Shared risk and protective factors between Alzheimer's disease and ischemic stroke : A population-based longitudinal study.

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This is the published version of a paper published in Alzheimer's & Dementia.

Citation for the original published paper (version of record):

Wang, R., Qiu, C., Dintica, C S., Shang, Y., Larrañaga, A C. et al. (2021)

Shared risk and protective factors between Alzheimer's disease and ischemic stroke: A

population-based longitudinal study.

Alzheimer's & Dementia

https://doi.org/10.1002/alz.12203

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DOI: 10.1002/alz.12203

R E S E A R C H A R T I C L E

Shared risk and protective factors between Alzheimer’s disease

and ischemic stroke: A population-based longitudinal study

Rui Wang

_{Chengxuan Qiu}

_{Christina S. Dintica}

_{Ying Shang}

Amaia Calderón Larrañaga

_{Hui-Xin Wang}

_{Weili Xu}

1_{Aging Research Center, Department of}

Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden

2_{The Swedish School of Sport and Health}

Sciences, GIH, Stockholm, Sweden

3_{Department of Medicine and Wisconsin}

Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

4_{Stress Research Institute, Stockholm}

University, Stockholm, Sweden

5_{Department of Epidemiology & Biostatistics,}

Tianjin Medical University, Tianjin, P. R. China

Correspondence

Rui Wang, The Swedish School of Sport and Health Sciences, GIH, Lidingövägen 1, Box 5626, SE-114 86 Stockholm, Sweden. E-mail:rui.wang@ki.seorrui.wang@gih.se

Weili Xu, Professor, Department of Epidemi-ology & Biostatistics, School of Public Health, Tianjin Medical University, Qixiangtai Road 22, Heping District, 300070 Tianjin, P. R. China. E-mail:xuweili@tmu.edu.cn

Abstract

Introduction: Stroke, especially ischemic stroke’s (IS) link with Alzheimer’s disease

(AD) remains unclear.

Methods: This prospective cohort study included 2459 AD- and cerebrovascular

disease-free older adults at baseline (mean age 71.9

± 10.3 years, Stockholm, Sweden).

Using Cox regressions, shared risk factors (SRFs) and shared protective factors (SPFs)

between AD and IS were recognized when their hazard ratios in both AD and IS models

were significant and in the same direction.

Results: During the follow-up period of up to 15 years, 132 AD and 260 IS mutually

exclusive cases were identified. SRFs were low education, sedentary lifestyle, and heart

diseases. High levels of psychological well-being, actively engaging in leisure activities,

and a rich social network were SPFs. Having

≥1 SPF reduced 47% of AD and 28% of IS

risk among people with a low risk profile (

<2 SRFs), and 38% of AD and 31% of IS risk

with a high risk profile (≥2 SRFs). In total, 57.8% of AD/IS cases could be prevented if

individuals have

≥1 SPF and no SRF.

Discussion: AD and IS share risk/protective profiles, and SPFs seem to counteract the

adverse effects of SRFs on both AD and IS.

Alzheimer’s diseases, Cohort study, Ischemic stroke, Leisure activity, Psychological well-being, Social network, Vascular risk factors

1

INTRODUCTION

Alzheimer’s disease (AD) has been related to the deposition of amyloid beta (A_{β) peptide plaques in brain tissues that may cause} neurodegeneration.1Stroke, especially ischemic stroke (IS), has been linked to embolism and small-vessel disease.2 _{Despite the different}

etiopathogeneses proposed for AD and stroke, clinical studies have shown that the co-existence of AD and stroke occurs more often than expected by chance, indicating a possible relationship between the two disorders.3_{However, the link between AD and stroke (particularly IS)}

has not been fully understood.

Both AD and IS develop as a result of multiple factors rather than a single cause. Evidence has been accumulating suggesting that vascular pathologies (eg, atherosclerosis) are correlated, and inter-connected with neurodegenerative pathologies preceding cognitive impairment, AD, and dementia.4Although pathological confirmation is lacking, stroke-related vascular conditions (eg, hypertension and heart diseases) were found to be associated with AD development.5,6_Yet,

the associations between certain vascular risk factors and AD vary by age. That is, middle-life vascular risk factors, such as hyperten-sion, high cholesterol, and obesity, increase late-life AD risk,7,8_{but the}

effect of late-life vascular risk factors on AD tends to be controversial.

Therefore, identifying which are the shared risk factors for both AD and stroke in old age requires further study and would shed light on possible common pathophysiologies.

Many studies have indicated that psychosocial factors, such as social networks, leisure activities, and psychosocial well-being, may reduce the risk of cognitive decline and AD.9–11_{Likewise, the protective effect}

of psychosocial factors on stroke has been established.12_Previous

find-ings indicate that stroke and AD may not only share vascular profiles, but also benefit from similar protective profiles related to psychosocial well-being. Thus, identifying the shared protective psychosocial fac-tors for both AD and stroke would prevent older adults from devel-oping either of the two disorders. Furthermore, it has been hypoth-esized that protective psychosocial factors in late life may increase the cognitive reserve making the individuals have a high susceptibil-ity to tolerate age-related brain changes or pathology related to AD.11

Whether these cognitive reserve-related factors can counteract the accumulated harmful effects of the shared risk factors on AD and stroke remains to be elucidated.

AD and IS are associated with multiple lifelong cumulative risk fac-tors. In the current study, we defined “risk” factors as either pathogenic or as negative exposures in early life (eg, genetic risk factors, vascu-lar risk factors, and early life low education level), and “protective” factors are salutogenic and potentially modifiable during late life (eg, psychosocial well-being, rich social network, and vigorous leisure-time activity; Figure S1 in supporting information). The identified shared risk/protective factors will serve as a new tool to be used in interven-tions designed to reduce the late-life risk of both AD or stroke. There-fore, using a population-based longitudinal cohort of older adults, we sought to (1) identify shared risk and protective profiles for AD and IS and (2) explore whether and to what extent the shared protective pro-file may decrease the adverse effect of risk factors on AD and IS.

