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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Alzheimer Dis Assoc Disord. Author manuscript; available in PMC 2016 July 1.
Published in final edited form as:
PMCID: PMC4514569

Mid-Life Proteinuria and Late-Life Cognitive Function and Dementia in Elderly Men: The Honolulu-Asia Aging Study



Impaired renal function has been linked to cognitive impairment. We assessed mid-life proteinuria and late-life cognitive function in elderly Asian males.


The Honolulu Heart Program is a prospective study that began in 1965 with 8,006 Japanese-American men ages 45–68 years. Mid-life proteinuria was detected by urine dipstick in 1971–74. The Honolulu-Asia Aging Study began 20 years later, with cognitive assessment by the Cognitive Abilities Screening Instrument (CASI) in 3,734 men. Standard criteria were used to classify 8-year incident dementia and subtypes.


The age-adjusted incidence of dementia increased significantly from 13.8, to 22.8, to 39.7 per 1,000 person years follow-up, among those with no, trace and positive mid-life proteinuria, p=0.004. Using linear regression adjusting for age, education, APOEε4, stroke, hypertension, systolic blood pressure, diabetes, fasting blood glucose, physical activity and baseline CASI, those with positive proteinuria had significantly higher annual change in CASI over 8 years follow-up (−1.24, p=0.02), reference=no proteinuria. Multivariate Cox regression found positive proteinuria had a significant association with incident all-cause dementia (RR=2.66, 95%CI=1.09–6.53, p=0.03), but no significant associations with incident Alzheimer’s disease or vascular dementia.


Mid-life proteinuria was an independent predictor for late-life incident all-cause dementia and cognitive decline over 8 years.

Keywords: dementia, cognitive decline, proteinuria, Japanese-American men, longitudinal cohort study


With the aging of the population, the worldwide estimate of the number of people with dementia is expected to rapidly increase over the next several decades, from 25 million in 2000, to 63 million by 2030 and 114 million by 2050.1 As treatments become available, the early recognition of dementia will become increasingly important.

Both albuminuria and lower estimated glomerular filtration rate (eGFR) have been linked to cognitive impairment in cross-sectional studies.24 One cross-sectional study also found that the prevalence of dementia is higher in populations with albuminuria.5 However, prospective studies of the association between renal function (using eGFR610 and albuminuria8,11 as the main predictors) and risk of cognitive decline have had mixed results.

There have been few prospective studies focusing on the association between renal function and incident dementia. Two small longitudinal studies in Japan showed mixed results. One found that chronic kidney disease (CKD) (defined as eGFR less than 60mL/min per 1.73m2 or continuous presence of kidney impairment such as albuminuria for 3 months or longer) was significantly associated with 5-year incident dementia,12 while the other found that proteinuria was not significantly associated with 7-year incident Alzheimer's disease (AD) or vascular dementia (VaD).13 One large population based study in the U.S., the Cardiovascular Health Cognition Study (CHCS), found that serum creatinine was significantly associated with 6-year incident all-cause dementia and VaD, but not AD.14 The CHCS did not examine the relationship between proteinuria and incident dementia.

The goal of this study was to assess whether mid-life proteinuria was associated with cognitive decline or incident dementia in late-life, over 20 years later, in a population of elderly Japanese-American men.


Study Design and Population

The Honolulu Heart Program (HHP) is a prospective, observational study that began in 1965–68 with 8,006 Japanese-American men living on the island of Oahu, Hawaii, ages 45–68 years.15 The Honolulu-Asia Aging Study (HAAS) was established 25 years later to study diseases of aging including cognitive function and dementia. Initiation of the HAAS began with exams that were given from 1991–93 to 3,734 men aged 71–93 years.16 Subjects have been followed with repeat examinations every 2–3 years.

For these analyses, we used data on proteinuria from 1971 to 1974. This early measurement of proteinuria was used to predict cognitive decline and incident dementia beginning with initiation of the HAAS 20 years later (1991–93). Longitudinal data on declines in cognitive function and incident dementia were based on 3 repeat exams that were given from 1994 to 2000.

This study was approved by the IRB of Kuakini Medical Center, and written informed consent was obtained from the study participants at each examination.

