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ASSOCIATION OF PREECLAMPSIA WITH INCIDENT DEMENTIA AND ALZHEIMER’S DISEASE AMONG WOMEN IN THE FRAMINGHAM OFFSPRING STUDY

 

K. Wang1,2,*, K. Guo3,*, Z. Ji4, Y. Liu5, F. Chen6, S. Wu6, Q. Zhang7, Y. Yao2, Q. Zhou8

 

1. Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China, 400016; 2. Department of Neurosurgery, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA, 02115; 3. Office of Bidding and Procurement, Chongqing University Cancer Hospital, Chongqing, 400030; 4. Department of Marketing, Fisher Business college, The Ohio State University, Columbus, OH, USA, 43212; 5. Department of Finance & Economics, Rutgers Business School, Rutgers Univerisity, Newark, NJ, USA, 07102; 6. Department of Mathematical Finance & Financial Technology, Questrom School of Business, Boston University, Boston, MA, USA, 02215; 7. Department of Computer Science and Engineering, School of Engineering, Santa Clara University, Santa Clara, CA, USA, 95053
8. Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China, 400016; * Kanran Wang and Kaining Guo are co-first authors, Kanran Wang’s ORCID is 0000-0002-6958-7677.

Corresponding Author: Yizheng Yao, MD, Ph.D., Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School. 75 Francis Street, Boston, MA, USA, 02115, yaoyizheng1990@gmail.com; Qin Zhou, MD, Department of Gynecology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Road, Yuzhong District, Chongqing, China, 400016, zhouqincq@qq.com

J Prev Alz Dis 2022;
Published online June 21, 2022, http://dx.doi.org/10.14283/jpad.2022.62

 


Abstract

Background: This study aimed to investigate the association between preeclampsia and all-cause dementia and Alzheimer’s Disease (AD).
Methods: This population-based cohort study was a secondary analysis of data from the Framingham Offspring Study (FOS). History of preeclampsia was assessed between 1986 and 1990(4th cycle). Participants were followed up until incident events or censorship from the study through 2014. Hazard ratios comparing dementia rates among women with and without a history of preeclampsia were estimated using Cox regression models.
Results: A total of 1249 women with 18631 person-years of follow-up were included in the analytic sample. Of those, 142 women had a history of preeclampsia, and 98 women experienced dementia of which 62 were AD during follow-up of nearly 15 years. After multivariate adjustments, women with a history of preeclampsia had a higher risk of all-cause dementia and AD compared with women without it, with HRs of 1.56 (95%CI, 1.03-2.15) for all-cause dementia and 1.65 (95%CI 1.08-2.20) for AD. And the comparable results were shown in the subgroup for elder women over 65 years old.
Conclusion: History of preeclampsia was associated with an increased risk of all-cause dementia and AD.

Key words: Preeclampsia, dementia, Alzheimer’s disease, long-term consequences Framingham Offspring Study.


 

Introduction

Dementia is the leading cause of death and disability in elderly western populations. Approximately 47 million people had dementia worldwide in 2015, and this number is projected to triple by 2050 (1, 2). Alzheimer’s disease (AD) is the most common type of dementia in humans, representing approximately 60–70% of all cases (3). However, the causes of dementia, especially AD, remain controversial, and there are no disease-modifying therapies. Therefore, the identification of etiology and risk factors has been prioritized as a strategy to prevent or delay the development of dementia (4-7).
Preeclampsia, broadly defined as new-onset hypertension during pregnancy with end-organ damage, is a common hypertensive disorder of pregnancy occurring in up to 8% of pregnancies which can result in acute cerebrovascular complications and increasing risks of later hypertension, cardiovascular disease, stroke, and diabetes (8-11). Endothelial and vascular dysfunction plays a remarkable role in the pathophysiology of this disorder, so it could be logically associated with an increased risk of dementia (12, 13). A recent nationwide cohort study showed that preeclampsia was associated with an increased risk of dementia, particularly vascular dementia (14). However, a Sweden cohort study indicated that there was no increased risk of dementia after self-reported pregnancy hypertensive disease, and a case-control study found that women with early-onset AD reported hypertensive disorders of pregnancy more often compared to women with late-onset AD (15, 16). To be specific, all studies were potentially underpowered due to either of the following two reasons: first, lacking enough longitudinal follow-up may neglect the late-onset outcomes, or, second, their use of self-reported information or electronic medical record (EMR) and the attendant possibility of both recall and survival bias and ambiguous diagnosis.
To overcome the limitations of the previous studies, we carried out a prospective cohort study to assess the association of preeclampsia with the incidence of all-cause dementia and AD with an analysis of potential confounding factors, using data from the Framingham Offspring Study in routinely collected clinical data and autopsies covering a nearly 15-year period. We hypothesized that preeclampsia would be associated with an increased risk of all-cause dementia and AD, and this association would be seen in both whole and over 65 years old subjects.

