With the aging of the population, there is a simultaneous rise in the burden of diverse age-related diseases. Among these, cancer and neurodegenerative diseases prominently influence various aspects of life in older adults. The diagnosis and treatment of cancer result in physical burdensomeness and psychosocial and economic adversities [1]. Likewise, neurodegenerative disease such as Alzheimer’s disease (AD) and Parkinson’s disease can profoundly impact daily lives. These conditions affect both cognitive function and motor skills, leading to difficulties in performing routine tasks, maintaining independence, and engaging in social activities [2,3].

Interestingly, solid evidence indicates an inverse association between the occurrence of cancer and neurodegenerative diseases, suggesting that individuals diagnosed with cancer have a reduced tendency to develop neurodegenerative diseases, while those with neurodegenerative diseases exhibit a diminished susceptibility to cancer [4,5]. One potential explanation revolves around the differing biological mechanisms present in each condition [6]. Cancer is characterized by uncontrolled cell proliferation, whereas neurodegenerative diseases typically involve programmed cell death known as apoptosis [7]. The reason for the inverse correlation is due to the occurrence of mechanisms is opposing directions.

Age-related macular degeneration (AMD) is a neurodegenerative disease affecting the retina and stands as a primary cause of visual impairment and severe loss of vision [8]. AMD shares features with AD, particularly in its relation with the accumulation of amyloid b [9]. In a cohort study conducted within the population of Finland, the study identified a correlation between visual impairment, including AMD, and cancer [10]. Nonetheless, the study focused exclusively on participant with visual impairment. A prospective cohort study found the AMD was linked with cancer mortality, but not incidence of cancer [11]. However, researches have predominantly focused on visual impairment of mortality, with few studies investigating the association between prevalence of AMD and cancer survivorship. Therefore, we aimed to evaluate the association between cancer history and the prevalence of AMD in a nationally representative Korean cohort.

1. Design and participants

The data used was obtained from the Korean National Health and Nutrition Examination Survey (KNHANES 2017-2018), which addressed the prevalence of AMD, as determined by ophthalmologic examinations, using a newly generated variable (E-AMD). KNHANES is a nationwide population-based survey conducted annually by the Korean Ministry of Health and Welfare on subjects randomly selected using a stratified, multistage, probability sampling design. Interview and examinations were conducted in specially designed and equipped mobile centers. All subjects that participated in KNHANES provided written informed consent. More detailed information on KNHANES has already been published [12]. In this study, a final dataset of 6,993 participants aged ≥40 years that provided information on AMD, were included in the analysis (Figure 1). The study received approval form the Institutional Review Board of Gachon University Gil Medical Center, in accordance with established ethical standards (IRB no. GFIRB2021-481).

Figure 1. Flow diagram illustrating participant selection

2. Ophthalmic variables

AMD was identified through screening tests. AMD was defined based on the ophthalmologic examinations performed by certificated ophthalmologists, and the Epidemiologic Survey Committee of the Korean Ophthalmologic Society verified the quality of the ophthalmic surveys [13]. Ophthalmologic examinations included measurements of visual acuity and intraocular pressure, autorefraction, slit-lamp biomicroscopy, and fundus photography. Digital fundus photographs centered on the fovea (Diabetic Retinopathy Study standard field 2) were taken with a non-mydriatic fundus camera (TRC-NW6S, Topcon, Tokyo, Japan; Nikon D-80, Nikon, Tokyo, Japan) under physiological mydriasis. The examinations results classified AMD into Yes/No categories. Hyperopia, a common refractive error in which distant objects are seen more clearly than near objects due to the light rays entering the eye being focused behind the retina, was defined as a refractory error >＋0.5 D [14]. A history of cataract surgery was determined using self-reported questionnaires. Conditions were considered present when one or both eyes were affected.

3. Other variables

Health interviews and health examinations were performed during a single day by trained medical staff and interviewers. Information on age, sex, health behaviors (smoking history, alcohol drinking, and physical activity), histories of physician-diagnosed diseases (any cancer, myocardial infarction, stroke, hypertension, and type 2 diabetes) were collected during interviews. Current smokers were defined as individuals who smoked cigarettes at the time of interview. Frequent drinking was defined as drinking twice per week. Regular exercise was defined ≥2.5 hours/week of moderate-intensity activity, ≥1.25 hours/week of high-intensity activity, or a considered combination of activities. After each interview, body height and weight were measured using a standard scale with participants wearing light clothing and no shoes, and body mass index (BMI) was calculated by dividing weight by height squared (kg/m²). Obesity was defined as BMI ≥25.0 kg/m² according to WHO criteria for the Asia-Pacific region [15].

