Positive Results from the Fecal Immunochemical Test Can Be Related to Dementia: A Nationwide Population-Based Study in South Korea

Abstract

Background:

The fecal immunochemical test (FIT) is widely used in screening for colorectal cancer (CRC), but FIT results can be positive for diseases other than CRC.

Objective:

We investigated the association between positive results of FIT and the incidence of dementia using a nationwide database.

Methods:

FIT-positive participants were collected from a database provided by the Korean National Health Insurance Service.

Results:

The incidence of all kinds of dementia was higher in FIT-positive than FIT-negative subjects (p < 0.0001). FIT-positive participants had a higher risk of Alzheimer’s disease (AD) (p < 0.0001) and vascular dementia (p = 0.0002), compared to participants with FIT negativity. The risk of all kinds of dementia or AD in FIT-positive participants was higher in younger (age < 65 years) than older participants (p < 0.0001 for all kinds of dementia; p = 0.0002 for AD).

Conclusion:

FIT positivity was correlated with an increased risk of dementia, especially in participants under 65 years of age. The study suggests that clinicians can consider dementia when FIT-positive participants fail to show any malignancies.

Keywords

Alzheimer’s disease dementia occult blood population surveillance vascular dementia

INTRODUCTION

In Korea, the National Cancer Screening Program (NCSP) recommends an annual fecal occult blood test for adults over 50 years of age for colorectal cancer (CRC) screening [1]. The fecal immunochemical test (FIT) is the most preferred fecal occult blood test and detects a globin from hemoglobin (Hb) in feces [2]. Studies reported a wide range of the specificity of FIT in detecting CRC with the highest specificity of 99% and the lowest 68% [3 –5]. The overall specificity was 94% according to a meta-analysis of 19 studies [6]. Because the NCSP provides the CRC screening test for almost all of the Korean population, about 4,000,000 Koreans were screened for CRC in 2012 alone [1]. Of these, the 240,000 (6%) who might get false-positive results is not a small number and so it is necessary to examine the risk factors for FIT positivity other than CRC.

Notably, inflammatory bowel disease (IBD), a chronic and relapsing inflammatory disease in gastrointestinal (GI) tract, can induce false positive FIT in CRC screening: participants with IBD are likely to have more than 14 times high risk of false positive FIT, compared to participants without IBD [7 –9]. Positive FIT is correlated with a poor prognosis of ulcerative colitis (UC), one kind of IBD [10, 11]. In addition, smoking, inducing chronic inflammation and modulating host immunity, is related to false positive FIT [12 –14]. Based on these previous studies, the inflammatory reaction might be associated with positive FIT in participants without CRC.

Systemic inflammation also has an influence on dementia, a clinical syndrome characterized by general cognitive impairment [15]. Alzheimer’s disease (AD), the most common type of dementia [16], can be caused by inflammatory cytokines, chemokines, and free radicals in the brain. Vascular dementia (VaD), the second most common type of dementia, is characterized by multiple strokes and vascular damage in deep white matter [17, 18]. Considering the critical role of inflammation in the pathogenesis of dementia, we hypothesized that participants with FIT positivity may have a higher risk of developing dementia.

Participants with dementia experience deterioration of memory, orientation, comprehension, and judgment. It is impossible to cure dementia and treatments are used to relieve symptoms. Dementia makes it difficult for family members as caregivers and increases the socioeconomic burden [19]. Moreover, early-onset dementia (EOD), dementia-related symptoms starting before 65 years of age, can provoke more serious problems [20]. Therefore, we investigated the association between positive results of FIT and the incidence of dementia using a nationwide database.

MATERIALS AND METHODS

Data sources

The National Health Insurance (NHI) service is a universal healthcare insurer providing health insurance coverage to nearly the total Korean population. The National Health Insurance Sharing Service (NHISS) was established to provide support for political and academic research using NHI public data. The database contains inpatient and outpatient information, such as participants’ general information, diagnostic procedures, prescription history, principal diagnoses, and comorbidities based on the International Classification of Disease, 10th revision (ICD-10).