2

METHODS

2.1

Study population

Data for this study were derived from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), an ongoing prospec-tive population-based study of the older population (_{≥60 years) with} longitudinal follow-up records. Data collection has been described previously.13

In this study, we included up to 15 years of follow-up data from January 2001 until December 2016. At baseline (2001 to 2004), of 3363 participants who were examined, we excluded 528 participants with prevalent dementia (n_{= 321; prevalent dementia n = 310,} miss-ing dementia status n_{= 11) or history of cerebrovascular diseases} (n= 347), and 376 participants who declined to participate in follow-up examinations, leaving 2459 participants who were free from both dementia and cerebrovascular disease in the analytical sample. Dur-ing the follow-up, 342 developed dementia (132 AD cases without any cerebrovascular diseases), 509 developed cerebrovascular diseases (260 IS cases without AD), and 1738 participants remained free from

HIGHLIGHTS

∙ The shared risk factors between Alzheimer’s disease (AD) and ischemic stroke (IS) include low education, sedentary lifestyle, and heart diseases.

∙ The shared protective factors between AD and IS are high levels of psychological well-being, actively engaging in mental and physical leisure activities, and a rich social network.

∙ Having one or more protective factor reduces ∼30% to 40% AD and IS risk among people with a low isk profile (_<2 risk factor) or with a high risk profile (≥2 risk factors). ∙ In total, 57.8% AD/IS cases could be prevented if

individ-uals had at least one shared protective factor and without any shared risk factor.

∙ Our findings provide the first evidence for the implemen-tation of shared preventive strategies for both AD and stroke.

∙ The findings highlight a combination of promoting cardiovascular-related health and psychosocial health, to prevent both AD and stroke.

RESEARCH IN CONTEXT

1. Systematic review: The authors reviewed the litera-ture using traditional (eg, PubMed) sources and meet-ing abstracts and presentations. There is no previous research identifying the shared risk and protective fac-tors between Alzheimer’s disease (AD) and ischemic stroke (IS), using mutually exclusive incident cases in one population.

2. Interpretation: Both AD and IS develop as a result of mul-tiple factors rather than a single cause, and the common underlying mechanisms between AD and IS may exist. 3. Future directions: Our findings proposed the further

directions on (1) multiple intervention on both AD and stroke by targeting the shared risk and protective fac-tors, (2) investigating the common underlying etiology between AD and stroke, and (3) exploring the possible compensatory mechanism of the protective effect of psy-chosocial factors on AD and stroke.

either dementia or cerebrovascular diseases (Figure S2 in support-ing information). Of the cerebrovascular disease and dementia cases developed at follow-up, 520 were with either AD or IS.

2.2

Data collection

Data collection was conducted through structured assessment by trained physicians, nurses, and psychologists. Information on health

history for all participants was obtained from the National Patient Reg-istry that covers all hospitalizations in Sweden since 1969. Informa-tion on death was obtained from the Swedish Cause of Death Registry until December 31, 2016. International Classification of Diseases (ICD) codes were used to identify the diseases or causes of death from the register data.

SNAC-K was approved by the Karolinska Institutet ethical commit-tee and the regional ethical review board in Stockholm, Sweden. Writ-ten informed consent was collected from each participant.

2.3

Assessment of cerebrovascular diseases and

dementia

2.3.1

Diagnosis of dementia and Alzheimer’s

disease

Dementia was determined through clinical and cognitive examinations administered according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition criteria (DSM-IV). A three-step proce-dure was followed, in which two physicians working independently made a preliminary diagnosis and a third opinion was obtained from a senior neurologist whenever a disagreement occurred.14_For

par-ticipants who had died before the subsequent follow-up examination, dementia diagnosis was made by reviewing the patient and death reg-isters. AD was diagnosed according to the National Institute of Neuro-logical and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria.15

2.3.2

Diagnosis of ischemic stroke

Information on cerebrovascular diseases and IS at baseline and during the follow-up period was obtained from clinical examinations in SNAC-K interviews as well as the patient and death registers. Specifically, fol-lowing the clinical practice routine, the diagnosis of cerebrovascular diseases and IS was made in consideration of clinical manifestations and neuroimaging, which is recorded regularly in the Swedish National Patient Register. If a participant died from acute cerebrovascular dis-eases or IS-related disorders, the relevant ICD codes were recorded in the Swedish Cause of Death Register. From the records in the registers, we identified participants with cerebrovascular diseases using ICD-10 codes I60-I64, I66, I67, I69, G45, and G46.16_{IS was specifically}

identi-fied using ICD-10 codes I63 and I64.

2.4

Demographic factors

Educational level was assessed as maximum years of schooling educa-tion, and divided into elementary school, secondary school, or univer-sity/above. Occupations were recorded according to the self-reported longest-held occupation in adult life.17_{The most recent work before}

retirement was used in defining occupational class if participants did not provide information on time periods but gave information on types

of work. The occupation was dichotomized as manual workers (blue-collar) versus non-manual workers (white-(blue-collar).18

2.5

Apolipoprotein E (

APOE) gene

At baseline, genomic deoxyribonucleic acid was obtained from periph-eral blood samples. Using a standard polymerase chain reaction proce-dure, apolipoprotein E (APOE) genotyping was performed by two tech-nicians who were blind to all other data.19

2.6

Vascular risk burden and mental health

2.6.1

Vascular risk factors

We used information from self-reported questionnaire to assess alco-hol consumption, smoking status, and sedentary lifestyle. Specifically, alcohol consumption was quantified as numbers of standard drinks per week, and a standard drink in Sweden contains roughly 12 g of alcohol. Heavy drinking was defined as alcohol consumption per week of_>14 standard drinks for males or>7 standard drinks for females. We clas-sified no/light-to-moderate drinking as alcohol consumption per week of≤14 standard drinks for males or ≤7 standard drinks for females.20

Smoking status was categorized as never, former, or current smoker. A sedentary lifestyle was defined as no exercise or no regularly health-/fitness-enhancing exercise according to the level of exercise.21

At baseline, we took non-fasting venous blood samples from par-ticipants, and the routine analyses of blood samples were applied at Sabbatsberg Hospital, Stockholm, Sweden. Glycated hemoglobin was measured using the Swedish Mono–S High Performance Liq-uid Chromatography.13 _{Diabetes was ascertained based on}

self-report, medical records, glycated hemoglobin_{≥6.5%, or use of} hypo-glycemic agents. Arterial blood pressure was measured with a sphyg-momanometer, on the right arm in a sitting position. We measured blood pressure twice with a 5-minute interval, and the mean of the two readings was recorded.13_{Hypertensive status was classified into three}

categories: no hypertension, controlled hypertension (<150/90 mm Hg), and uncontrolled hypertension (_{≥150/90 mmHg).}22, 23_We

mea-sured height and weight of participants when they wore light clothes and no shoes. Body mass index (BMI) was calculated as weight (kilogram) divided by height (meter) squared, and categorized into three groups: <18.5 kg/m2_{, 18.5 to 24.9 kg/m}2_{, or ≥25 kg/m}2_. Serum total cholesterol was assessed using standardized enzymatic assay.13 High cholesterol was defined as non-fasting serum total cholesterol_{≥6.22 mmol/L or self-reported use of cholesterol-lowering} medications.24

2.6.2

Heart diseases

Heart diseases at baseline were assessed using the ICD codes derived from the physical examination at baseline and integrated with infor-mation from the patient registry. The major heart diseases included

coronary heart disease (ICD-10: I20-I22, I24, I25, Z951, Z955), heart failure (ICD-10: I110, I130, I132, I27, I28, I42, I43, I50, I515, I517, I528, Z941, Z943), and atrial fibrillation (ICD-10: I48).

