Visual Impairment and Cognitive Function in Aging Adults: Sex and Age Differences in Mediating Effect of Social Isolation and Depression.

Visual Impairment and Cognitive Function in Aging Adults: Sex and Age Differences in Mediating Effect of Social Isolation and Depression - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Am J Ophthalmol . Author manuscript; available in PMC: 2026 Jun 1. Published in final edited form as: Am J Ophthalmol. 2025 Mar 5;274:196–208. doi: 10.1016/j.ajo.2025.02.043 Visual Impairment and Cognitive Function in Aging Adults: Sex and Age Differences in Mediating Effect of Social Isolation and Depression D Diane Zheng 1 , David J Lee 2 , Tatjana Rundek 3 , Byron L Lam 4 , Ninel Z Gregori 4 , Rosie E Curiel 1 , David A Loewenstein 1 Author information Article notes Copyright and License information 1 Center for Cognitive Neurosciences & Aging, Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, Miami FL, USA 2 Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami FL, USA 3 Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami FL, USA 4 Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Author Contribution: D. Diane Zheng, David A. Loewenstein, David J. Lee, Tatjana Rundek, Byron L. Lam, Ninel Z Gregori, and Rosie E. Curiel participated in the interpretation of findings, manuscript development, and editing. D. Diane Zheng was involved in the acquisition of data and analysis of data ✉ Corresponding Author: D. Diane Zheng, Ph.D., Center for Cognitive Neurosciences & Aging, Department of Psychiatry and Behavioral Science, University of Miami Miller School of Medicine, 1695 NW 9th Avenue, Suite 3204G, Miami FL 33136, dzheng@med.miami.edu Issue date 2025 Jun. PMC Copyright notice PMCID: PMC12043430  NIHMSID: NIHMS2063563  PMID: 40054544 The publisher's version of this article is available at Am J Ophthalmol Abstract Purpose: Visual impairment (VI) is prevalent in older adults and associated with cognitive decline. However, the mechanisms through which visual impairment affects cognitive functioning during the aging process are poorly understood. Our study aims to estimate the direct effect of visual acuity on cognitive function and its indirect effect through social isolation and depressive symptoms by sex and age. Design: Cross-sectional study Participants: 117,231 individuals aged 40–70 participated in the UK Biobank baseline and ocular assessment. Of these, 81% were white, 54% were female, and 45.6% were aged 60–70. The mean age was 56.8 (SD 8.1) years. Methods: Path analyses with multiple equations were conducted to examine the direct and indirect effects of visual acuity (VA). Stratified analyses by gender and age were performed. Main Outcome Measures: LogMAR VA was the exposure, with social isolation and depressive symptoms as mediators. Cognitive functions, including visual memory, verbal-numerical reasoning, processing speed, and prospective memory, were the outcomes. Results: VA had a direct effect on cognitive function (β=−0.979, p<0.01 for reasoning and OR=0.67, p<0.01 for prospective memory). VA also influenced cognition indirectly through social isolation and depressive symptoms (All p<0.01). The direct effect of VA on cognitive function was similar in men vs. women and middle-aged vs. older (all P<0.05). However, there is a marked difference in the mediating effect via social isolation and depressive symptoms by age and sex. The mediating effect of VI on cognition via social isolation was stronger in older adults than middle-aged and in men than women; while the mediating effect via depressive symptoms was stronger in women and middle-aged individuals. VI had the largest mediating effect via social isolation in older males. Conclusion and Relevance: Vision, social isolation, and depressive symptoms are modifiable factors and can be treated to preserve cognition. Encouraging social engagement among male and older adults with VI and promoting mental health awareness in women and middle-aged individuals with VI will reduce the negative impact of VI on cognition, lower dementia risk, and improve the well-being of aging adults. Keywords: visual impairment, visual acuity, cognitive function, aging adults, middle-aged, social isolation, depressive symptoms, mediating effect Table of Contents Visual acuity influences cognition directly and indirectly via social isolation and depressive symptoms. The indirect effect of vision via social isolation was stronger in older adults and men, while the indirect effect via depressive symptoms was stronger in women and middle-aged individuals. Vision had the largest influence via social isolation in older men. These findings will help guide targeted intervention to reduce the adverse effects of VI and mitigate cognitive decline in aging adults. Visual impairment (VI) and cognitive impairment (CI) are disabling chronic conditions that disproportionately affect older adults. 