Study design and identification of participants

The NHISS database used in this study covered the period of 2009– 2019. All participants had an anonymous identification number for personal information protection. First, 7,946,454 participants who got medical checkups for CRC were identified. Among them, 7,946,396 participants who were more than 50 years old were selected because the Korean NCSP provides average-risked individuals who are more than 50 years old with screening for CRC [21]. Of the 7,409,716 participants matched to their medical checkup results, we excluded 164,774 participants due to missing data. Because we aimed to investigate causes other than all kinds of cancer that result in FIT positivity, we excluded 270,366 participants diagnosed with all kinds of cancers. We excluded wash-out subjects and extracted 6,929,174 participants. To avoid a diagnostic bias, a one-year-lag time between dementia onset and the start of FIT was considered. Finally, 6,880,030 participants were selected for analysis.

Fecal sample management for FIT

Every participant was provided a sampling container or sampling kit and instructed to follow the appropriate procedure for fecal collection and storage [22]. They should collect a proper amount of their fecal samples the day before or the morning of the hospital visit day. Also, they should be cautious not to contaminate the samples with other body fluids like urine. Samples should be stored in the refrigerator or in a cool place [23].

FIT testing is divided into qualitative and quantitative FITs and more than 80% of Korean institutes use qualitative FIT kits [13]. SD Bioline FOB test (Standard Diagnostics Co., Seoul, Korea; cut-off point of 6μg Hb/g feces), YD FOB test (YD Diagnostics Co., Yong-in, Korea), Asan FOB easy test (Asan Pharmaceutical Co., Seoul, Korea; cut-off point of 10μg Hb/g feces), and Eiken Hemocatch light (Eiken Chemical Co., Tokyo, Japan; cut-off point of 10μg Hb/g feces) are most widely used qualitative FIT kits, and Eiken (Eiken Chemical Co., Tokyo, Japan), Alfresa (Alfresa Pharma Co., Osaka, Japan), and Kyowa (Kyowa Chemical Industry Co., Kagawa, Japan) analyzers are most popularly used for quantitative FIT [24]. The cut-off concentration for a positive result in most quantitative FIT analyzers widely used in Korea is 20μg Hb/g feces [13]. To maintain a high quality of FIT, Korean Association of External Quality Assessment Service performs quality assessment of FIT testing. FIT steadily maintained low false positive rates and the disconcordance rates among qualitative FIT were lower than5% [25].

Definitions

We identified participants with dementia having prescriptions with anti-dementia drugs at least twice and diagnosis of dementia (ICD-10 F00, F01, F02, F03, G30, or G31). The anti-dementia drugs included rivastigmine, galantamine, memantine, and donepezil hydrochloride. The AD was diagnosed with codes F00 and G30 and VaD with code F01. Our identification of participants with dementia was reliable because the diagnostic accuracy of dementia cases using diagnostic codes according to ICD-10 was validated [26].

The dataset included inpatient and outpatient information on sex, age (years), smoking status, alcohol consumption, economic status, regular physical activity, baseline comorbidities, height (cm), weight (kg), body mass index (BMI) (kg/m²), waist circumference (WC) (cm), blood glucose (mg/dl), systolic blood pressure/diastolic blood pressure (SBP/DBP) (mm Hg), serum total cholesterol (mg/dl), and estimated glomerular filtration rate (eGFR; GFR calculated by the abbreviated MDRD equation) [27].

Participants who were currently smoking at the time of the medical checkups were classified as current smokers. A heavy drinker was defined as > 30 g per day. A participant with regular physical activity did vigorous exercise≥3 days per week or mid-term exercise≥5 days per week. Low income was defined as a monthly income in the lowest 20% of the total population distribution. Obesity was defined as BMI≥25 kg/m². Male with WC≥90 cm and female with WC≥85 cm were included in the abdominal obesity group.