 

Methods

Study Population

The Framingham Heart Study (FHS) involves a series of ongoing, prospective, population-based cohorts from the town of Framingham, MA, USA (17). The present study used data from the second generation, Framingham Offspring Study (FOS), which was enrolled from 1971 to 1975. The FOS enrolled 5,124 participants (age=12–58 years) who have undergone a clinical examination every 4 years approximately (18). Each examination consisted of medical history, physical exam, lifestyle habits, and laboratory assessments using a standardized protocol (19). For the present investigation, we included participants of the offspring cohort who were examined between 1986 and 1990 (4th cycle) and for whom data of detailed information on preeclampsia during 1 or more pregnancies were available. All participants provided written informed consent. The study protocol was approved by the institutional review board and Boston University Medical Center. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has approved this study protocol as well (ID: 6955).

Assessment of preeclampsia

The study exposure was the presence or absence of preeclampsia during 1or more pregnancies during 4th visit. Preeclampsia was evaluated by a questionnaire (yes/no) in the visit regarding their history of toxemia, the prevailing nomenclature for preeclampsia at the time. We included women who were dementia-free with complete data on preeclampsia at the time of examination 4 and had a minimum of 3 study visits and 1 pregnancy before menopause, hysterectomy, or age 45 years, which was a reliable cutoff age for the loss of fertility in that era. Furthermore, 7 women were excluded from this analysis if they had a pregnancy that was not complicated by preeclampsia at baseline but subsequently reported preeclampsia during the outcome period.

Ascertainment of dementia and AD

All FHS participants were under ongoing continuous surveillance for the onset of cognitive impairment and clinical dementia (4). A diagnosis of dementia was made in line with the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. A diagnosis of AD dementia was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association for definite, probable, or possible AD. Detailed procedures for the diagnosis of AD dementia within the FHS are reported elsewhere. Complete details on our methods of surveillance, diagnosis, and case ascertainment on dementia and AD were shown in eMethods in the Supplement.

Covariates

The most recent covariate information during the period of preeclampsia assessment (Exam 4) was collected. Hypertension was defined as systolic blood pressure>140 mm Hg, diastolic blood pressure>90 mm Hg, or use of antihypertensive medications; diabetes mellitus was defined as fasting glucose>7 mmol/L or use of antidiabetic therapy; body mass index was defined as the weight (in kilograms) divided by the square of height (in meters). Mini-Mental State Examination (MMSE) scores, smoking status (smoked cigarettes regularly in last year; yes/no), alcohol consumption (g/day), total caloric intake (cal/d), saturated fat (g/d), dietary fiber (g/d), employment status (working, retired or unemployed), depression scale scores, personal income, marital status, and educational level were assessed by medical interviews. Total cholesterol, low-density lipoprotein cholesterol, glucose, and serum creatinine were measured after an overnight (>10 hours) fast.

Statistical Analysis

In descriptive statistics of all variables, the t-test or rank sum-test was used for continuous variables, and the Chi-square test was used for categorical variables. Follow-up for dementia was from the baseline examination to the time of the incident event. And for persons with no incident events, follow-up was censored at the time of death or the date the participant was last known to be dementia-free. Multivariate Cox proportional hazards regression models then estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of dementia and AD incidence after adjusting for covariates: 1) Model 1 adjusted for MMSE at baseline, education level, personal income, marital status, and age; 2) Model 2 adjusted for additional to model 1 for SBP, treatment of hypertension, TC, LDL, prevalent diabetes mellitus, current smoking, alcohol consumption, depression scale, employment status, and BMI. The proportional hazard assumption was checked for each model. The same analysis was carried out for individuals over 65 years at baseline. Analyses were performed using SAS software, version 9.4 (SAS Institute Inc, Cary, North Carolina) and Stata statistical software, version 15 (Stata Corporation, College Station, Texas, USA). A 2-sided with P<0.05 was considered statistically significant.