2.6.3

Depressive symptoms

Depressive symptoms were assessed at baseline during the medical examinations and defined as present versus absent, according to items from the DSM-5 and DSM-IV-TR, which list nine different symptom domains for depression diagnoses.26_{We further used the}

Comprehen-sive Psychopathological Rating Scale (CPRS) to diagnose depression and identified the items from the CPRS that represent each of the nine different symptom domains. Depressive symptoms according to DSM were defined as present or absent based on rating according to the CPRS.25

2.7

Psychosocial factors

2.7.1

Psychological well-being

The 10-item short version of Positive and Negative Affect Sched-ule (PANAS) was used to measure the emotional components of well-being.26 _{At baseline, participants were asked to report the}

fre-quency of specific positive and negative emotional states during the last 12 months. The emotional states included in the PANAS Posi-tive Affect (PANAS-PA) are acPosi-tive, enthusiastic, alert, inspired, and determined. PANAS Negative Affect (PANAS-NA) includes distressed, scared, upset, nervous, and afraid. The response options were “not at all,” “a little,” “somewhat,” “quite a bit,” and “very much,” which were coded from one to five. Using confirmatory factor analysis based on the first-level original scores of the 10 items, a second-level psychological well-being latent score was generated (Figure S3 in supporting infor-mation), and further divided into tertiles (low, medium, and high).

2.7.2

Social network index

The social network index was derived from two components, social connections and social support, and it was in agreement with a pre-viously validated procedure.27_{Social connections describe social}

net-work size and contact frequency, including the information on mari-tal status; living arrangement; number of children; friendships; parent-hood; the number of contacts available to turn to; frequency of direct or remote contacts with parents, children, relatives, neighbors, and friends. Social support measures perceived support and satisfaction with the aforementioned contacts, perceived material and psychologi-cal support, sense of affinity with relatives and neighbors, and whether the participant was part of a group of friends. Raw scores on social con-nections and social support were standardized into z scores and then averaged to create a social connection index and a social support index. The correlation between the social connection index and support index

was substantial (0.76); we, therefore, generated a social network index by averaging the two subindices. According to the tertiles of the social network index, we divided participants into three groups (low, moder-ate, or rich) to reflect their social network levels.

2.7.3

Leisure activity

Leisure activity was defined according to a list of 26 predefined activ-ities for which participants reported their engagement and frequency during the past 12 months. Activities were categorized into three groups depending on whether they were predominantly mental, phys-ical, or social.17,27_{Mental activities included those that require}

cog-nitive involvement but not social engagement (ie, playing chess/cards, reading books, listening to music, playing an instrument, using the internet or playing computer games, and creation with clay), and was coded as low (≥1 activity), moderate (2 to 3 activities), or high (≥4 activities). Social activities included those that involve social interac-tions (ie, cinema/theater/concerts, sports events, museums/art exhi-bitions, restaurants/bar/cafés, dancing, bingo, church service, travel-ing, study circles/courses, volunteertravel-ing, and other social meetings), and was coded as low (0 activities), moderate (1 activity), or high (≥2 activities). Physical activities included light to vigorous exercise (ie, jogging, bicycling, gym/golf/other sports, walking, gardening, strolling through the woods and countryside, picking mushrooms/berries, fish-ing/hunting, and home repair or car/other repair), and was coded as low (<once/week), moderate (once/week), or high (>once/week).

2.8

Statistical analysis

We compared the baseline characteristics by incident AD and IS using t test for continuous variables and chi-squared test for categorical vari-ables. If the continuous variables were not following the normal distri-bution, Wilcoxon signed-rank tests were applied.

Cox proportional hazards regression models were applied to esti-mate the hazard ratios (HRs) and 95% confidence intervals (CIs) of AD or IS in relation to the risk factors and protective factors. Follow-up year was used as the time scale in the model. We calculated the follow-up time from the entry time (the date of the first interview at SNAC-K) until death, stroke diagnosis, AD diagnosis, or last interview date in the SNAC-K data collection, whichever came first. The proportional haz-ard assumption was tested for all predictors based on the Schoenfeld Residuals.

In order to identify shared risk and protective factors between AD and IS, a statistical threshold of P_{< .10 was applied in order not to} miss any potential factors. Specifically, we included the participants who were free of dementia and cerebrovascular disease at baseline, and two separate Cox regression models were performed to estimate the association of risk/protective factors with (1) incident AD without cerebrovascular diseases and (2) incident IS without AD, after adjust-ing for demographic factors. With a P-value_{<.10, a shared risk factor} between AD and IS was identified if the HRs in both models were>1,

and a shared protective factor was identified if the HRs in both mod-els were_{<1. To investigate the dose-response associations of shared} risk/protective factors with AD, IS, and AD/IS, aggregated scores were calculated by counting the number of shared risk and protective fac-tors, respectively. The aggregated risk/protective scores were treated as categorical variables (0, 1, and≥2) in the Cox proportional hazards regression models. Population attributable fractions (PAF) were calcu-lated to estimate the magnitude of the protective effect by levels of risk profile, following the formula: PAF_{= (proportion of cases exposed) ×} (attributable proportion in the exposed)= Pe(RRe– 1)/(1+ Pe[RRe– 1]), in which Peis the prevalence of exposure and RReis the relative risk of disease because of the exposure.28

Additional analyses were further conducted: (1) Following different guidelines, we used multiple cut-offs for cardiovascular risk factors to investigate if their associations with AD and IS vary. (2) To detect the influence of age on our results, we conducted stratification analysis by age strata (<75 vs >75 years). This is to investigate whether the asso-ciations of shared risk and shared protective factors with AD/IS var-ied by age groups. (3) To explore the role of potential reverse causal-ity, we repeated the main analyses in a sample excluding incident AD and IS cases detected in the first 3-year follow-up period or excluding those who died within 3 years from baseline. (4) To minimize residual confounding, we further adjusted for all the covariates in the model as categorical variables with more than two groups and as continu-ous variables, respectively. (5) Multiple imputations were conducted to replace the missing covariates. (6) To investigate whether a change of psychosocial well-being would play a critical role and influence its asso-ciations with AD and IS, we included PANAS data measured at 3- and 6-year visits and performed an analysis to estimate the effect of changing in psychosocial well-being on AD and IS.