Data Collection

Predictor Variable - Proteinuria

Mid-life proteinuria was detected by urine dipstick performed during HHP exams in 1971–74. Subjects were classified into 3 groups: no proteinuria, trace, and positive (1+ to 4+ on screening dipstick). No data related to chronic kidney disease or serum creatinine were available at that time.

Outcome Variables – Cognitive Decline and Incident Dementia

We used the Cognitive Abilities Screening Instrument (CASI) to measure global cognitive function. The CASI tests 9 cognitive domains and has been validated for use in cross-cultural and cross-national studies.17 CASI scores range from 0 to 100, with higher scores indicating better cognitive function. We computed annual cognitive decline as the difference in CASI scores divided by the number of years of follow-up from baseline if there were only one repeat CASI measure available; for subjects who had two or more repeat CASI scores measured during the follow-up period, annual cognitive decline was computed as the regression coefficient of time by regressing CASI score on the lag time (years) from baseline.

At baseline, a 3-phase dementia screening process was used. Subjects were stratified by baseline CASI score and other measures, using a random sampling approach that has previously been described elsewhere.16,1820 At baseline, 209 cases of prevalent dementia were identified, and these were excluded from our analytic sample. To identify cases of incident dementia and subtypes, three follow-up examinations were performed.21 At the first follow-up examination (1994–1996), the CASI was administered at the first phase, followed by a second phase with comprehensive dementia assessment if the CASI score had dropped by at least 9 points from the initial CASI at exam 4, or if the CASI score was 77 or lower in subjects with less than 12 years of education, or if the CASI score was 79 or lower in subjects with 12 or more years of education. At the second (1997–99) and third (1999–2000) follow-up examinations, the complete dementia assessment was performed in all participants with CASI scores less than 70.

Detailed methods about dementia case-finding have been previously described.18 Standardized criteria were used to classify 8-year incident dementia (DSM-IIIR) and subtypes (AD: NINDS-ADRDA criteria22; VaD: California ADDTC criteria23), using data from follow-up HAAS examinations in 1994–1996 (3-year follow up), 1997–1999 (6-year follow up), and 1999–2000 (8-year follow up). Information used for diagnosis of dementia included history provided by a family member or proxy informant, a standardized neuropsychological test battery, and a thorough neurological examination. Standardized laboratory tests and neuroimaging (computed tomography or magnetic resonance imaging) were also used to classify the subtypes of dementia.16 Final diagnoses were assigned by consensus by an expert panel, consisting of a neurologist and two other physicians with expertise in dementia. All analyses of incidence excluded subjects with prevalent dementia identified at the baseline HAAS exam.


We identified baseline covariates based on their potential associations with both the predictor (proteinuria) and outcome variables (cognitive function). Years of formal education were determined by self-report. Apolipoprotein E genotyping was performed with restriction isotyping using a polymerase chain reaction, and subjects were classified as APOEε4 positive if they were either homozygous or heterozygous for the ε4 allele.21 Other covariates were measured during the 1991–93 exam, which served as baseline for the cognitive examinations. These included age in years and prevalent stroke (determined by hospital surveillance, with final diagnosis by consensus from a trained physician panel using standardized research criteria).24 Hypertension was defined as systolic blood pressure of 140 mmHg or higher, or diastolic blood pressure of 90 mmHg or higher, or taking medications for hypertension. In addition to hypertension, systolic blood pressure measured in mmHg was also used as a covariate since there may be residual confounding not completely captured by the dichotomous hypertension variable. We used the modified American Diabetes Association criteria for Diabetes Mellitus, defined as fasting glucose of 126 mg/dL or higher, 2-hour post load glucose of 200 mg/dL or higher, or taking diabetes medications. In addition to diabetes mellitus, fasting blood glucose measured in mg/dL was also used as a covariate since glucose abnormalities may not be completely captured by the dichotomous variable diabetes.25 Physical activity index (PAI) quantified overall metabolic output during a typical 24-hour day, by multiplying a weighting factor by the number of hours spent in a day performing each of five activity levels (no activity=1.0, sedentary=1.1, slight=1.5, moderate=2.4, and heavy=5.0).26 Smoking status was measured as pack-years of smoking by self-report. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Fasting total cholesterol level was measured in mg/dl. Alcohol consumption was determined by self-report as ounces ingested per month.