 

Results

Subjects

Of the 1513 women participants of the FHS Offspring Cohort attending the 4th exam, 1462 subjects who had undergone the preeclampsia at examination cycles 4 were eligible for the initial investigation but 7 of them were excluded since they claimed no preeclampsia in this cycles but so in the outcome period. Thereof, 206 individuals were excluded since 181 subjects lacked assessment on dementia, 3 subjects were diagnosed with dementia at baseline, and 22 subjects were without follow-up. Therefore, the final analysis included 1249 women enrolled who had an accumulated 18631 person-years of observation. A history of preeclampsia was present in 142 women, and dementia occurred in 98 women, of which 62 were AD dementia. (See Figure 1)

Figure 1. Selection of Study Participants in the Framingham Offspring Study

 

At baseline, women with a history of preeclampsia vs those without a history of preeclampsia were substantially older and more likely to have diabetes mellitus, have higher BMI, systolic blood pressure, diastolic blood pressure, fasting blood glucose, LDL, and TC. And the two groups descriptively differed concerning employment, education, and marital status as well. (See Table 1)

Table 1. Characteristics of the study sample of the Framingham Heart Study at baseline preeclampsia assessment

Continuous variables were expressed as mean ± SD for normal distributions, or median (interquartile range) for skewed distributions, and categorical variables as number and percentage. Abbreviations: WSP: widespread pain; BMI, body mass index; LDL, low-density lipoprotein, TC: total cholesterol, MMSE, mini-mental state examination.

 

Dementia events

The mean follow-up time for dementia was 12 years (interquartile range, 7-21years). Dementia events occurred in 24 of 142 women (16.9%) with a history of preeclampsia and 74 of 1107 women (6.7%) without a history of preeclampsia. Regarding dementia events concerning subtypes and status, see Table 2.

Table 2. Dementia events in subjects with preeclampsia compared to those without

Categorical variables were expressed as numbers and percentages and compared with the Chi-Squared test. Abbreviations: AD, Alzheimer’s disease.

 

Preeclampsia and Risk for Dementia and AD

When adjusting for MMSE at baseline, education level, personal income, marital status, age, SBP, treatment of hypertension, TC, LDL, prevalent diabetes mellitus, current smoking, alcohol consumption, depression scale, employment status, and BMI, using Cox regression analysis, subjects with preeclampsia had a 56% greater risk of incident all-cause dementia (HR, 1.56; 95%CI, 1.03-2.15), a 65% greater risk of AD dementia (HR, 1.65; 95% CI, 1.08-2.20), compared with women with no history of preeclampsia. A history of preeclampsia seemed to be more strongly associated with late-onset dementia (age≥65 years, which were at high-risk for dementia), see Table 3. Figure 2 shows the cumulative incidence curves for all-cause dementia and AD stratified by groups with or without preeclampsia after adjusting for age and sex.

Table 3. Hazard ratios for the association between preeclampsia and all-cause dementia and AD dementia

Model 1: Adjusted for MMSE at baseline, education level, personal income, marital status, and age. Model 2: Adjusted additional to model 1 for SBP, treatment of hypertension, TC, LDL, prevalent diabetes mellitus, current smoking, alcohol consumption, depression scale, employment status, and BMI. Abbreviations: HR, hazard ratio; AD, Alzheimer’s disease; MMSE, mini-mental state examination; SBP: systolic blood pressure; TC: total cholesterol; LDL: low-density lipoprotein; BMI: body mass index.

Figure 2. Adjusted cumulative incidence of all-cause dementia and AD dementia based on preeclampsia

Abbreviations: AD, Alzheimer’s disease. Data are for the cumulative incidence of (A) all-cause dementia and (B) Alzheimer’s disease dementia among participants with and without preeclampsia in the Framingham Offspring Cohort. Adjustments were made for age and sex.

 