We applied STATA 15.0 (StataCorp, College Station, Texas) and R software (version 3.6.0) for the analyses.

3

RESULTS

3.1

Baseline characteristics by incident AD/IS

The average follow-up time was 8.10 years (standard deviation [SD] 3.88 years, range from 0.05 to 15.33 years, 17250.84 person-years in total). Compared to the individuals without dementia or cerebrovas-cular diseases at follow-up, those who developed incident AD without cerebrovascular diseases were older; more likely to be females, seden-tary, underweight, and to have heart diseases or an APOE_{ɛ4 allele; but} less educated, less likely to be smokers, white collar, to have diabetes, high levels of psychosocial well-being and leisure activities, or a rich social network (Table1). There was no significant difference between the two groups in the proportion of alcohol consumption, hypertension, cholesterol level, or depression (P_{> .05). Compared to people without} incident IS/AD, participants with incident IS without AD were older; more likely to be sedentary, and to have cardiovascular burden; but less educated, less likely to be heavy drinkers, white collar, engaging in leisure activities; or have a high level of psychological well-being. There

was no significant difference between the two groups in terms of sex, smoking status, diabetic status, depression, APOE_{ɛ4 status, and social} network size (P> .05).

3.2

Shared risk and protective factors between

AD and IS

The shared risk factors between AD and IS were low education, a sedentary lifestyle, and having at least one heart disease (Figure1). Shared protective factors included high levels of psychological well-being, leisure-time mental activity, and physical activity, and a rich social network.

Apart from the shared risk factors, specific risk factors for AD included current smoking, depression, and positive APOE_{ɛ4 status,} and specific risk factors for IS were male sex, hypertension (either controlled or not controlled), high cholesterol, and overweight/obesity (Table S1 in supporting information).

3.3

Aggregated scores of shared risk/protective

factors and AD/IS

An aggregated shared risk score (range: 0 to 4) and shared protective score (range: 0 to 4) were generated by counting the number of the shared risk or protective factors at the individual level, respectively. When we scored for heart diseases, a score of 1 was given to those who had only one heart disease, and a score of 2 was given to those who had two or more heart diseases. This is because the estimated risk (HRs) of AD/IS varied by the numbers of heart diseases.

Compared to the group without any shared risk factor, the group with only one shared risk factor did not show significantly increased risk of AD (HR: 1.86, 95% CI: 0.96 to 3.57) or IS (HR: 1.09, 95% CI: 0.74 to 1.59), but the group with two or more shared risk factors showed substantially increased risk of AD (HR: 3.83, 95% CI: 1.94 to 7.53) and IS (HR: 2.20, 95% CI: 1.46 to 3.32; Table2). Participants were, there-fore, classified into two groups: “low risk profile group” (risk index 0 to 1) or “high risk profile group” (risk index≥2). Compared to the group with low risk profile, the high risk profile group showed a higher risk of AD as well as IS in the multi-adjusted models. Similar associations were observed when either AD or IS were combined as one outcome (Table S2 in supporting information).

Similarly, given that the significant association of protective factors with IS or AS was already observed when one shared protective fac-tor was present, we further categorized participants into two groups: positive protective profile (_{≥1 protective factor) and negative} protec-tive profile (0 protecprotec-tive factors). Compared to the group with nega-tive protecnega-tive profile, the posinega-tive protecnega-tive profile group displayed significantly reduced risk of AD (HR: 0.56, 95% CI: 0.36 to 0.87) and IS (HR: 0.51, 95% CI: 0.38 to 0.68), and results were consistent between age- and sex-adjusted models and multi-adjusted models. When using AD/IS as a combined outcome, a decrease in the risk of IS/AD of around 50% was observed in the protective profile group (HR: 0.54, 95% CI: 0.44 to 0.66; Table S2).

TA B L E 1 Baseline characteristics of participants by incident Alzheimer’s disease or ischemic stroke developed during the 15-year follow-up perioda

No dementia and cerebrovascular disease

Incident AD without cerebrovascular diseasea

Incident cerebrovascular disease without ADa

(n= 1738) (n= 132) P-valueb _{(n= 260) P-value}c

Age (y), mean (SD) 70.40 (10.05) 81.09 (8.19) <.001 77.03 (9.22) <.001

Females, n (%) 1083 (62.31) 99 (75.00) .004 131 (61.92) .904 Education level, n (%)d Elementary 217 (12.49) 30 (22.73) 48 (18.46) Secondary 834 (47.99) 78 (59.09) 144 (55.38) University 686 (39.49) 24 (18.18) _<.001 68 (26.15) _<.001 Occupation, n (%)d Blue collar 315 (18.25) 42 (32.06) 78 (30.35) White collar 1411 (81.75) 89 (67.94) _<.001 179 (69.65) _<.001 Smoking status, n (%)d Never 789 (45.74) 78 (60.00) 127 (48.85) Former 680 (39.42) 34 (26.15) 108 (41.54) Current 256 (14.84) 18 (13.85) .004 25 (9.62) .079 Heavy drinking, n (%)d _{331 (19.14) 19 (14.39) .178 34 (13.23) .022} Sedentary lifestyle, n (%) 443 (25.49) 49 (37.12) .003 80 (30.77) _<.001 Diabetes, n (%) 160 (9.21) 5 (3.79) .034 33 (12.69) .076 Hypertension, n (%)d _{1222 (70.64) 98 (74.24) .379 234 (90.00) <.001} High cholesterol, n (%)d _{608 (36.04) 53 (43.09) .117 111 (43.53) .021} BMI, n (%)d <18.5 734 (42.23) 67 (50.76) 98 (11.78) 18.5–24.9 45 (2.59) 6 (4.55) 1 (0.38) ≥25 911 (52.42) 43 (32.58) <.001 147 (56.54) .009 Heart diseases 0 1470 (84.58) 98 (74.24) 179 (68.85) 1 176 (10.13) 22 (16.67) 50 (19.23) ≥2 92 (5.29) 12 (9.09) .008 31 (11.92) _<.001 APOE_{ɛ4 allele, n (%)}d _{460 (26.47) 54 (40.91) <.001 63 (24.23) .609} Depression, n (%)d _{86 (4.95) 9 (6.82) .358 9 (3.46) .484}

