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Cross-sectional association between high-sensitivity C-reactive protein and cognitive function in community-dwelling older adults: the SONIC study

BMC Geriatrics volume 24, Article number: 756 (2024) Cite this article

Abstract

Background

A decline in cognitive function is associated with inflammatory processes. However, the association between high-sensitivity C-reactive protein (hs-CRP) levels and cognitive decline in the Japanese population remains inconclusive. Thus, this study aimed to determine whether hs-CRP is associated with low cognitive function in 70- and 80-year-old community-dwelling Japanese individuals.

Methods

The participants in this cross-sectional study were 872 Japanese residents aged 70 and 80 years who voluntarily participated in the Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study between 2010 and 2011. Blood sample collection, cognitive assessment, and other measurements were performed at the venue. Low cognitive function was defined as a score of 25 points or lower on the Japanese version of the Montreal Cognitive Assessment. The odds ratio (OR) and 95% confidence interval (95% CI) for each hs-CRP quartile were calculated using logistic regression analysis.

Results

A total of 288 (69.9%) parsons in the 70-year-old group and 372 (80.9%) in the 80-year-old group exhibited low cognitive function. The association between hs-CRP levels and low cognitive function was significant among 70- and 80-year-old Japanese community-dwelling adults. In particular, the fourth quartile of hs-CRP (0.727–7.420 mg/L) in the 70-year-old group and the second and fourth quartiles (0.214–0.404 and 0.911–9.890 mg/L) in the 80-year-old group were associated with low cognitive function. Furthermore, the third quartile (0.409–0.892 mg/L) in the 80-year-old group was closely associated with low cognitive function.

Conclusions

High hs-CRP levels were associated with lower cognitive function in 70- and 80-year-old Japanese community-dwelling individuals, suggesting that high hs-CRP levels may influence cognitive function.

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Background

The incidence of dementia, one of the leading causes of care dependence and disability in older adults, is rapidly increasing worldwide [1]. The number of people living with dementia worldwide was estimated to be 55.2 million in 2019. This number is projected to increase to 78 million by 2030 and 139 million by 2050 [1]. In Japan, one of the most aged countries worldwide, the numbers of people living with dementia were estimated to be 4.6 million in 2012 and 7 million in 2025 [2]. Identifying individuals at high risk of developing dementia is crucial, as this condition has no cure [3]. Several risk factors for dementia were identified: aging [1], smoking [4], excessive alcohol consumption [5], obesity [6], diabetes [7], systolic hypertension [8], physical inactivity [9], and chronic inflammation. Determining the risk factors in persons aged 70 years and older is especially important as the prevalence of this disease increases with age.

The development of dementia appears to be associated with inflammatory processes. A meta-analysis demonstrated that several surrogates of systemic inflammation, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were associated with Alzheimer’s disease [10]. Previous research found a negative correlation between serum CRP levels and cognitive function in community-dwelling older Japanese people [11]. However, serum CRP is a clinical marker of high inflammation levels (> 3.0 mg/L). Evidence suggests that low-grade chronic inflammation is associated with cognitive decline and disorders such as Alzheimer’s disease [12, 13]. High-sensitivity CRP (hs-CRP) is useful for identifying low-grade chronic inflammation that cannot be detected using standard CRP testing. hs-CRP is associated with cognitive decline in the general population of England [12] and in Japanese Americans in Hawaii [13]. Therefore, we hypothesized that hs-CRP may serve as a biomarker of cognitive decline in older Japanese people.

However, the association between hs-CRP level and cognitive decline in the Japanese population remains inconclusive. Watanabe et al. showed an association between high hs-CRP levels (> 1.0 mg/L) and cognitive decline but failed to show an association between low hs-CRP levels (< 1.0 mg/L) and cognitive decline [14]. This study has three limitations. First, the study population comprised outpatients of a general hospital, not community residents. Second, the participants’ age ranged from 29 to 91 years. Third, the criteria for selecting the cognitive test changed during the period of participant recruitment. Only those participants suspected of having cognitive problems during the first and second periods underwent the Mini-Mental State Examination. Therefore, the association between hs-CRP levels and cognitive decline in older Japanese community residents remains unclear.