Statistical Analysis

Mean age-adjusted risk factor levels and decline in cognitive scores were compared by the 3 proteinuria groups using standard analysis of covariance methods. Age-adjusted incidence rates over 8 years of follow-up for all-cause dementia, AD and VaD were calculated by the three proteinuria groups. All analyses of incidence excluded subjects with prevalent dementia at the baseline HAAS exam.

For cognitive decline, we used linear regression to compare the effects of proteinuria on annual change in CASI score, using the “no proteinuria” group as reference. Multivariate Cox proportional hazards models were used to calculate relative risks of 8-year incident dementia and sub-types (AD and VaD) by the 3 proteinuria groups, using those with no proteinuria as reference. For both linear regression and Cox models, we performed a test for trend across proteinuria groups (no proteinuria, trace and positive). All analyses used the SAS software package (version 9.2; SAS Institute, Cary, North Carolina).


Among subjects who had proteinuria measured in mid-life and returned for cognitive testing in late-life 20 years later (n=3,583), 3,483 had no proteinuria (97.2%), 60 had trace proteinuria (1.7%) and 40 had positive proteinuria (1.1%). For the analyses on 8-year incident dementia, there were 282 cases of all-cause dementia, 166 cases of AD and 59 cases of VaD.

Table 1 compares mean characteristics at baseline cognitive testing by the three proteinuria groups using general linear models. Those with proteinuria were significantly more likely to have lower physical activity, and had significantly higher systolic blood pressure and fasting glucose levels. Otherwise, there were no significant differences in age, education, APOEε4 status, prevalent stroke, hypertension and diabetes mellitus, pack-years of smoking, BMI, cholesterol or alcohol consumption between proteinuria groups.

Table 1
Mean Characteristics at Baseline Cognitive Testing by Three Proteinuria Groups in Mid-Life.

Table 2 describes mean age-adjusted cognitive variables in late-life according to the three proteinuria groups in mid-life. We found that those with proteinuria had significantly higher declines in CASI scores at 3 years, 6 years and 8 years of follow-up (all p values < 0.05).

Table 2
Age Adjusted Mean Cognitive Variables in Late-Life by Three Proteinuria Groups in Mid-Life.

Table 3 shows number and percentages of events, and rates of incident dementia and sub-types in late-life by the three proteinuria groups. The age-adjusted rates of incident all-cause dementia increased significantly by proteinuria status, from 13.80 to 22.75 to 39.74 per 1,000 person years follow-up among those with no proteinuria, trace proteinuria and positive proteinuria respectively, p for trend = 0.004. Similarly, the age-adjusted rates of incident VaD increased significantly by proteinuria status, from 2.78 to 2.88 to 18.03 per 1,000 person years follow-up among those with no proteinuria, trace proteinuria and positive proteinuria respectively, p for trend = 0.005. We found no significant difference between rates of AD by proteinuria groups (p for trend = 0.07).

Table 3
Age Adjusted Rate of Incident Dementia and Sub-Types in Late-Life by Proteinuria Groups in Mid-Life.

We used linear regression analyses to assess annual cognitive decline (change in CASI score) by proteinuria groups (Table 4). After adjusting for age, education, APOEε4, prevalent stroke, hypertension, systolic blood pressure, diabetes, fasting blood glucose, PAI and baseline CASI score, those with positive proteinuria at baseline had a significantly higher annual decline in CASI scores over 8 years of follow-up (−1.24, p=0.02), using the no proteinuria group as reference. There was no significant association between trace proteinuria and cognitive decline.

Table 4
Linear Regression Models for Cognitive Decline Over Eight Years of Follow-up.

Incident Dementia

Separate analyses to assess risk of 8-year incident all-cause dementia and sub-types using multivariate Cox Proportional Hazards models are shown in Table 5. After adjusting for age, education, APOEε4, prevalent stroke, hypertension, systolic blood pressure, diabetes, fasting blood glucose, PAI and baseline CASI score, positive proteinuria was significantly associated with incident all-cause dementia. No significant associations were found between positive proteinuria and incident AD or VaD.

Table 5
Risk of 8-Year Incident Dementia and Subtypes using Multivariate Cox Proportional Hazards Models.