Baseline comorbidities included DM, hypertension (HTN), dyslipidemia, and chronic kidney disease (CKD). The DM was diagnosed according to ICD-10 diagnostic codes (E11– E14) and prescription of anti-diabetic medications (insulin, sulfonylureas, metformin, meglitinides, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and α-glucosidase inhibitors) or fasting glucose concentration≥126 mg/dl. The HTN was diagnosed according to the ICD-10 diagnostic codes I10– I13 or I15 and prescription of anti-hypertensive medications (α-blockers, β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor inhibitors, calcium channel blockers, and diuretics), SBP≥140 mm Hg, or DBP≥90 mm Hg. Participants with dyslipidemia were defined as the ICD-10 diagnostic code (E78) with antidyslipidemic medications (ezetimibe, fibrate, and statin) or total cholesterol≥240 mg/dl. Participants with eGFR < 60 ml/min/1.73 m² were included in the CKD group.

Study outcomes

The primary endpoint was newly diagnosed dementia in participants with FIT positivity. The FIT is widely performed for Korean adults as a primary screening tool for CRC. The positive predictive values of FIT for CRC are reported to be only about 50%, and some FIT results may be positive for causes other than CRC [28]. To rule out the possibility that the FIT result was positive due to all kinds of cancer, participants who were diagnosed with all kinds of cancer were excluded from this analysis. Participants with FIT positivity at least once belonged to the FIT-positive group, regardless of the times of FIT positivity. The study population was followed up until the date of incident dementia or December 2019, whichever came first.

Statistical analysis

In all analyses, not only all kinds of dementia but also the development of AD and VaD were considered. Continuous variables are shown as mean±standard deviation, and categorical variables are displayed using numbers and percentages. To compare the difference between groups, Student’s t– test was used for continuous variables, and the chi– squared test for binary and categorical variables. The incidence rate of dementia was presented as the number of occurrences per 1,000 person– years. We conducted Cox proportional hazards regression analysis to investigate the relationship between risk factors and dementia. Multivariate analysis models were adjusted for age, sex, smoking, alcohol consumption, physical activity, obesity, and baseline comorbidities. The impact of variables was assessed through subgroup analysis. Kaplan– Meier curves were used to evaluate the cumulated occurrence of dementia using the log-rank test. Statistical analysis was performed through SAS version 9.4 (Cary, NC, USA) and p-value < 0.05 was consideredsignificant.

RESULTS

Baseline characteristics according to FIT positivity

The study population consisted of 430,977 FIT-positive participants and 6,449,053 FIT-negative participants (Table 1). The mean follow-up duration was 7.71±1.72 years. Baseline demographic characteristics of the study population are presented according to FIT results. The FIT positivity was significantly related to male (p < 0.0001), old age (p < 0.0001), current smoking (p < 0.0001), heavy drinking (p < 0.0001), low physical activity (p < 0.0001), and low income (p = 0.0061), compared to FIT negativity. The FIT-positive participants showed a significantly higher proportion of multiple baseline comorbidities, including obesity, DM, hypertension, dyslipidemia, and CKD than FIT-negative participants. Importantly, FIT positivity was significantly associated with occurrence of all kinds of dementia (p < 0.0001), AD (p < 0.0001), and VaD (p < 0.0001).