Psychological well-being, mean (SD)d _{0.07 (0.52) –0.20 (0.46) <.001 –0.08 (0.50) <.001}

Leisure activity, mean (SD)d _{2.58 (1.49) 1.85 (1.35) <.001 2.25 (1.41) .002}

Social network, mean (SD)d _{0.09 (0.53) −0.09 (0.59) <.001 0.04 (0.52) .158}

Abbreviations: AD, Alzheimer’s disease; APOE, apolipoprotein gene; BMI, body mass index; IQR, interquartile range; SD, standard deviation.

a_{Participants with incident ischemic stroke in the table did not include those that developed AD, and participants with incident AD did not include those that}

developed ischemic stroke.

b_{P-value was calculated by comparing the baseline characteristics between the non-demented & non-stroke participants and participants who developed AD.} c_{P-value was calculated by comparing the baseline characteristics between the non-demented & non-stroke participants and participants who developed}

ischemic stroke.

d_{Missing values: 1 person for education level, 16 for occupation, 15 for smoking status, 12 for heavy drinking, 8 for hypertension, 65 for high cholesterol, 78}

F I G U R E 1 Hazard ratio (95% CI) of Alzheimer’s disease (AD) and ischemic stroke by shared risk and protective factors. CI, confidence interval; Ref, reference. Notes: Models were adjusted for age, sex, and education. Psychological well-being, leisure activity, and social network were divided into three groups, according to their tertiles. High level of psychological well-being or leisure activity refers to the top tertile group, and low level of psychological well-being or leisure activity refers to the bottom tertile group. Rich social network refers to individuals in the top tertile group, and limited social network refers to those in the bottom tertile group. Table S1 and Table S2 provide detailed information related to each risk and protective factor for incident AD and ischemic stroke.╪.05_{< P < .10,}*_{.01< P < .05,}**_{P< .01}

TA B L E 2 Hazard Ratio (95% CI) of Alzheimer’s disease and ischemic stroke by shared risk/protective profiles

Incident Alzheimer’s disease (n= 132/N = 1586) Incident ischemic stroke (n= 260/N = 1998)

Rate per 1000 person-years (95% CI) Model 1a HR (95% CI) Model 2a HR (95% CI) Rate per 1000 person-years (95% CI) Model 1a HR (95% CI) Model 2a HR (95% CI)

Shared risk profileb

Risk factor score, categorical

0 2.76 (1.64—4.67) Ref. (1.00) Ref. (1.00) 8.06 (5.98—10.87) Ref. (1.00) Ref. (1.00)

1 7.51 (5.78—9.76) 1.43 (0.79—2.59) 1.69 (0.87—3.29) 13.32 (11.00—16.13) 1.20 (0.83—1.73) 1.12 (0.77—1.63)

≥2 20.75 (16.17—26.61) 2.64 (1.44—4.85)** 3.45 (1.72—6.90)** 34.45 (29.62—41.45) 2.58 (1.77—3.77)** 2.49 (1.66—3.72)** Risk profile groups

Low (score 0-1) 5.59 (4.42—7.07) Ref. (1.00) Ref. (1.00) 11.20 (9.53—13.16) Ref. (1.00) Ref. (1.00)

High (_≥2) 20.75 (16.17—26.61) 1.99 (1.39—2.95)** 2.25 (1.50—3.37)** 34.45 (28.62—41.45) 2.26 (1.73—2.96)** 2.29 (1.71—3.07)** Shared protective profileb

Protective factor score, categorical

0 17.51 (13.92—22.03) Ref. (1.00) Ref. (1.00) 28.20 (23.67—33.61) Ref. (1.00) Ref. (1.00)

1 7.26 (5.13—10.27) 0.44 (0.29—0.67)** 0.64 (0.40—1.03)╪ 13.96 (10.96—17.76) 0.51 (0.38—0.70)** 0.56 (0.40—0.78)** ≥2 2.61 (1.63—4.21) 0.30 (0.17—0.51)** 0.44 (0.24—0.80)** 8.88 (6.91—11.41) 0.43 (0.31—0.60)** 0.44 (0.30—0.64)** Protective profile groups

– (score 0) 17.51 (13.92—22.03) Ref. (1.00) Ref. (1.00) 28.20 (23.67—33.61) Ref. (1.00) Ref. (1.00)

+ (score ≥1) 4.49 (3.39—5.94) 0.38 (0.26—0.55)** 0.56 (0.36—0.87)* 10.95 (9.20—13.03) 0.47 (0.36—0.62)** 0.51 (0.38—0.68)**

a_{When modeling shared risk factor profile, we adjusted for age and sex in model 1, and additionally for hypertension, diabetes, obesity, high cholesterol,}

depression, APOE status, and number of drugs used in Model 2. In the models in which incident Alzheimer’s disease was treated as the outcome, the missing value of covariates was 8 (0.4%) for hypertension, 60 (3.2%) for high cholesterol, 64 (3.4%) for obesity, 98 (5.2%) for APOE status, and 6 (0.3%) for number of drugs used. In the models in which incident ischemic stroke was treated as the outcome, the missing value of covariates was 8 (0.4%) for hypertension, 56 (2.8%) for high cholesterol, 62 (3.1%) for obesity, 104 (5.2%) for APOE status, and 6 (0.3%) for number of drugs used. When modeling shared protective factor profile, we adjusted for age and sex in model 1, and additionally for social leisure activity in model 2. In the models in which incident Alzheimer’s disease was treated as the outcome, the missing value of covariates was 198 (10.6%) for social leisure activity. In the models in which incident ischemic stroke was treated as the outcome, the missing value of covariates was 202 (10.1%) for social leisure activity.

b_{Shared risk factor score was generated by counting the number of following features in an individual: education level below university or college, sedentary}

lifestyle, and the number of heart diseases. Shared protective score was calculated by counting the numbers of following features in an individual: high level of psychological well-being, intensive leisure-time mental activity, intensive leisure-time physical activity, and rich social network.