1 , 2 Research has revealed a relationship between VI and CI and dementia in older adults. 3 – 6 VI is a risk factor for Alzheimer’s Disease and is associated with cognitive decline in community-residing older adults who are cognitively unimpaired. 3 , 6 VI and cognitive impairment also affect each other as older adults age. 4 , 5 However, the mechanisms and pathways through which VI affects cognitive functioning during the aging process remain poorly understood. Both VI and cognitive decline could result from a common underlying cause, such as brain neurodegeneration. 7. 8 Alternatively, VI may increase cognitive load, 9 reduce older adults’ ability to participate in activities and social engagement and become a risk factor for cognitive decline. 10 , 11 Social connection is a crucial aspect of human life and affects a person’s health and well-being. 12 Social isolation (SI) and loneliness are two distinct aspects of social connection. Social isolation is an objective measure of lack of social interaction and encompasses elements such as living alone, withdrawal from social connections, and limited engagement in social activities. 13 Loneliness, in contrast, is a subjective feeling of being isolated. 14 Social isolation and loneliness have become widespread problems in modern society, particularly in recent years. Approximately one-quarter of community-dwelling Americans aged 65 and older are socially isolated, and a significant proportion report feeling lonely. 12 Social isolation and loneliness are associated with poor physical and mental health outcomes, including cognitive decline and higher mortality. 12 Limited research examined the role of SI and depression in the relationship between VI and cognition. The few studies relied on self-reported vision status instead of objective measures, 15 and findings are inconsistent. 15 – 18 Self-reported sensory status is strongly influenced by the respondent’s psychological state and can be biased. 19 , 20 Additionally, most research on VI and cognition focuses on older adults. 15 – 17 Middle age is a critical stage for brain aging and offers opportunities for disease prevention and risk mitigation for diseases such as dementia. 21 Social interactions also vary by sex and life stage. 22 This study aims to use objective vision measurements to investigate the roles of social isolation, loneliness, and depressive symptoms in the relationship between VI and cognitive impairment in a large middle-aged and older adult population. We also explore the sex and age differences in these relationships. Methods Data source The UK Biobank is a large, multisite prospective study of over 500,000 UK residents aged 40 to 70 years, enrolled between 2006 and 2010. 23 Participants completed touchscreen questionnaires and face-to-face interviews. Extensive data were collected including socio-demographics, family history, psychosocial, lifestyle, and cognitive functions. 24 Various physical measures and biological specimens were also collected. In 2009, over 117,000 participants took part in the ocular assessment, which included visual acuity (VA). 