This study aimed to determine whether hs-CRP is associated with low cognitive function among 70- and 80-year-old Japanese community-dwelling people. A cross-sectional analysis was performed using data from a survey of community-dwelling older adults.

Methods

Study participants

This was a cross-sectional analysis of an epidemiological study on older Japanese adults called the Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study [15]. It is a joint research project involving researchers from various fields of expertise at the Osaka University Graduate School of Medicine, Human Sciences, and Dentistry; the National Center of Gerontology and Geriatrics; and Keio University. The participants were randomly selected from the basic resident registry by stratified sampling based on age, and invitations were sent to those who voluntarily participated in the survey. The 70-year-old group (aged 69–71 years) was invited to the venue for the survey in 2010 and the 80-year-old group (aged 79–81 years) in 2011. A narrow age-range cohort design was employed, with each cohort comprising individuals within the 3-year age range. The study focused on assessing the individual differences in the aging process and health outcomes in each age group without age adjustment [15].

A total of 1,005 70- or 80-year-old adults who participated in the Kansai region (Hyogo Prefecture) SONIC study between 2010 and 2011 were included in the present study. We excluded 59 participants with a history of dementia and/or stroke; 2 participants who did not undergo a cognitive function test; 58 participants who did not undergo a serum hs-CRP test; 11 participants with a serum hs-CRP level of ≥ 10 mg/L; which is indicative of acute inflammation [16]; and 3 participants with missing covariate data. The final number of participants in the analysis was 872, with 412 comprising the 70-year-old group and 460 comprising the 80-year-old group (Fig. 1).

Fig. 1
figure 1

Flowchart of the participant selection process

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The institutional review boards approved the SONIC study of the Osaka University Graduate School of Medicine, Dentistry, and Human Sciences and the Tokyo Metropolitan Institute of Gerontology (approval numbers 266, H22-E9, 22018, and 38). All participants provided written informed consent.

Data collection

High-sensitivity C-reactive protein

CRP is often used in clinical practice as an inflammatory marker for understanding inflammatory responses. hs-CRP measures low levels of CRP that cannot be detected by conventional measurements. In other words, hs-CRP is useful for identifying a low-grade chronic inflammation than that detectable using a standard CRP testing. The hs-CRP level can be used to assess inflammation due to atherosclerosis and predict cardiovascular disease independent of the traditional risk assessments such as the Framingham risk score [17, 18].

In this study, non-fasting blood sampling was performed by a physician or nurse at the survey venue. The total blood sample required for serum blood laboratory tests was approximately 6 mL. The hs-CRP level was determined using a latex nephelometry assay with an automatic analyzer (Behring Nephelometer II (BNII); Siemens Healthcare Diagnostics, Inc.). The intra- and inter-assay coefficients of variation values were 1.1–4.0% and 2.1–4.6%, respectively.

Other measurements and diagnostic criteria

Blood pressure measurements, blood sampling, and carotid ultrasonography examinations were performed at the venue. Carotid ultrasonography (GE Logiq Book X-P; GE Healthcare, Tokyo, Japan) was performed by an experienced physician to measure the intima-media thickness (IMT) of the left and right common carotid arteries as a surrogate marker of atherosclerosis [19]. Two measurements were taken on the left and right sides, and the mean IMT was calculated [20]. The body mass index (BMI) was calculated as weight/height2 (kg/m2). A physician or nurse conducted individual interviews with the participants regarding their smoking habits (never, past, or current), alcohol intake (never, moderate, or excessive), medical history, medications, and years of education. Diabetes mellitus was defined as a casual plasma glucose level of ≥ 200 mg/dL, a hemoglobin A1c level of ≥ 6.5%, a self-reported diagnosis of diabetes, or the use of antidiabetic agents based on the Japan Diabetes Society criteria [21]. Dyslipidemia was defined as a low-density lipoprotein cholesterol level of ≥ 140 mg dL, a high-density lipoprotein cholesterol level of < 40 mg dL, a triglyceride level of ≥ 150 mg dL, or the use of antidyslipidemic medications according to the Japan Atherosclerosis Society Guidelines [22]. The blood pressure was measured twice in each arm by a physician or nurse, and the mean value from the two measurements was calculated. Hypertension was defined as a systolic blood pressure of ≥ 140 mmHg, a diastolic blood pressure of ≥ 90 mmHg, or the use of antihypertensive medications according to the hypertension management guidelines of the Japanese Society of Hypertension [23].