Discussion

In this FOS study of 1249 women, preeclampsia was associated with a modest (56%) increase in the overall risk of all-cause dementia and a stronger (65%) for AD after a full adjustment for sociodemographic and morbidity confounders. Subtype-specific associations of participants over 65 years old were even stronger than the whole population (91% higher risk for all-cause dementia and double for AD). These findings may provide important information on the association of a history of preeclampsia with the risk of dementia for early attention to modifiable risk factors for dementia.
Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria (8, 20). It was associated with an increased risk of not only fetal death and the birth of small-for-gestational-age neonates, but also the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease in mothers (21-23). A previous national-wide cohort study including 1178005 women showed that preeclampsia was associated with an increased risk of dementia, particularly vascular dementia, instead of AD (14). A meta-analysis including 13 observational studies indicated that preeclampsia is associated with subjective cognitive symptoms, but no clear evidence of impairment on standard neurocognitive tests was demonstrated (24). A case-control study found that hypertensive disorders of pregnancy might be associated with early but not late-onset AD (16). In a contrast, A Sweden cohort enrolling 3232 women 65 years or older concluded that there was no increased risk (HR 1.19; 95% CI 0.79 to 1.73) of dementia after self-reported pregnancy hypertensive disease (15). And a prospective population-based registry study on all women giving birth in Sweden between 1973 and 1975 (n=284 598) illustrated that no increased risks were seen for vascular dementia or dementia after all hypertensive disorders in pregnancy (25). While previous studies have produced mixed findings on whether preeclampsia is associated with an increased risk of dementia or not, our results extend existing data and suggest the association between preeclampsia and dementia and AD based on community-based follow-up of nearly 15 years, standard clinical assessment for not only preeclampsia but also dementia and full adjustment of confounding factors.
Several mechanisms through which preeclampsia may causally affect dementia risk have been proposed. Firstly, preeclampsia was related to vascular (endothelial) dysfunction and heightened inflammatory with large vessel atherosclerosis and small vessel arteriosclerosis (26, 27). Microvascular and macrovascular changes that disrupt blood flow integrity can cause structural and functional brain changes, which can lead to vascular cognitive impairment (28). Secondly, women with a history of hypertensive pregnancy disorders have been shown to have smaller brain volumes and greater white matter lesions than women with normotensive pregnancies decades later, even after adjusting for traditional cardiovascular risk factors, which are linked with cognitive decline and dementia (29, 30). Thirdly, basic research showed that the preeclampsia susceptibility gene STOX1 is functionally involved in late-onset AD. Isoform A of STOX1 is abundantly expressed in not only the placenta but also the brain, correlates with the severity of disease, and selectively transactivates LRRTM3 in neural cells with increased amyloid-β protein precursor processing which could lead to dementia and AD (31). Our finding that preeclampsia was strongly associated with all-cause dementia and AD adds convincing epidemiological evidence to suggest that they may share underlying mechanisms and/or susceptibility pathways, and further basic and larger-scale clinical research would be needed to confirm our observations and to investigate the mechanisms.
The strengths of the present study include its longitudinal population-based design and its perfect follow-up of study subjects, in which the development of dementia and its subtypes were diagnosed as accurately as possible based on neuropsychological tests, medical examinations, clinical records, and autopsy findings. In addition, the extensive medical record data allowed us to closely match women with and without preeclampsia and minimize the effect of residual confounding. However, some limitations need to be acknowledged. Firstly, our study was observational with the small numbers of incident events, which precludes conclusions about the causality of the observed associations due to residual confounding and potential reverse causality. Regarding reverse causality, the fact that we constructed a follow-up over 10 years makes such a reverse causation bias less likely. Secondly, the history of preeclampsia was patient self-reported and could be susceptible to recall bias. Thirdly, although our analyses were adjusted for multiple potential sources of bias, the possibility of unmeasured and/or unprovided confounding in the public database cannot be ruled out, such as APOE ε4, which could increase the risk of dementia. Lastly, participants included in our study were mainly Caucasian Americans, limiting the generalizability of our findings to other races/ethnicity.

 

Conclusions

In conclusion, our study provides further evidence that a history of pre-eclampsia was associated with an increased risk of all-cause dementia and AD independent of multiple demographic factors. It suggests that asking about a history of preeclampsia could help physicians to identify a group of women who might benefit from early attention to modifiable risk factors for dementia. Research is needed to confirm our observations and explore the mechanisms underlying the reported associations which may be an avenue for future studies of candidate biological pathways and targets for intervention.

 

Data Availability: Data described in the manuscript, code book, and analytic code will not be made available because the authors are prohibited from distributing or transferring the data and codebooks on which their research was based to any other individual or entity under the terms of an approved NHLBI Framingham Heart Study Research Proposal and Data and Materials Distribution Agreement through which the authors obtained these data.

Conflicts of Interest: The authors declare that they have no conflicts of interest.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition, analysis, or interpretation of data: Wang, Guo, Ji, Liu. Drafting of the manuscript: Wang and Guo. Critical revision of the manuscript for important intellectual content: Yao and Zhou.Statistical analysis: Wang, Guo, Ji, Liu, Chen, Wu, Zhang. Obtained funding: Wang, Yao, and Zhou.Supervision: Yao and Zhou.

Acknowledgments: The authors thank the National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA, Chongqing Medical University, Chongqing, China and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.Thanks for the support from my wife especially in the stormy Boston.

Grant Support: Chongqing Medical University Scholarship Fund for Development of Young Talents (XRJH201901).

Ethical standard: The study procedures followed were in accordance with the ethical standards of the Institutional Review Board and the Principles of the Declaration of Helsinki.

 

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