4. Statistical analysis

Demographics and clinical characteristics of participants were assessed using Chi-square test. A multiple logistic regression model adjusted for potential confounding factors, extracted by stepwise multivariate logistic regression analysis, was used to evaluate associations between cancer history and AMD prevalence. We determined the prevalence of AMD with 95% confidence intervals (CIs) by cancer history in the whole cohort and in age subgroups (40-54, 55-64, and ≥65 years old). All statistical analyses were performed using Stata/MP software (version 17.0; Stata Corp., College Station, TX, USA). All statistical tests were two-tailed, and statistical significance was accepted for P-value <0.05.

The demographics and clinical characteristics of participants are presented in Table 1. Among the 6,993 participants, 43.4% (n=3,038) were male. Individuals under the age of 55 comprised 39.2% (n=2,743), whereas those aged 65 and older represented 33.1% (n=2,312). Hyperopia was observed in 56.7% (n=3,965) of the participants, while 12.5% (n=873) had undergone cataract surgery. History of cancer was identified in 6.5% (n=452) and AMD was found in 16.0% (n=1,118).

Table 1 . Demographics and clinical characteristics of participants.

	N (%)
Sex
Male	3,038 (43.4)
Female	3,955 (56.6)
Age
40-55	2,743 (39.2)
55-64	1,938 (27.7)
≥65	2,312 (33.1)
Body mass index ≥25 kg/m2
No	4,445 (63.6)
Yes	2,548 (36.4)
Smoking status
Non- or ex-smoker	5,790 (83.3)
Current smoker	1,157 (16.7)
Drinking frequency
<2 per week	4,593 (75.2)
≥2 per week	1,516 (24.8)
Aerobic exercise*
No	4,140 (61.9)
Yes	2,548 (38.1)
Hypertension
No	4,771 (68.2)
Yes	2,222 (31.8)
Type 2 diabetes
No	6,153 (88.0)
Yes	840 (12.0)
Major cardiovascular diseases†
No	6,699 (95.8)
Yes	294 (4.2)
Hyperopia
No	3,028 (43.3)
Yes	3,965 (56.7)
Cataract surgery
No	6,120 (87.5)
Yes	873 (12.5)
Cancer history
No	6,541 (93.5)
Yes	452 (6.5)
AMD
No	5,875 (84.0)
Yes	1,118 (16.0)

AMD, age-related macular degeneration..

*≥2.5 Hours/week moderate intensity activity, ≥1.25 hours/week high-intensity activity or a considered combination of activities. ^†Including myocardial infarction and stroke..

Table 2 shows age-adjusted prevalence of AMD by subject characteristic. Male sex, frequent drinking, and history of hyperopia were linked with a higher prevalence of AMD. Factors associated with AMD were detailed in Table 3. Older age (OR, 1.06; P<0.001), male sex (OR, 1.26; P=0.003), and hyperopia (OR, 1.55; P<0.001) were associated with AMD.

Table 2 . Age adjusted prevalence of AMD by participant charac-teristics.

	AMD prevalence (95% CI)	P-value*
Sex
Male	14.8 (13.6-16.2)	0.001
Female	12.2 (11.2-13.3)
Body mass index ≥25 kg/m2
No	13.9 (12.8-15.0)	0.100
Yes	12.5 (11.2-13.9)
Smoking status
Non- or ex-smoker	13.0 (12.1-14.0)	0.060
Current smoker	15.2 (13.1-17.6)
Drinking frequency
<2 per week	11.9 (10.9-12.9)	0.043
≥2 per week	13.8 (12.1-15.7)
Aerobic exercise†
No	13.1 (12.0-14.2)	0.559
Yes	13.6 (12.2-15.0)
Hypertension
No	13.2 (12.2-14.3)	0.599
Yes	13.7 (12.3-15.2)
Type 2 diabetes
No	13.4 (12.5-14.4)	0.550
Yes	12.8 (10.9-15.0)
Major cardiovascular diseases‡
No	13.5 (12.6-14.4)	0.083
Yes	10.7 (8.1-13.9)
Hyperopia
No	11.0 (9.9-12.3)	<0.001
Yes	15.0 (13.8-16.3)
Cataract surgery
No	13.3 (12.4-14.2)	0.638
Yes	13.8 (11.8-16.1)
Cancer history
No	13.4 (12.5-14.3)	0.681
Yes	12.8 (10.3-15.8)

AMD, age-related macular degeneration; CI, confidence interval..