Table 1

Demographic and clinical characteristics of the study population

Characteristics, N (%)	FIT
	Negative N = 6,449,053	Positive N = 430,977	p
Male gender	2,839,516 (44.03)	227,415 (52.77)	<0.0001
Age≥65 y	1,842,424 (28.57)	137,843 (31.98)	<0.0001
Age^† (y)	60.22±8.1	60.93±8.41	<0.0001
Current smoker	993,694 (15.41)	84,009 (19.49)	<0.0001
Heavy drinker	388,925 (6.03)	37,824 (8.78)	<0.0001
Regular physical activity	1,393,328 (21.61)	89,807 (20.84)	<0.0001
Low income	1,273,057 (19.74)	85,816 (19.91)	0.0061
Obesity	2,402,739 (37.26)	165,084 (38.3)	<0.0001
Abdominal obesity	1,706,229 (26.46)	122,576 (28.44)	<0.0001
Height^† (cm)	159.76±8.49	160.68±8.62	<0.0001
Weight^† (kg)	61.83±9.98	62.67±10.26	<0.0001
BMI^† (kg/m²)	24.16±3.02	24.21±3.05	<0.0001
WC^† (cm)	81.95±8.45	82.84±8.5	<0.0001
DM	960,235 (14.89)	72,261 (16.77)	<0.0001
HTN	2,882,567 (44.7)	211,925 (49.17)	<0.0001
Dyslipidemia	1,889,456 (29.3)	129,779 (30.11)	<0.0001
CKD	531,364 (8.24)	40,509 (9.4)	<0.0001
Blood glucose^† (mg/dl)	101.77±25.29	103.04±27.49	<0.0001
SBP^† (mm Hg)	126.05±15.7	127.03±15.89	<0.0001
DBP^† (mm Hg)	77.46±10.12	78.09±10.29	<0.0001
Total cholesterol^† (mg/dl)	200.98±38.27	200.07±39.2	<0.0001
eGFR^† (60 ml/min/1.73 m²)	84.86±31.94	84.43±30.87	<0.0001
All kinds of Dementia	398,690 (6.18)	30,677 (7.12)	<0.0001
AD	316,264 (4.9)	24,146 (5.6)	<0.0001
VaD	43,461 (0.67)	3,434 (0.8)	<0.0001
Follow-up duration^† (y)	7.71±1.71	7.58±1.88	<0.0001

^†Mean±standard deviation. FIT, fecal immunochemical test; N, number; BMI, body mass index; WC, waist circumference; DM, diabetes mellitus; HTN, hypertension; CKD, chronic kidney disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; AD, Alzheimer’s disease; VaD, vascular dementia.

The study population was categorized as the type of dementia as Supplementary Table 1. After FIT surveillance, 429,367 participants were diagnosed with all kinds of dementia. Among 6,880,030 participants who had FIT tests, 340,410 and 46,895 were diagnosed with AD and VaD, respectively. Participants who were female (p < 0.0001), older (p < 0.0001), not current smoker (p < 0.0001), not heavy drinker (p < 0.0001), did not regularly exercise (p < 0.0001), and had low income (p = 0.0073) had more incident dementia. Participants with abdominal obesity (p < 0.0001) developed dementia more frequently, but participants with obesity (p < 0.0001) did not. The following were significantly related with incident dementia: DM (p < 0.0001), HTN (p < 0.0001), dyslipidemia (p < 0.0001), and CKD (p < 0.0001). Similar patterns were observed in participants with AD or VaD, but smoking and income had not significant association with VaD.

Risk of dementia in participants with FIT positivity

Participants with a FIT-positive result had a significantly higher incidence of all kinds of dementia, AD, and VaD (Fig. 1). Multiple Cox proportional hazard analysis after adjusting for sex, age, smoking, alcohol consumption, physical activity, economic status, obesity, DM, HTN, dyslipidemia, and CKD did not modify the associations between risk of FIT positivity and development of dementia (Table 2). The incidence (per 1,000 person-years) of all kinds of dementia was 9.394 in FIT-positive participants and 8.014 in FIT-negative participants (adjusted hazard ratio (aHR), 1.055; 95% confidence interval (CI) 1.042– 1.067; p < 0.0001). The incidence of AD was higher in FIT-positive than FIT-negative participants (aHR, 1.05; 95% CI, 1.037– 1.064; p < 0.0001). In addition, VaD incidence was higher in FIT-positive than FIT-negative participants (aHR, 1.068; 95% CI 1.031– 1.105; p = 0.0002).

Fig. 1

Cumulative incidence of all kinds of dementia (a), Alzheimer’s disease (b), and vascular dementia (c) in fecal immunochemical test (FIT)-positive participants without previously diagnosed cancer, compared with FIT-negative participants.