*01< P < .05. **P_{< 01.}

╪_{05< P < .10.}

Abbreviations: CI, confidence interval; HR, hazard ratio.

3.4

Counteracting effect of the shared protective

profile on AD/IS in relation to levels of the shared

risk profile

There was an interaction between the shared risk score and shared protective score on AD (P= .04), but not on IS (P = .38). A four-category variable of joint exposures was created, by combining the shared risk profile (high vs low) and the shared protective profile (negative vs pos-itive). Figure2shows the associations of incident AD and IS with the joint exposures.

Compared to the “high risk and protective (–)” group, only the “low risk and protective (_{+)” group presented significantly reduced AD risk} (Figure2A), whereas the other three groups all showed substantial reduced IS risk (Figure2B). The proportion of incident AD cases that could be prevented due to a positive protective profile was 47% (95% CI: 0.22 to 0.64) in participants with a low risk profile and 38% (95%

CI: 0.00 to 0.62) in those with a high risk profile. In addition, 28% (95% CI: 0.12 to 0.41) of incident IS cases in participants with a low risk pro-file and 31% (95% CI: 0.02 to 0.52) of IS cases in participants with a high risk profile were attributable to a positive protective profile. Sim-ilar results were obtained when AD and IS were combined (Figure2C). The protective profile seemed to reduce the risk of AD/IS by 33% (95% CI 0.21 to 0.42) among individuals with a low risk profile and by 28% (95% CI: 0.08 to 0.44) among individuals with a high risk profile.

3.5

Population attributable fraction of shared risk

and protective factors for AD/IS

The proportions of either AD or IS cases that would be reduced by con-trolling the shared risk factors and promoting the shared protective factors are shown in Figure3. Specifically, 26% (95% CI: 0.10 to 0.38)

F I G U R E 2 Joint effects of shared risk and protective profiles on incident Alzheimer’s disease (AD) and ischemic stroke. CI, confidence interval; HR, hazard ratio. Notes: P-values were obtained by estimating the effect of the protective profile (positive versus negative) on incident AD (a), incident ischemic stroke (b), and incident AD or ischemic stroke (c) by levels of risk profiles

F I G U R E 3 Population attributable fraction of shared risk and protective factors for either incident Alzheimer’s disease (AD) or incident ischemic stroke (IS).a_{Protective psychosocial factors are the shared protective factors between AD and IS, including high levels of psychological} well-being, intensive mental leisure activity, intensive physical leisure activity, and a rich social network. Protective psychosocial factors (₊₎ indicates that an individual has at least one of the shared protective factors. Notes: The figures in the circles represent the percentage reduction of cases of either AD or IS if one risk factor (low education level), two risk factors (low education level and sedentary lifestyle), three risk factors (low education level, sedentary lifestyle, and heart diseases) were eliminated, and at least one protective factor was additionally promoted

of AD/IS cases could be prevented if all individuals in a population had a high level of education, and 42% (95% CI: 0.26 to 0.55) of AD/IS cases could be prevented if all individuals in a population were free from any of the shared risk factors (ie, low level of education, sedentary lifestyle, and heart diseases). In total, 58% (95% CI: 0.42 to 0.69) of AD/IS cases could be prevented by promoting a positive protective profile in indi-viduals free from any of the shared risk factors.

3.6

Additional analyses

Similar results were observed in the old-old group (_{>75 years) and} the young-old group (<75 years) regarding the association of shared risk/protective factors with AD/IS (Tables S3 and S4 in supporting information). Furthermore, the findings were similar when we applied different cut-offs for cardiovascular risk factors (Table S5 in supporting information), when we removed the incident AD and IS cases detected in the first year follow-up period or those who had died within 3-years from baseline (Table S6 in supporting information), when covari-ates were adjusted for as either 3 levels of categorical variables or as continuous variables, and when we conducted multiple imputation to replace the missing covariates in the models. Finally, change in psy-chosocial well-being was not significantly associated with either AD (HR [95% CI]_{= 0.78 [0.46 to 1.34]) or IS (HR 0.82, 95% CI: 0.60 to 1.13)} in our additional analyses.

4

DISCUSSION

In this population-based long-term follow-up study of Swedish older adults aged 60 years and above, we found that: (1) low level of educa-tion, a sedentary lifestyle, and heart diseases are the shared risk fac-tors for AD and IS. High levels of psychological well-being, leisure-time mental and physical activity, and a rich social network are the shared protective factors for AD and IS; (2) a protective profile may decrease 47% of AD and 28% of IS risk among older adults with a low risk pro-file, and 38% of AD and 31% of IS risk in those with a high risk profile; and (3) more than half of the cases with either AD or IS could be theo-retically preventable by controlling the risk profile and promoting the protective profile.

Previous population-based studies have demonstrated that certain risk and protective factors are related to both AD and stroke, including vascular risk factor burden, depression, and social networks.8,9,29–31

When investigating the association of these factors with AD or IS, previous researchers focused exclusively on one of the outcomes, or treated stroke and dementia as a combined outcome. In the current study, we examined AD and IS cases in a mutually exclusive manner, and the shared risk factors identified accordingly may suggest shared pathophysiologies between AD and IS. To the best of our knowledge, this is the first study attempting to detect shared risk/protective fac-tors for AD and IS, involving a large range of demographic, genetic, vas-cular, mental, and psychosocial factors.

Several studies have developed scores or indices to predict the risk of stroke or dementia, based on the expected accumulated synergis-tic effect of multiple risk factors.30,32,33The Framingham Stroke Risk Score (FSRS) and the Cardiovascular Risk Factors, Aging and Demen-tia (CAIDE) demenDemen-tia risk score are two recognized examples.34_The

only overlapping modifiable risk factor between the two scores is high systolic blood pressure. However, the Whitehall II study has revealed that the FSRS is associated with accelerated cognitive decline over 10 years,35_{and another study showed that the FSRS score might even}

perform better than the CAIDE score in predicting cognitive decline.34 These findings indicate that the stroke risk–related factors, may play a potential role, either independently or synergistically, in the develop-ment of dedevelop-mentia or AD.

