically defined by the neurologists via reviewing all records from the interviews, clinical examination, and comprehensive assessments of sub-cognitive domains, following the Petersen’s criteria, as previously reported.21 At follow-up, participants with MCI were further categorized as having amnestic MCI (aMCI) if the memory domain was impaired or non-amnestic MCI (non-aMCI) if there was no impairment in the memory domain.22
We compared the baseline characteristics of study participants by age groups (60–74 vs. ≥75 years), using the general linear regression model for continuous variables and the χ2 test for categorical variables. Next, we used the Cox proportional-hazards models to examine the association of lifelong CR capacity (as both a continuous score and a categorical variable) with incident dementia, AD, and vascular dementia. Likewise, among participants who were free of MCI at baseline, we used the Cox models to examine the association of CR capacity with incident MCI, aMCI, and non-aMCI. Finally, we examined the statistical interaction of CR capacity with sex, age groups, and APOE ε4 allele on the risks of dementia, MCI, and their subtypes. If any statistical interaction was detected (P for interaction < 0.05), we further performed the stratified analysis to assess the direction and extent of the interaction. We reported the results from statistical models that were adjusted for age, ever smoking, ever alcohol consumption, hypertension, hyperlipidemia, diabetes, coronary heart disease, and stroke, and if applicable, for sex and APOE genotypes. We used Stata Statistical Software: Release16, for Windows (StataCorp LLC, College Station, TX, USA) for all the statistical analyses.