Table 2

Incidence rate and hazard ratio of dementia in fecal immunochemical test-positive participants without previously diagnosed all kinds of cancer

FIT	Number	Cases (N)	Duration (PY)	IR (per 1,000 PY)	HR (95% CI)^†	p
All kinds of dementia
Negative	6,449,053	398,690	49,751,101.5	8.014	1 (Reference)	<0.0001
Positive	430,977	30,677	3,265,632.8	9.394	1.055 (1.042,1.067)
AD
Negative	6,449,053	316,264	49,751,101.5	6.357	1 (Reference)	<0.0001
Positive	430,977	24,146	3,265,632.8	7.394	1.05 (1.037,1.064)
VaD
Negative	6,449,053	43,461	49,751,101.5	0.874	1 (Reference)	0.0002
Positive	430,977	3,434	3,265,632.8	1.052	1.068 (1.031,1.105)

^†Models were adjusted for age, gender, smoking, alcohol consumption, physical activity, economic status, obesity, diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease. FIT, fecal immunochemical test; PY, person-year; IR, incidence ratio; HR, hazard ratio; CI, confidence interval; AD, Alzheimer’s disease; VaD, vascular dementia.

Subgroup analysis

Subgroup analysis demonstrated that the relationship between FIT positivity and development of dementia was irrespective of sex, smoking, alcohol consumption, physical activity, obesity, DM, hypertension, dyslipidemia, and high blood glucose concentration (Table 3). However, a significantly increased risk for developing all kinds of dementia and AD was observed among those FIT-positive participants younger than 65 years old (aHR, 1.092 versus 1.052, p < 0.0001 for all kinds of dementia; aHR, 1.089 versus 1.049, p = 0.0003 for AD).

Table 3

Subgroup analysis of risk for dementia in fecal immunochemical test-positive participants without previously diagnosed all kinds of cancer

Subgroup		All kinds of dementia		AD		VaD
		HR (95 % CI)	p for interaction	HR (95 % CI)	p for interaction	HR (95 % CI)	p for interaction
Gender	Male	1.051 (1.033,1.07)	0.5364	1.047 (1.026,1.068)	0.6011	1.038 (0.988,1.091)	0.0793
	Female	1.057 (1.041,1.074)		1.053 (1.035,1.072)		1.098 (1.045,1.153)
Age (y)	<65	1.092 (1.063,1.121)	<0.0001	1.089 (1.056,1.124)	0.0002	1.066 (0.996,1.14)	0.4065
	≥65	1.052 (1.039,1.066)		1.049 (1.034,1.064)		1.073 (1.03,1.118)
Current smoker	No	1.057 (1.043,1.07)	0.5581	1.054 (1.039,1.069)	0.2646	1.064 (1.024,1.106)	0.803
	Yes	1.041 (1.01,1.074)		1.025 (0.989,1.063)		1.081 (0.997,1.171)
Heavy drinker	No	1.057 (1.044,1.069)	0.1838	1.052 (1.038,1.066)	0.3762	1.071 (1.033,1.111)	0.4584
	Yes	1.023 (0.976,1.073)		1.025 (0.97,1.083)		1.027 (0.904,1.167)
Regular physical activity	No	1.051 (1.038,1.065)	0.1235	1.046 (1.031,1.061)	0.1002	1.062 (1.022,1.104)	0.4626
	Yes	1.071 (1.042,1.101)		1.07 (1.037,1.104)		1.094 (1.008,1.188)
Obesity	No	1.058 (1.043,1.074)	0.1252	1.054 (1.037,1.072)	0.1643	1.065 (1.019,1.113)	0.882
	Yes	1.048 (1.028,1.068)		1.043 (1.02,1.066)		1.073 (1.014,1.135)
DM	No	1.057 (1.042,1.071)	0.1833	1.053 (1.037,1.069)	0.1428	1.056 (1.013,1.1)	0.4961
	Yes	1.048 (1.024,1.073)		1.041 (1.014,1.069)		1.098 (1.028,1.173)
HTN	No	1.067 (1.046,1.089)	0.0087	1.057 (1.033,1.081)	0.0717	1.089 (1.022,1.16)	0.2167
	Yes	1.05 (1.036,1.065)		1.049 (1.032,1.066)		1.061 (1.018,1.106)
Dyslipidemia	No	1.055 (1.04,1.071)	0.6262	1.05 (1.033,1.067)	0.8436	1.08 (1.034,1.127)	0.3729
	Yes	1.053 (1.033,1.074)		1.052 (1.029,1.075)		1.046 (0.986,1.109)
Blood glucose (mg/dl)	<100	1.05 (1.034,1.067)	0.9489	1.049 (1.03,1.068)	0.6529	1.041 (0.991,1.093)	0.2194
	≥100	1.058 (1.041,1.076)		1.051 (1.031,1.072)		1.095 (1.043,1.151)