Assessment of cognitive function

The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was used to assess cognitive function. MoCA-J is a simple cognitive screening tool for detecting mild cognitive impairment (MCI) [24, 25]. The cognitive tasks included visuospatial ability, naming, attention, language, abstraction, delayed recall, and orientation. A self-administered questionnaire was used to ascertain the number of years of education, with a maximum of 30 years. One point was added to the MoCA-J score if the number of years of education was less than 12 years. The MoCA-J score ranged from 0 to 30, with a sensitivity of 80–100% and a specificity of 50–87%. A score of ≤ 25 points is considered indicative of MCI [24, 25]. In this study, low cognitive function was defined as a score of ≤ 25 points.

Statistical analysis

The participants were classified into four groups according to hs-CRP quartiles. The characteristics by hs-CRP quartiles in the 70- and 80-year-old groups were expressed as percentages for categorical variables or mean ± standard deviation for continuous variables. The Spearman’s rank correlation test was used to determine the trend of each item in the hs-CRP quartiles. The associations between the prevalence of low cognitive function (MoCA-J score ≤ 25) and quartiles of hs-CRP concentrations were assessed by calculating the odds ratio (OR) and 95% confidence intervals (95% CIs) using logistic regression analysis. Subsequent analyses involved three models: Model 1 adjusted for sex; Model 2 adjusted for sex, education, and smoking; and Model 3 adjusted for sex, education, smoking, hypertension, diabetes mellitus, dyslipidemia, and mean IMT. These adjustments were made as these variables were associated with the progression of dementia and hs-CRP level in previous studies [4, 6,7,8]. All statistical analyses were performed using SPSS Statistics software (version 25.0; IBM Japan, Tokyo, Japan). A p-value of < 0.05 was considered significant.

Results

A total of 288 (69.9%) patients in the 70-year-old group and 372 (80.9%) in the 80-year-old group exhibited low cognitive function. The first, second, third, and fourth quartiles were abbreviated as Q1, Q2, Q3, and Q4, respectively, in ascending order of the hs-CRP level. The hs-CRP distribution in this study was skewed (Additional file 1).

Table 1 shows the participants’ characteristics according to the hs-CRP quartile in the 70-year-old group. The hs-CRP (mg/L) ranges were 0.050–0.160 for Q1, 0.161–0.364 for Q2, 0.365–0.720 for Q3, and 0.727–7.420 for Q4. Univariate analysis showed significant trends in the MoCA-J score, BMI, and dyslipidemia incidence toward the quartiles of hs-CRP. Table 2 shows the characteristics of the 80-year-old group across the hs-CRP quartiles. The hs-CRP (mg/L) ranges were 0.050–0.212 for Q1, 0.214–0.404 for Q2, 0.409–0.892 for Q3, and 0.911–9.890 for Q4. Univariate analysis showed significant trends in BMI, years of education, and dyslipidemia incidence across the hs-CRP quartiles.

Table 1 Participant characteristics by quartile of serum high-sensitivity CRP (70-year-old group)
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Table 2 Participant characteristics by quartile of serum high-sensitivity CRP (80-year-old group)
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Table 3 presents the OR and 95% CI for low cognitive function across the hs-CRP quartiles in the 70-year-old group. The OR for Q4 was significantly higher than that for Q1, and the trend across hs-CRP quartiles toward low cognitive function was significant (p for trend = 0.023) after adjusting for sex, education, smoking, hypertension, diabetes mellitus, dyslipidemia, and mean IMT. Table 4 shows the OR and 95% CI for low cognitive function across the hs-CRP quartiles in the 80-year-old group. The ORs for Q2 and Q4 were significantly higher than those for Q1, while the OR for Q3 was marginally higher than that for Q1. The trend across the hs-CRP quartile toward low cognitive function was significant (p for trend = 0.038) after adjusting for sex, education, smoking, hypertension, diabetes mellitus, dyslipidemia, and mean IMT.