In this large, well-described, prospective cohort study, we found that mid-life proteinuria was significantly associated with cognitive decline and 8-year incident all-cause dementia in late life, over 20 years after measurement of proteinuria. These associations persisted after adjusting for factors known to be strongly associated with dementia, including age, education, APOEε4 genotype and prevalent stroke, as well as hypertension, systolic blood pressure, diabetes mellitus, fasting blood glucose, and physical activity. These results indicate that mid-life proteinuria may have significant predictive value for future cognitive decline and all-cause dementia in late life in Japanese-American men.

Several previous cross-sectional studies have found a significant association between low scores on cognitive function tests and abnormalities on eGFR.27,28 Cross-sectional studies have also found significant associations between low cognitive scores and microalbuminuria.2,4,29 One small cross-sectional observational study found a high prevalence (76%) of mild cognitive impairment in subjects with hemodialysis and stage III or IV chronic kidney disease (CKD).30 The Chronic Renal Insufficiency Cohort Study reported that among patients with CKD, cross-sectional analysis found that lower eGFR was associated with lower cognitive function.3 The Cardiovascular Health Cognition Study found that the odds of prevalent dementia increased in the presence of albuminuria.5

Various surrogate markers have been used to study renal function, including estimated glomerular filtration rate (eGFR), quantified microalbuminuria, or urine albumin to urine creatinine ratio. A cross-sectional analysis from the Third National Health and Nutrition Examination Survey (NHANES III) found that although reduced eGFR and proteinuria do not always coexist, there was a correlation between proteinuria and eGFR, with prevalence of albuminuria increasing in a step-wise fashion with decline in eGFR.31

There have been a few longitudinal studies on the relationship between kidney function and cognitive decline, with mixed results. The Rancho Bernardo Study found that urine albumin to creatinine ratio was associated with a significantly greater decline in cognitive function tests over 6.6 years in men, but not in women.8 In this same study, eGFR was not significantly associated with cognitive decline in men or women. Two other studies found that eGFR was a significant predictor of cognitive decline over 4 and 3.4 years of follow-up.6,10 A study performed among elderly diabetic patients found that microalbuminuria was a significant risk factor for cognitive decline over 1.6 years of follow-up.11 A large study among subjects with either vascular disease or diabetes found that baseline albuminuria was significantly associated with cognitive decline over 5 years.29 The Osteoporosis Fractures in Men Study (MrOS) found a significant association between eGFR and cognitive decline over 4.6 years of follow-up in unadjusted analyses, however this association was no longer significant in multivariate analyses.7

Only a few longitudinal community-based studies have focused on impaired renal function as a risk factor for incident dementia and its subtypes. The Cardiovascular Health Cognition Study (CHCS) found a significant relationship between inverse of serum creatinine level (defined as 1/serum creatinine) and incident dementia over 6 years of follow-up, but only among those who reported good to excellent health at baseline.14 This association was seen for VaD, but not for AD. The Adult Changes in Thought (ACT) Study found that those with lower eGFR had a higher incidence of dementia over 6 years of follow up, however there was no significance in adjusted analyses.32 There were trends toward higher incident dementia among those with positive eGFR trajectories and greater variability in eGFR over time. The Osaki-Tajiri Project is a community-based study including 497 subjects (45% men) over 65 in an agricultural area of northern Japan. This study found a significant association between prevalent CKD and incident all-cause dementia over 5 years of follow-up.12 However, the Hisayama Study, a community-based prospective cohort study in Hisayama town, Kyushu Japan, found no significant association between proteinuria and incident AD or VaD over 7 years of follow-up.13

This study has some limitations which should be considered when interpreting our results. Proteinuria was measured using urine dipstick, which lacks accurate quantitative data of microalbumin in urine. In this analysis, we used a single measure of proteinuria, and may have missed those with transient proteinuria. Also, we did not have data on serum or urine creatinine or other underlying renal disease such as IGA nephropathy. Although we were able to adjust for several confounders, we were unable to adjust for results of the oral glucose tolerance test due to many missing values (41.6% of the population). We had small numbers of cases of incident dementia within each proteinuria group, limiting our power to detect associations among the subtypes of dementia. This study also lacked data on cognitive function at the time of proteinuria measurement. Finally, this is an observational study with only Japanese-American men, which may limit generalizability for women or other ethnic groups.