*From multivariate logistic regression models. ^†≥2.5 Hours/week moderate intensity activity, ≥1.25 hours/week high-intensity activity or a considered combination of activities, as suggested by KNHANES. ^‡Including myocardial infarction and stroke..

Table 3 . Factors associated with AMD.

	Odds ratio (95% CI)	P-value*
Age	1.06 (1.06-1.07)	<0.001
Male sex	1.26 (1.08-1.46)	0.003
Hyperopia	1.55 (1.29-1.85)	<0.001

AMD, age-related macular degeneration..

*From multivariate logistic regression models with stepwise selection..

Figure 2 presents AMD prevalence by cancer history after adjusting for the selected variables in the 6,993 participants and the three age subgroups. Participants with a cancer history were found to be less likely to have AMD, though this was not significant (P=0.62). However, age-stratified analysis revealed that cancer history tended to be associated with low prevalence of AMD among young subjects (P_trend=0.076).

Figure 2. Association between cancer history and AMD by age group. AMD, age-related macular degeneration. *Adjusted for age, sex, and hyperopia

In this nationally representative study, we investigated whether the association between a history of cancer and prevalence of AMD was significant in middle-aged and older adults. Our finding suggests that while this association was not remarkable in older adults, a potential reduction in AMD risk among cancer survivors may be influential in the younger population. Another robustness of our study was conducting an age-stratified analysis, which enabled us to discern the correlation between cancer and AMD across different age groups. A larger-scale study with adequate statistical power, particularly in younger individuals, is needed to refute or confirm our findings. The strength of our study resided in the accurate ophthalmic assessments rather than dependence on ICD codes.

Among participants younger than 55 years old, an inverse association between cancer and AMD was observed. A meta-analysis study further confirmed the inverse correlation between neurodegenerative diseases such as AD and Parkinson’s disease, and cancer occurrence [16]. Notably, a significant interaction was found between genes exhibiting upregulation in such neurodegenerative disorders and downregulation in cancers, as well as genes demonstrating downregulation in neurodegenerative disorders and upregulation in cancer [17]. Cancer is defined by uncontrolled cell proliferation, while neurodegenerative diseases often entail apoptosis, leading to an inverse relationship attributed to mechanisms functioning in divergent pathways. However, due to the multifactorial nature of factors influencing occurrence of cancer and AMD, further analysis is needed to determine which factors exert greater effect depending on age.

In our age-stratified analysis, we observed a simultaneous increase in the occurrence of both cancer and AMD among participants aged 65 and over, although statistical significance was not observed. A retrospective outpatient cohort study of US veterans reported a higher risk of AMD in people with a cancer history (hazard ratio, 1.37; CI, 1.36-1.39) than in those without [18]. Their study cohort comprised patients aged ≥65 years and older—corresponds to our oldest group, and their findings parallel our own results. This could be attributed to the fact that both cancer and AMD are linked with the aging process. Moreover, cancer and AMD exhibit overlapping risk factors. For instance, alcohol consumption has been identified as a prominent risk factor for both cancer and AMD [19]. Smoking, inflammation-related genes, and oxidative stress have also been identified as shared risk factors [11,20]. These findings imply the potential presence of shared pathogenic mechanisms between AMD and cancer.

Several limitations of the present study should be acknowledged. First, our study confirmed the history of cancer without categorizing cancer type. A population-based cohort study discovered variations in the occurrence of AMD depending on the type of cancer [21]. Hence, additional research is warranted based on the specific types of cancer. Second, the cross-sectional design could not resolve the issue of selective mortality. However, if cancer patients, who might have a lower risk of AMD, are more likely to die before they can develop AMD, this would rather have biased our results toward the null. A prospective cohort study with frequent examinations designed to timely detect cancer or AMD is warranted. Third, AMD was identified through screening tests rather than confirmatory diagnostics. Further research should focus on accurate diagnosis using confirmatory tests. Lastly, information on cancer treatment were unavailable for assessment, potentially confounding our findings due to the unknown influence of cancer treatments on AMD risk [22].

Nonetheless, our exploratory results support the possibility of an inverse relation between a history of cancer and AMD, as determined through precise ophthalmic examination. Thus, our findings suggest that a cancer history or vulnerability to cancer may protect younger individuals from neurodegenerative disease.

This research was supported by Gachon University Gil Medical Center under Grant FRD2021-14.

No potential conflict of interest relevant to this article was reported.