Table 3 Association between high-sensitivity CRP and low cognitive function (70-year-old group)
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Table 4 Association between high-sensitivity CRP and low cognitive function (80-year-old group)
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Discussion

This study examined the association between hs-CRP levels and low cognitive function among 70- and 80-year-old Japanese community-dwelling people. The results showed that this association was significant in both groups. In particular, the fourth quartile of hs-CRP (0.727–7.420 mg/L) in the 70-year-old group and the second and fourth quartiles (0.214–0.404 and 0.911–9.890 mg/L) in the 80-year-old group were associated with low cognitive function. Furthermore, the third quartile (0.409–0.892 mg/L) in the 80-year-old group was closely associated with low cognitive function.

Watanabe et al. identified an association between the fourth quartile of hs-CRP (≥ 1.09 mg/L) and cognitive decline but did not find an association between the second and third quartiles (0.223–0.471 and 0.471–1.09 mg/L) and cognitive decline in Japanese outpatients aged 29–91 years [14]. Another Japanese study showed an association between hs-CRP and the risk of disabling dementia in patients with a history of stroke, but failed to show an association between hs-CRP and the risk of total disabling dementia in community residents aged 40–69 years [26]. This study assessed dementia using information from a national long-term care insurance program. In age-, sex, and community-matched model, the second to fourth quartiles of hs-CRP (0.17–0.41, 0.42–0.88, and 0.90–3.11 mg/L) was associated with risk of disabling dementia among individuals with a history of stroke. These findings suggest that both high hs-CRP levels (> 1.0 mg/L) and low hs-CRP levels (< 1.0 mg/L) are significant in assessing cognitive function in older Japanese community residents, particularly those with subclinical cerebrovascular changes.

The CRP levels in Japanese individuals are lower than those in individuals of other ethnicities. The median CRP levels in Japanese individuals (0.5 mg/L) were lower than those in African-American (3.2 mg/L), Hispanic (2.3 mg/L), white (1.5 mg/L), and Chinese individuals (0.7 mg/L) [27]. The Japanese study participants appeared to be well-suited for assessing an hs-CRP level below 1.0 mg/L.

A 25-year follow-up study showed that the second to fourth quartiles of hs-CRP (0.34–0.56, 0.57–1.00, and > 1.00 mg/L) were associated with dementia risk in Japanese-American male residents [13]. Long-term systemic inflammation appears to be associated with the development of dementia.

The association between CRP level and dementia varies across dementia subtypes. Previous studies have shown that CRP concentration is associated with vascular dementia risk but not with Alzheimer’s disease risk [28, 29]. Data on the dementia subtypes were not collected in this study. Dyslipidemia and BMI correlated with hs-CRP levels (Tables 1 and 2). Vascular dementia related to atherosclerosis was associated with both dyslipidemia and a higher BMI [30, 31], which were considered important risk factors for low cognitive function in the present study.

Years of education were correlated with hs-CRP levels in the 80-year-old group (Table 2). Lower years of education were associated with lower cognitive function [32]. In the present study, longer years of education were associated with the highest hs-CRP levels. Although the exact reason remains unclear, survivor bias may explain why thr participants with the highest hs-CRP levels had more years of education. To account for this confounding variable, Models 2 and 3 were adjusted for years of education.

Inflammation is a biological “response to injury.” It is the response of cells and related substances in the body to external invasion, such as infection or traumatic stress, to protect the body from attack [33]. Although this study did not elucidate the specific pathophysiology of chronic inflammation, elevated blood cytokine levels due to chronic systemic inflammation caused by various factors can stimulate receptors in cerebral vascular cells, promote the opening of the tight junctions of the blood-brain barrier, and stimulate medullary reticular formation and the hypothalamus via the vagus nerve [34, 35]. This mechanism promotes excessive activation of microglia and astrocytes in the brain and causes neuronal degeneration and dementia [34].

The strength of the SONIC study was its narrow age range. Although aging is a major risk factor for cognitive decline, the present study examined the association between hs-CRP levels and MoCA-J scores in different age groups. This study involved a multidisciplinary team (physicians, nurses, nutritionists, dentists, and psychologists) and collected reliable data that included a wide range of confounding factors.