25 Details of these assessments and data are available at the UK Biobank website: https://biobank.ndph.ox.ac.uk/ukb/ . This study included 117,231 participants with available data on VA, cognition, social connection, and depression. Our study is a cross-sectional analysis within the large longitudinal UK Biobank study. The University of Miami institutional review board approved this study. Visual acuity VA was measured using the LogMAR chart on a computer screen under standard illumination. Participants wore their distance correction if any, and were tested at 4-meter distance, or 1-meter if unable to read at 4 meters. The right eye was measured first. Participants read letters sequentially from the top to the smallest-sized letter they could identify until 2 letters on the same screen were identified incorrectly. The total number of letters correctly identified was converted to LogMAR visual acuity. VA worse than 0.3 logMAR in the better-seeing eye was considered visually impaired. VA was treated as a continuous variable in our analyses. Social connection -- Social isolation and loneliness Social isolation and loneliness were measured using scales similar to other UK Biobank studies. 26 – 29 Social isolation is the structural measure of social connection and comprises three dichotomized items: (1) Live alone - ‘Including yourself, how many people are living together in your household?” (1 alone, 0 otherwise); (2) Frequency of friends or family visit -’How often do you visit friends or family or have them visit you?’ (1-less than once a month); and (3) ‘Which of the following [leisure/social activities] do you attend once a week or more often?” (1-not attending at least weekly). Social isolation is the sum of the above items and ranges from 0 to 3, a high score indicating worse social isolation. An individual was considered socially isolated if scored 2 or 3. The loneliness scale comprised two items: 1) ‘Do you often feel lonely?’ (1 yes, 0 otherwise); 2) ‘How often are you able to confide in someone close to you?’ (1-once every few months to never or almost never). Loneliness is the functional component of the social connection. An individual was considered lonely if scored 2. Depressive symptoms were measured by four items from the Patient Health Questionnaire (PHQ-8) 30 , 31 : Over the past two weeks, 1) How often have you felt down, depressed or hopeless? 2) How often have you had little interest or pleasure in doing things? 3) How often have you felt tense, fidgety, or restless? 4) How often have you felt tired or had little energy? Answers to the questions include: 1- Not at all, 2- several days, 3- more than half the days, and 4 - nearly every day. 32 The depressive symptoms score was calculated by averaging the answers to the four items. An average score greater than 2 is considered to have some depressive symptoms. 31 Cognitive functions: The cognitive functions were assessed through touch screen tests 24 and included the following: 1. Pairs Matching (visual memory): Participants were shown 12 cards with six matching pairs for 5 seconds then asked to match the pairs from memory. Unlimited attempts could be made without a time limit. The score was the number of errors made, with a higher score indicating worse cognitive function. The pair matching score was log (+1) transformed to obtain normality for analysis. 2. Verbal-numerical reasoning (fluid intelligence): This measures one’s ability to think quickly and recall information. Participants were presented with 6 verbal and 7 numerical questions with multiple-choice answers and had to answer as many questions as possible within 2 minutes. The total number of correct answers was the verbal numerical reasoning score. 3. Reaction Time (processing speed): Participants were shown one pair of cards out of 12 pairs. If both cards displayed a matching symbol, participants pressed a response button as quickly as possible. The score was the mean response time in milliseconds across 4 trials. The reaction time was log-transformed to obtain normality for analysis. 4. Prospective Memory: Participants were instructed: ‘At the end of the games, we will show you four colored symbols and ask you to touch the blue square. However, to test your memory, we want you to actually touch the Orange Circle instead’. The score is binary (0/1) with one representing the task completed correctly on the first attempt. Covariates: We controlled for an extensive list of confounding variables in our models. The sociodemographic variables included age (years), sex (biological sex: male vs. female), Race (White vs. all other), education (college degree vs. other), and Townsend deprivation index, where a higher score indicates a greater degree of deprivation. 