AD, Alzheimer’s disease; VaD, vascular dementia; HR, hazard ratios; CI, confidence interval; DM, diabetes mellitus; HTN, hypertension.

DISCUSSION

Participants with FIT positivity had a higher risk of developing dementia than those with FIT negativity in our current study based on the Korean NHISS database. The FIT positivity was significantly associated with a high risk of all kinds of dementia, AD, and VaD regardless of sex, age, smoking, alcohol consumption, physical activity, economic status, and baseline comorbidities. Especially, FIT positivity in younger compared to older participants strongly suggested a risk of all kinds of dementia and AD.

Specific antibodies in the FIT detect the globin portion of Hb, and a small amount of stool blood is enough for positive FIT results: the cut-off concentration of the positive result is usually 20μg Hb/g feces in quantitative FITs and 10μg Hb/g feces in qualitative FIT despite different exact cut-off concentration of each FIT brands [29 –31]. Multiple factors other than CRC can provoke positive results of FIT. Sex, age, smoking, medications, and several GI diseases, such as IBD, hemorrhoid, and diverticulosis, are reported to increase the risk of FIT positivity [7 , 13]. In addition, positive FIT is discovered in patients with multiple diseases with inflammatory reactions other than CRC [32, 33]. FIT-positive participants have a higher risk of ischemic stroke, myocardial infarction, and diabetes mellitus (DM), compared to FIT-negative participants [34, 35]— all of which are metabolic diseases that result from a systemic inflammatory reaction [36]. Rheumatoid diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis, are associated with positive FIT [37, 38]. Moreover, periodontal inflammation is related to positive FIT [39]. Dementia is also related to excessive and abnormal inflammatory reactions. The inflammatory reaction which facilitates amyloid-β accumulation is one of the risk factors of AD [40], and abnormal neuroinflammation is related to brain vascular damage, cerebral infarction, and vascular dementia [41]. Consistent with previous results, our data indicates that dementia can be one of the true risk factors of FIT positivity.

The correlation of FIT with dementia can be explained by gut dysbiosis, inflammation, and barrier dysfunction. The result of FIT reflects gut microbial composition because the fecal microbial composition is changed by the presence of blood in the feces. Bacteroides spp., Escherichia coli, Faecalibacterium prausnitzii, Collinsella aerofaciens, Eggerthella lenta, and Clostridium symbiosum increase in participants with FIT positivity [42, 43]. Gut microbiota and the brain communicate through the immune system, tryptophan metabolism, vagus nerve, and the enteric nerve system [44]. Gut dysbiosis promotes neuroinflammation and facilitates amyloid deposition [45, 46]. Subjects with AD have different compositions of gut microbiota [47, 48]. Bacteriodes spp., Clostridium, and Eggerthella lenta increased in feces from FIT-positive participants and were abundant in patients with cognitive impairment [49 –51].