This study has several limitations. Owing to the cross-sectional and observational nature of this study, a causal relationship between hs-CRP levels and low cognitive function could not be established. Therefore, the relationship between hs-CRP levels and low cognitive function must be investigated in a prospective study. Further studies are needed to determine whether inflammatory markers are associated with the onset and progression of dementia in the Japanese population. Older adults who voluntarily participated in this study appeared to be healthier than those who did not. A previous study showed that the apolipoprotein E4 allele alters the association between CRP and dementia [36]; however, these data were not obtained.

Conclusions

This study found that high hs-CRP levels were associated with low cognitive function in both 70- and 80-year-old community-dwelling Japanese individuals.

Data availability

The datasets analyzed during this study cannot be publicly shared due to ethical restrictions but are available from the corresponding author upon reasonable request.

Abbreviations

Hs-CRP:

High-sensitivity C-reactive protein

OR:

Odds ratio

CI:

Confidence interval

CRP:

C-reactive protein

SONIC study:

Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study

IMT:

Intima-media thickness

BMI:

Body mass index

MCI:

Mild cognitive impairment

MoCA-J:

Japanese version of the Montreal Cognitive Assessment

Q:

Quartile

SD:

Standard deviation

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Acknowledgements

We are grateful to all the participants in these studies. We would like to thank the staff members involved in the SONIC study. We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This work was supported by research grants from JSPS KAKENHI 19K11138 (MK, KK), 19K07888 (KK), Osaka University’s International Joint Research Promotion Program Support Type A (KK), and JST SPRING (grant number: JPMJSP2138) (KK, MH).

Author information

Authors and Affiliations

  1. Division of Health Sciences, Graduate School of Medicine, Osaka University, 1-7 Yamada-Oka, Suita, 565-0871, Osaka, Japan

    Mariko Hosokawa, Mai Kabayama, Kayo Godai, Yuya Akagi, Yuka Tachibana, Yasushi Takeya & Kei Kamide

  2. Department of Clinical Thanatology and Geriatric Behavioral Sciences, Graduate School of Human Sciences, Osaka University, Osaka, Japan

    Yasuyuki Gondo

  3. Office of International Exchange, Graduate School of Human Sciences, Osaka University, Osaka, Japan

    Saori Yasumoto

  4. Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

    Yukie Masui, Takumi Hirata & Tatsuro Ishizaki

  5. Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

    Hiroshi Akasaka, Yasushi Takeya, Yoichi Takami, Koichi Yamamoto, Hiromi Rakugi & Kei Kamide

  6. Department of Periodontology and Regenerative Dentistry, Osaka University Graduate School of Dentistry, Osaka, Japan

    Masahiro Kitamura

  7. Department of Removable Prosthodontics and Gerodontology, Osaka University Graduate School of Dentistry, Osaka, Japan

    Kazunori Ikebe

  8. Center of Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan

    Yasumichi Arai

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  1. Mariko Hosokawa
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Contributions

KK, YG, KI, and HR designed the study. KK, HR, MK, KG, YA, YT, HA, YT, YT, KY, MK, TH, TI, YA, and MH collected the medical data. YG, SY, and YM collected the cognitive, psychological, and social data. MH conducted the statistical analyses. MH, MK, and KK wrote the manuscript. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Kei Kamide.

Ethics declarations

Ethics approval and consent to participate

The institutional review boards approved the SONIC study of the Osaka University Graduate School of Medicine, Dentistry, and Human Sciences and the Tokyo Metropolitan Institute of Gerontology (approval numbers 266, H22-E9, 22018, and 38, respectively). All participants provided written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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12877_2024_5354_MOESM1_ESM.docx

Additional files 1: Description of data: (A) Histogram of the hs-CRP levels in the 70-year-old group; (B) Histogram of the hs-CRP levels in 80-year-old group

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Hosokawa, M., Kabayama, M., Godai, K. et al. Cross-sectional association between high-sensitivity C-reactive protein and cognitive function in community-dwelling older adults: the SONIC study. BMC Geriatr 24, 756 (2024). https://doi.org/10.1186/s12877-024-05354-x

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Keywords

BMC Geriatrics

ISSN: 1471-2318

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