33 Health behavior variables include smoking (previous or current smoker vs. non-smoker) and alcohol drinking frequency (3 or more times weekly vs. other). Biological and medical covariates include Body Mass Index (BMI) (<25, 25–30, ≥30 kg/m 2 ), diabetes, and cardiovascular diseases (e.g., heart attack, angina, stroke, high blood pressure) diagnosed by a doctor. Depressive symptoms and social isolation were also controlled when they did not serve as the dependent variable. Statistical analysis: Descriptive statistics and correlation analysis were performed. Path analyses with multiple equations were estimated in the structural equation modeling (SEM) framework. As depicted in Figure 1 , We first assessed the associations between visual acuity and cognitive outcomes – the direct effect. Secondly, we examined the association between visual acuity and the three potential mediators, social isolation, loneliness, and depression. Thirdly, we evaluate the associations between the potential mediators and cognitive outcomes. The latter two pathways yielded the indirect effects of the three mediators. Figure 1. Open in a new tab The diagram of path analyses in the structural equation modeling framework. The above paths were estimated simultaneously while controlling for an extensive list of covariates. Paths or covariates that were not statistically significant were removed from the model for purposes of model parsimony. Social isolation, loneliness, and depressive symptoms were also controlled when evaluating the direct effect between VA and cognitive function. Logistic regression analyses were performed when the outcome was categorical (e.g., prospective memory) and the regression coefficients were exponentiated to obtain Odds Ratios (OR). Indirect effects were calculated by multiplying the two parameters involved in the mediation relationship. 34 , 35 The total effects were calculated by summing the direct and indirect effects. Standard errors for both indirect and total effects were obtained using the delta method. 36 To examine the gender and age differences in these relationships, analyses stratified by sex (male vs. female) and age group (middle-aged 40–59 vs. older age 60–70) were performed. We included all participants with available VA values in the analysis, regardless of whether there were missing values in the covariates. Maximum Likelihood Robust for missing data (full-information MLR) estimation was used to obtain estimates in the presence of missing data. 37 All Analyses were conducted using SAS 9.4 38 and Mplus 8.10. 39 Results This analysis included 117,231 adults aged 40–70 from the baseline eye assessment. The average age was 56.8 (SD 8.1), with 45.6% aged 60–70. Women made up 54%, and 81% were White. Nearly 35% had a college education or higher. Regarding health behaviors, 44.5% were current or former smokers, 42% drank alcohol three or more times weekly, 42% were overweight (BMI 25–30), and 24.5% were obese (BMI > 30). ( Table 1 ) Table 1. Characteristics of Study Participants. All Age 40–59 Age 60–70 Female Male N 117,231 63,805 53,426 61,227 52,000 Age, Mean (SD) (range 40–70 years) 56.8 (8.1) 50.7 (5.6) 64.2 (2.8) 56.6 (8.0) 57.1 (8.2) Age 40–59 years 63,805 (54.4%) 63,805 (100%) 0 (0%) 34373 (56.1%) 27192 (52.3%) 60–70 years 53,426 (45.6%) 0 (0%) 53,426 (100%) 26854 (43.9%) 24808 (47.7%) Sex - Female 61,227 (54.1%) 34,373 (55.8%) 26854 (52.0%) 61,227 (100%) 0 (0%) Male 52,000 (45.9%) 27,192 (44.2%) 24808 (48.0%) 0 (0%) 52000 (100%) White 95159 (81.2%) 48,747 (76.4%) 46412 (86.9%) 49420 (80.8%) 42718 (82.2%) College or University degree 40570 (34.6%) 25,114 (39.4%) 15456 (28.9%) 20540 (33.6%) 18662 (35.9%) Townsend deprivation index, mean (SD) −0.93 (3.0) −0.65 (3.1) −1.28 (2.9) −0.97 (3.0) −0.91 (3.1) Never smoker 64617 (55.4%) 37,633 (59.4%) 26984 (50.9%) 36737 (60.4%) 25628 (49.6%) Alcohol consumption ≥3 times/week 49299 (42.25%) 25,151 (39.6%) 24148 (45.3%) 21761 (35.7%) 25995 (50.2%) BMI < 25 kg/m2 39350 (33.6%) 22,936 (36.0%) 16414 (30.7%) 24606 (40.2%) 13363 (25.7%) 25–30 kg/m2 49202 (42.0%) 25,517 (40.0%) 23685 (44.3%) 22156 (36.2%) 25522 (49.1%) >=30 kg/m2 28679 (24.5%) 15,352 (24.1%) 13327 (24.9%) 14465 (23.6%) 13115 (25.2%) Ever being told by a doctor had diabetes 6915 (5.9%) 2,833 (4.5%) 4082 (7.7%) 2634 (4.3%) 4020 (7.8%) Ever being told by a doctor had CVD * 34788 (29.8%) 