When gut inflammation becomes excessive, the gut mucosal barrier is broken and fails to prevent the penetration of macromolecules and pathogens. IBD is one of the inflammatory diseases that occur in the GI tract. Patients with IBD have chronic mucosal inflammation and high gut permeability [52] and IBD can be a risk factor of FIT positivity, so researchers investigated the availability of FIT as a convenient and economic biomarker for IBD [9, 10]. IBD is composed of UC and Crohn’s disease (CD), and UC is mostly confined to the colon but CD can cause inflammation anywhere in the GI tract [8]. The applicability of FIT for a diagnostic or prognostic indicator is different between UC and CD. FIT positivity is well correlated to endoscopic severity in UC [53]. And FIT can be applied for early diagnosis of asymptomatic patients and detection of clinical relapse of quiescent UC [54, 55]. In CD, FIT poorly reflect mucosal activity in patients who do not have colon involvement [56].

Gut barrier dysfunction is also associated with cognitive impairment. Patients with dementia show higher levels of intestinal permeability makers, such as serum diaminooxide and fecal zonulin [57]. High gut permeability promotes bacterial translocation and inflammatory reaction in patients with dementia. Bacterial endotoxin and inflammatory cytokines increase in serum and fecal samples from the patients. Metabolites induced by gut barrier dysfunction alter the expression of tight junction proteins, especially in the hippocampus and amygdala [58]. Therefore, a malfunctioning gut– brain axis can influence a positive FIT result and the development of cognitive impairment.

Remarkably, the difference in incidence probabilities between FIT-positive and -negative participants was significant in the group younger than 65 (Table 3). Although the prevalence of dementia was 42.3 per 100,000 for an age group of 20– 64 years, which was smaller than for those aged 65 and older [59], patients with EOD were in serious situations in both clinical and socioeconomic aspects. The EOD is poorly understood and easily misdiagnosed because it can present more diverse symptoms than late-onset dementia (LOD) and sometimes accompany motional dysfunction or neuropsychiatric symptoms [60]. Younger patients with EOD have difficulties continuing their socioeconomic activities and require caregiving [61]. However, care service for LOD is inappropriate for younger patients, and special age-related support is insufficient due to lack of social interest and EOD expertise [62]. Our data confirmed a prominent association between FIT positivity and dementia in younger subjects after adjusting for well-known risk factors, implying a potential role of FIT in EOD diagnosis.

The major strength of the current study is the first suggestion of a relationship between FIT and dementia. Thus, if the FIT performed for CRC screening is positive, but no CRC is found, other diseases related to chronic inflammation can be considered and dementia is one of the possible diseases causing a false positive FIT. Furthermore, this was a population-based study with a large sample size of more than 6,000,000 participants. It covered the period 2009– 2019, and participants were followed for a long period— a maximum duration of 10 years.

There are several limitations in this study. We relied on the NHISS database and so it is difficult to guarantee accuracy because all information should be defined by diagnostic and treatment codes. Disease codes may not represent a patient’s actual disease status because the codes were created to claim health insurance services. Clinically diagnosed dementia may differ from that defined only by disease codes and treatment information [63]. Participants with mild cognitive impairment, a clinical process changing from healthy aging to dementia [64], were not well reflected in this study. Medications, which are prescribed for diseases related to chronic inflammation, like antiplatelet agents, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), and steroids, can work as confounders for FIT [13 , 65– 67]. However, our study cannot analyze the relationship between the medication and FIT positivity, because the exact reason for the drug prescription is not available from the Korean NHISS database. Additionally, information about over-the-counter medications, including NSAIDs and anti-ulcer agents, is missing in the NHISS database [68].

In conclusion, FIT positivity in participants was significantly related to increased risk of dementia, compared to FIT negativity. Notably, the risk of dementia was more prominent in younger FIT-positive participants under 65 years of age. In participants with false positive FIT, physicians can consider other diseases related to inflammatory reactions and dementia can be one possible cause of FIT positivity.

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

This work was supported by National Research Foundation (NRF) of Korea grand funded by the Korea government (No. NRF-2021R1I1A1A01056204).

Additionally, this study was supported by the SK Chemical Research Fund of The Korean Society of Gastroenterology and Inha University Research Grant.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The supplementary material is available in the electronic version of this article: .

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