Female sex is a well-established risk factor for AD, but sex was not associated with AD in our analyses. The population in the current study consists of a random sample (63.6% females) from central Stockholm (Kungsholmen) during the years 2001 to 2003. Interestingly, females in our sample were more likely to drop out either at baseline or during the follow-up period. Specifically, among those who refused to partic-ipate in follow-up interviews, 64.36% were female, and among those who died before the first follow-up interview, 57.39% were female. A lower education level and a higher burden of multimorbidity in females than in males may contribute to the higher attrition rates in females, which may further influence the association between female sex and the risk of AD. The associations of cardiovascular risk factors (eg, high blood pressure, and high total cholesterol level) with AD and IS may vary by age, the presence of frailty, multimorbidities, and treatments. Guidelines for the diagnosis and management of certain cardiovascular risk factors (eg, hypertension and high cholesterol) have been updated recently.36,37_{In our additional analysis, we have applied multiple}

cut-offs to cardiovascular measurements in the additional analyses, and the results are consistent with our main findings—cardiovascular measure-ments (eg, blood pressure and BMI) showed a tendency of protective effect on AD but a risk effect on IS. The reduced hazard of AD asso-ciated with cardiovascular measurements may be driven partially by reverse causality.

In the current study, three major heart diseases (ie, coronary heart disease, atrial fibrillation, and heart failure) were involved in the analy-sis, and we counted the numbers of heart diseases in each participant as a proxy of aggregation. Yet, future studies need to pay attention when the AD/IS risk was estimated in relation to a distinct combina-tion of two heart diseases, especially when treatments were taken into account. For example, heart failure or atrial fibrillation alone was asso-ciated with a higher risk of mortality than coronary heart disease.38

Co-existince of atrial fibrillation and heart failure may worsen the disease progression and complicate treatments. Subtypes of heart failure (eg, heart failure with preserved ejection fraction and heart failure reduced ejection fraction) are linked to variations in treatments, survival rates, and subsequent stroke risk. In addition, treatments for heart dis-ease (eg, anticoagulant therapy, antiplatelet agents, and statins), could modify the association between burden of heart diseases and AD/IS. Anticoagulation medication in particular may significantly reduce the stroke risk in atrial fibrillation patients; however, there is still debate

regarding whether warfarin anticoagulation may increase the risk of all dementia types in atrial fibrillation patients.39_{Therefore, the diverse}

cardiovascular pathologies, specific aggregations of heart diseases, and treatments are vital factors to consider for future studies when inves-tigating the association of AD/IS with heart diseases.

Moreover, psychosocial factors, such as an active and socially inte-grated lifestyle, have been suggested to protect older adults from both stroke and dementia/AD.12,40_{A dose-response association of}

psy-chosocial factors with AD has been reported when such factors were aggregated together into a cognitive reserve score,41as was the case in our study. We moreover found that a positive protective profile can offset the risk of AD or IS due to shared risk profiles. This is encourag-ing because, even in older adults with a high risk profile with a low level of education, a sedentary lifestyle, and multiple heart diseases, approx-imately one third of AD and IS risk, could be counteracted through pro-moting psychological well-being, leisure activity, and social network.

The Lancet Commission life-course model has demonstrated that up to 35% of dementia cases were potentially preventable if nine life-long factors were diminished, including early life low education, mid-life risk factors (hearing loss, hypertension, and obesity), and late-life risk factors (smoking, depression, physical inactivity, social isolation, and diabetes).42_{The INTERSTROKE study, a world-wide study including}

32 countries and focusing on 10 potentially modifiable risk factors (ie, blood pressure, physical activity, apolipoprotein B-to-apolipoprotein A ratio, diet, waist-to-hip ratio, psychological factors, smoking, cardiac events, alcohol consumption, and diabetes), has presented that the 10 factors were collectively linked to about 90% of PAF of IS. In addition, 90% of the PAF of IS was independent with regions, ethnic groups, sex, and age. In the current study, we found that shared risk and pro-tective factors were associated with nearly 60% of PAF of AD/IS. The varied PAF between our study and others may be due to the different age, diversity in the combination of risk/protective factors, and inclu-sion/exclusion criteria of outcomes.

Vascular dysfunction, atherosclerosis, and deposition of amyloid in cerebral vessels may partially explain the common underlying mecha-nism between AD and IS.44,45_{The hypoperfusion and hypoxia caused}

by atherosclerosis may boost the production of A_{β. The Aβ, in turn, may} accelerate the formation of atherosclerotic lesions through endothe-lial dysfunction or vascular oxidative stress, leading to further vas-cular damage in the brain.40,41_{Mitochondrial dysfunction with}

epi-genetic impairment in oxidative respiration appears to be the earli-est mechanism in the progression of AD and IS, and they are closely linked to the age-related energy deficits.46_{Certain risk factors, such}

as peripheral insulin resistance, could largely contribute to this energy deficit and exacerbate A_{β/tau accumulation. Life-long risk factors (eg,} low education, sedentary lifestyle, and heart diseases), in theory, may act in different cascades of IS and AD pathologies. For example, one factor may cause oxidative stress and trigger atherosclerosis in mid-dle age, and another factor may lead to the thickening of vascular basement membranes and hypoperfusion in older age. Other patholo-gies or clinical profiles that are captured by neuroimaging or molec-ular levels, such as microbleeds and cerebrovascmolec-ular reactivity, may play an essential role in connecting AD and IS, and may easily be

influenced by shared risk factors as well.47_{However, it is difficult to}

speculate the direct causality from the shared risk factors to the com-mon mechanisms, due to lacking neuroimaging and biomarker confir-mation, and unmeasured confounding. Moreover, mixed pathologies are frequently observed in AD patients or the aging brain.48

Specif-ically, cerebral amyloid angiopathy and small vessel disease are the common vascular pathologies in the aging brain and in AD cases. Cer-tain risk factors, such as heart diseases and cardiovascular risk fac-tors, may give rise to cerebral small vessel disease and consequently, a higher AD or IS risk.49,50The mechanisms in which positive psy-chosocial factors may lower or compensate the risk of AD and IS are not fully understood. Nevertheless it is plausible to assume that the reduction in AD risk could be achieved through vascular mechanisms that are in part independent of AD pathology. This hypothesis is sup-ported by a recent study displaying that midlife physical activity is associated with a lower incidence of vascular dementia, but not AD.51