This study also has many strengths. To our knowledge, this is the first population-based longitudinal study to examine the association between proteinuria in mid-life, and cognitive decline and incident dementia in late-life, over 20 years later. The urine dipstick test is a simple inexpensive test, which is readily available. The Honolulu-Asia Aging Study (HAAS) has good case-finding methods for dementia, with a long follow-up period and low dropout rates.

Although there are no clear explanations for the relationship between proteinuria and dementia, there are several biologically plausible mechanisms. The presence of proteinuria may be a surrogate marker of oxidative stress that is associated with renal impairment, and may also play a significant role in the pathogenesis of dementia.33 For example, paroxonase, one of the antioxidative enzymes that reduces the oxidation of low-density lipoprotein (LDL) cholesterol and prevents accumulation of lipid peroxides in LDL, has been linked with both AD and VaD.34 Another hypothesis is that proteinuria is a surrogate marker for microvascular pathology that has been linked to increased risk of vascular disease in the kidney and the brain, leading to vascular dementia, and possibly AD. Autopsy data from the HAAS have shown the importance of microvascular pathology related not only to VaD, but also to AD and all-cause dementia.35 Similarly, data from the Rotterdam Study suggest that atherosclerosis can play an important role in neurodegeneration related to AD.36 Atherosclerosis develops over several decades due to endothelial damage caused by hypertension and diabetes. A previous analysis from the HAAS found that mid-life hypertension was associated with poor performance on global cognitive function test,37 increased risk of dementia38 and hippocampal atrophy39, more than 25 years after initial measurement of blood pressure. There have been several cross-sectional studies that found that microalbuminuria is associated with white matter hyperintensities (WMH) suggestive of brain microvascular lesions.40

Future studies should confirm this association in other populations, including other ethnic groups and women. There also need to be large longitudinal studies of other markers of renal function (serum creatinine and urine microalbumin) and their relationship to cognitive function and dementia. As the population ages and new treatments or preventive strategies become available, it will be increasingly important to identify factors that predict future incident dementia. Targeting the cause of proteinuria or treating modifiable risk factors may have potential clinical implications for prevention of dementia, or delay in disease progression.


Sources of Funding:

This study was supported by the John A. Hartford Foundation Center of Excellence in Geriatrics, Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii; Kuakini Medical Center; the National Institutes of Health (Contract N01-HC-05102 from the National Heart, Lung, and Blood Institute, and Contract N01-AG-4-2149 and Grants U01-AG019349, R01AG027060 and R01AG038707 from the National Institute on Aging, Kuakini Medical Center, Hawaii Community Foundation grant 2004-0463, and the Office for Research and Development, Department of Veterans Affairs. The views expressed in this paper do not necessarily represent those of the federal government.

Helen Petrovitch, MD: works for the Pacific Health Research & Education Institute and receives salary from grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke.

Kamal Masaki, MD: received grant funding from National Institutes of Health grants.

Sponsor’s Role: none


Conflicts of Interest/ Financial Disclosure:

None of the authors report conflicts of interest with commercial enterprises.

The conflict of interest disclosure form will also be submitted.

Conflict of Interest Checklist:

Elements of
Masaya Higuchi,
Randi Chen, MSRobert D.
Abbott, PhD
Christina Bell, MD
Employment or Affiliationxxxx
Speaker Forumxxxx
Expert Testimonyxxxx
Board Memberxxxx
Personal Relationshipxxxx
Elements of
Lenore Launer, PhDG. Webster Ross,
Helen Petrovitch,
Kamal Masaki, MD
Employment or Affiliationxxxx
Speaker Forumxxxx
Expert Testimonyxxxx
Board Memberxxxx
Personal Relationshipxxxx

For “yes”, provide a brief explanation:

Kamal Masaki, MD: No commercial conflicts of interest.

Presentation at Meeting:

This study was presented at the Presidential poster session at the Annual Meeting of the American Geriatrics Society in May 2012.

Data Access and Responsibility:

The corresponding authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Author Contributions: All authors participated in the design, interpretation of the studies and analysis of the data and review of the manuscript.


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