The cognitive reserve concept assumes that individuals with certain lifestyles and psychosocial factors could cope better with increasing brain lesions (eg, AD pathology), reflecting a more flexible or adap-tive cogniadap-tive network.40,41 _{In the current study, the findings}

sug-gest that individuals with more positive psychological profiles tend to have better self-perceptions of aging, which may impact their val-ues, health behaviors, health-care use, and access to instrumental and emotional support.52 These factors may reduce and/or make people more resilient to psychosocial stress, and therefore improve cardio-vascular health by enhancing the immune system or reducing systemic inflammation.40

This study has several strengths, including the relatively large study sample with a long follow-up period, the high rate of participation, and the comprehensive diagnoses using multiple resources (eg, phys-ical examination, patient and death registers). The structured SNAC-K interviews provide a wide range of information on demographics, clin-ical, lifestyle, psychosocial, and behavioral factors. Yet, several limita-tions need to be pointed out. First, using self-reported questionnaire data on psychosocial factors may introduce measurement bias. This is especially true among older adults who may have cognitive impair-ment or memory complaints. Second, selection bias may have been introduced by excluding those subjects who did not have any follow-up information or who refused to participate in follow-follow-up interviews, although the proportion of those people was rather small (10.3%). A few factors need to be taken into accounts in future validation stud-ies, such as heart diseases, cancer, and COVID-19. Specifically, when a world pandemic that is associated with elevated mortality in older pop-ulations occurs, such as COVID-19, survival bias might be introduced to a study to affect the link of shared risk/protective factors to AD/IS. Third, similar to most observational studies, bias that may be caused by unmeasured confounding factors remains (eg, low-density lipopro-tein), even though multiple sensitivity analyses have been carried out in the current study. The factors that we included in this study were from baseline. With a rather long follow-up period in the current study, certain risk or protective factors may vary with time, for instance, the increasing number of heart diseases and reduction in social networks. Furthermore, certain factors, such as the use of medications, treatment

of heart diseases, or psychosocial factors, may interact with shared risk factors to influence the AD/IS risk over time. Future studies should fur-ther verify the time-varying effect of those factors in relation to both AD and IS. High education is often treated as one of the important cog-nitive reserve proxies, and showed a protective effect on both AD and IS. The risk factors in our study have been predefined as being either pathogenic or as negative exposures in early life, hence, both low edu-cation and sedentary lifestyles are identified as risk factors. However, it is worth investigating the underlying mechanisms of resilience and reserve between AD and IS with respect to the cognitive reserve prox-ies. Fourth, IS includes a wide range of subtypes, and it can be sub-divided into several categories including cardioembolism, small-vessel occlusion, large-artery atherosclerosis, and stroke of undetermined etiology. For example, cardioembolic stroke (embolic events occur in the valve or chambers of the heart) and lacunar stroke (blood vessel occlusion in a perforating artery) are two subtypes of IS. The diverse etiologies and treatments of the two IS categories may display different risk factors; disease burden; comorbidity; and eventually, influence the connection with AD. In the current study, we focused only on general IS without specifying subcategories. Fifth, the AD and IS cases in the cur-rent study were based on the clinical diagnosis, which do not represent “pure” AD or “pure” ischemic damage. The advent of molecular neu-roimaging techniques enables us to identify the often-combined cere-brovascular disease and AD pathologies in vivo, and more evidence has accumulatively suggested that mixed pathologies are common in aging and important in lowering the threshold for cognitive impairment and dementia.53_{Lack of neuroimaging and biomarkers in this study makes} it difficult to relate the shared factors to a “pure” specific pathology. Sixth, although our results display a sufficient reduction in AD/IS risk at the population level by targeting both shared risk and protective factors, proper interpretation is needed at the individual level because PAF does not allow the designation of affected individuals. Finally, our study participants live in central Stockholm and have a relatively higher socioeconomic status and education level than the general older popu-lation. Caution is therefore needed when generalizing our findings to other populations.

In conclusion, several shared risk and protective factors between AD and IS were identified among adults aged 60 years and above. Late-life AD and IS risk may be mitigated by targeting multiple lifelong risk/protective factors, including (1) early-life education; (2) midlife lifestyles and risk factors of heart diseases; and (3) late-life psychoso-cial well-being, sopsychoso-cial network, and leisure time activity. Moreover, late-life psychosocial factors may even counteract the harmful effect of risk factors that occurred earlier in life on both AD and IS. Our find-ings support the notion that AD and IS may share pathophysiologi-cal mechanisms or mixed pathologies (eg, neurodegenerative and vas-cular pathologies), which may be the dominant etiology for AD. We, therefore, provide evidence for the implementation of common pre-ventive strategies for both disorders. Future studies are essential to better understand the compensatory mechanisms in AD and IS pathol-ogy. Clinical trials may consider using multifactor interventions, such as targeting heart diseases and psychosocial factors, to prevent AD and stroke.

AC K N O W L E D G M E N T S

The SNAC-K (http://www.snac.org) is financially supported by the Swedish Ministry of Health and Social Affairs; the participating county councils and municipalities; the Swedish Research Council; and the Swedish Research Council for Health, Working Life and Welfare. In addition, W.X. received grants from the Swedish Research Council (No 2017-00981), the National Natural Science Foundation of China (No. 81771519), the Konung Gustaf V:s och Drottning Victorias Frimurare Foundation (No. 2016-2019), Alzheimerfonden (2017-2018), and Eva och Wera Cornell Stiftelsen. R.W. received grants from the Swedish Research Council (No 2016-06658), Loo and Hans Osterman tion (No. 2017-00205, 2019-01265), and Swedish Dementia Founda-tion (2019-0000). Finally, this project is part of the CoSTREAM (www. costream.eu) and received funding from the European Union’s Horizon 2020 research and innovation program (No. 667375).

C O N F L I C T S O F I N T E R E S T

The authors have no conflicts of interest to declare.

AU T H O R C O N T R I B U T I O N S

R.W. and W.X. conceptualized and designed the study, R.W. performed the data analysis and drafted the manuscript. C.Q., H.-X. W., C.S.D., Y.S., and A.C.-L. contributed to the data interpretation and revision of the manuscript and approved the final draft. R.W. has the full access to all the data in this study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

O RC I D

Rui Wang https://orcid.org/0000-0001-7209-741X

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S U P P O RT I N G I N F O R M AT I O N

Additional supporting information may be found online in the Support-ing Information section at the end of the article.

How to cite this article: Wang R, Qiu C, Dintica CS, et al.

Shared risk and protective factors between Alzheimer’s disease and ischemic stroke: A population-based longitudinal study. Alzheimer’s Dement. 2021;1-14.