13,540 (21.4%) 21248 (40.0%) 15457 (25.4%) 18121 (35.1%) Social isolation score, Mean (SD) 0.59 (0.68) 0.60 (0.69) 0.57 (0.68) 0.58 (0.67) 0.60 (0.70) Socially isolated, N(%) 11,495 (9.8%) 6592 (10.3%) 4903 (9.2%) 5665 (9.3%) 5376 (10.4%) Depressive symptoms, Mean (SD) 1.43 (0.57) 1.51 (0.62) 1.34 (0.49) 1.46 (0.58) −0.0517 (0.154) Report depressive symtoms, N(%) 11,598 (9.9%) 8128 (12.7%) 3470 (6.5%) 6525 (10.7%) 4586 (8.8%) Loneliness score, Mean (SD) 0.38 (0.60) 0.40 (0.61) 0.36 (0.58) 0.37 (0.59) 0.39 (0.61) Report being lonely, N (%) 7,061 (6.1%) 4263 (6.7%) 2798 (5.3%) 3391 (5.6%) 3416 (6.6%) Visual acuity in LogMAR, Mean (SD) −0.0427 (0.153) −0.0656 (0.149) −0.0157 (0.153) −0.0357 (0.151) −0.0517 (0.155) Visually impaired, N(%) 3614 (3.1%) 1653 (2.6%) 1961 (3.7%) 1894 (3.1%) 1588 (3.1%) Pair match error, Median (IQR) * 3.0 (3.0) 3.0 (3.0) 4.0 (4.0) 3.0 (3.0) 3.0 (3.0) Verbal numeric reasoning, Mean (SD) 5.98 (2.18) 6.08 (2.23) 5.85(2.11) 5.88 (2.10) 6.11 (2.26) Reaction time in milliseconds, Median (IQR) * 547 (138) 523 (126) 575 (142) 554 (138) 535 (138) Prospective memory (%) 89,068 (76.6%) 50,281 (79.5%) 38,787 (73.1%) 46386 (76.3%) 39738 (77.1%) Open in a new tab * CVD - cardiovascular diseases * IQR - Interquartile range The mean social isolation score was 0.59 (SD 0.66) with 9.8% reporting being socially isolated. The mean loneliness score was 0.38 (SD 0.60), with 6.1% reported being lonely. The average depressive symptom score was 1.43 (SD 0.57), the median was 1.25 (interquartile range (IQR) 0.75), with 9.9% reporting some depressive symptoms in the past 2 weeks. The mean verbal numeric reasoning score was 5.98 (SD 2.18), median pair match error 3 (IQR) 3); median reaction time was 547 milliseconds (IQR 138), and 76.6% completed the prospective memory task correctly on the first try, indicating average cognitive status is within the normal range for middle-aged to older adults. The mean visual acuity was −0.043 log MAR, close to 20/20 on the ETDRS chart, indicating good vision in this middle-aged to older adult population. About 3.08% had worse than 0.3 logMAR in the better-seeing eye, which is considered visually impaired. The study population characteristics stratified by age (40–59 vs. 60–70) and sex (Female vs. Male) are presented in Table 1 . The direct and indirect effect of vision on cognitive outcomes in the overall population VA was statistically significantly associated with three of the four cognitive outcomes. One standard deviation (SD) worsening of VA (0.15 logMAR, equivalent to one and a half lines on the ETDRS chart or close to 7.5 letters) was associated with a 0.069 SD reduction in the verbal numeric reasoning score which is 0.15 (=0.069 × 2.18) lower reasoning score (standardized β=−0.069, 95% CI [−0.075, −0.063], unstandardized β=−0.979, [−1.07,−0.90], p<0.0001). One SD worsening in VA was associated with a 0.049 SD higher in log reaction time or 1 millisecond slower in reaction time (standardized β for log RT=0.049 [0.043, 0.55], unstandardized β log RT=0.063, [0.056, 0.071], p<0.001), and 5.5% less chance of getting the prospective memory task correctly on the first try (Odds Ratio 0.945 [0.937,0.952] from standardized β 0.057 [−0.065, −0.49], unstandardized β −0.422, [−0.477, −0.367] equivalent to OR 0.67 [0.64, 0.71]; all p<0.0001). VA was not directly associated with the pair match score. ( Table 2 ) Table 2. The direct, indirect, and total effect of visual acuity on cognitive outcomes. Overall population Verbal Numeric Reasoning 95% Confidence Interval P value Pair match in log scale 95% Confidence Interval P value Reaction time in log scale 95% Confidence Interval P value Prospective memory 95% confidence interval P value Unstandardized coefficients Direct effect of VA on cognition −0.979 [−1.061, −0.898] <0.001 0.021 [−0.006, 0.047] 0.12 0.063 [0.056, 0.071] <0.001 −0.398 [−0.454, −0.343] <0.001 Indirect effect through depression −0.038 [−0.045, −0.031] <0.001 0.002 [0.001, 0.003] 0.001 0.0021 [0.0017, 0.0026] <0.001 −0.021 [−0.025, −0.017] <0.001 Indirect effect through social isolation −0.004 [−0.006, −0.001] 0.002 0.0014 [0.0006, 0.0022] <0.001 0.0004 [0.0002, 0.0006] <0.001 −0.003 [−0.004, −0.001] 0.001 Total effect (direct plus indirect effect) −1.021 [−1.102, −0.94] <0.001 0.024 [−0.002, 0.05] 0.076 0.066 [0.059, 0.073] <0.001 −0.422 [−0.477, −0.367] <0.001 Standardized coefficients Direct effect of VA on cognition −0.068 [−0.074, −0.063] <0.001 0.005 [−0.001, 0.011] 0.12 0.049 [0.043, 0.055] <0.001 −0.057 [−0.065, −0.049] <0.001 Total effect direct plus indirect effect −0.071 [−0.077, −0.066] <0.001 0.005 [−0.001, 0.011] 0.076 0.051 [0.045, 0.057] <0.001 −0.06 [−0.068, −0.052] <0.001 Open in a new tab * The odds ratio for prospective memory was obtained by exponentiating the coefficient. Social isolation was a statistically significant mediator in the relationship between VA and all four cognitive outcomes. The indirect effects of VA on cognition through social isolation were (β=−0.004, 95% CI [−0.006, −0.001], p=0.002) for verbal-numerical reason, (β =0.0004 [0.0002, 0.0006] on log scale, p<0.001) for reaction time, and a 0.3% reduction in getting the prospective memory task correctly (OR=0.997 [0.996, 0.999], p<0.001). Although VA had no direct effect on pair match scores, it had an indirect effect on them through social isolation (β=0.001 [0.001, 0.002], p<0.0001). The effect sizes of social isolation were small but statistically significant, indicating poor vision influences cognition by impacting social isolation. ( Table 2 ) Depressive symptoms were also a statistically significant mediator in the relationship between VA and all cognitive measures. The indirect effect through DS was (β=−0.038 [−0.045, −0.031], p<0.001) for verbal-numerical reasoning, (β =0.002 [0.002, 0.003] on the log scale, p<0.001) for reaction time, and a 2.1% reduction in getting the prospective memory correct (OR=0.979 [0.975, 0.983], p<0.001). ( Table 2 ) Although no direct effect was observed, VA indirectly influenced pair match scores through depressive symptoms (β =0.002 [0.001, 0.003] on the log scale, p<0.001). Loneliness didn’t mediate the relationship between VA and cognition. Its association with VA and cognition disappeared once depressive symptom was controlled as a confounder. The correlation of loneliness with depressive symptoms and social isolation were 0.34 and 0.20, respectively (both p<0.001). The age and sex differences in mediating effect of social isolation and depressive symptoms The direct effect of VA on cognitive function was similar in men vs. women and middle-aged vs. older age (all P<0.05). However, there are marked age and gender differences in the mediating effect of vision through social isolation and depressive symptoms. Using verbal numerical reasoning as an example, the mediating effect of VA on cognition through depressive symptoms was β=−0.049 [−0.06, −0.038] in middle-aged vs. −0.024 [−0.032, −0.017] in older adults, with both p < 0.001 and no overlap in 95% confidence intervals. The effect size is almost twice in middle-aged compared to the older-aged. In contrast, in older adults, VA mediated cognition more through increased social isolation (β −0.011 [−0.015, 0.006], p<0.001 for older adults) compared to zero mediating effect in the middle-aged (β = 0, p=0.9). These patterns of differences were consistently observed across all four cognitive outcomes. ( Tables 3 and 4 , Figures 2 and 3 ). Therefore, VA had a stronger influence on cognition by exacerbating depressive symptoms in the middle-aged, but VA affects cognition in older adults more through increased social isolation. Table 3. The direct, indirect, and total effect of visual acuity on cognitive outcomes by age groups Verbal numeric reasoning 95% Confidence Interval P value Pair match in log scale 95% Confidence Interval P value Reaction time in log scale 95% Confidence Interval P value Prospective memory * 95% confidence interval P value Age 40–59, Middle-aged Direct effect of VA on cognition −1.004 [−1.117, −0.891] <0.001 0.065 [0.028, 0.101] <0.001 0.069 [0.059, 0.079] <0.001 −0.454 [−0.533, −0.376] <0.001 indirect effect through depression −0.049 [−0.06, −0.038] <0.001 0.0027 [0.0012, 0.0043] <0.001 0.0026 [0.002, 0.0033] <0.001 −0.026 [−0.032, −0.021] <0.001 Indirect effect through social isolation 0 [−0.003, 0.003] 0.99 0.0008 [−0.0001, 0.0017] 0.072 0.0004 [0.0001, 0.0007] 0.007 −0.001 [−0.003, 0.001] 0.194 Total effect direct plus indirect effect −1.053 [−1.166, −0.939] <0.001 0.068 [0.032, 0.104] <0.001 0.072 [0.062, 0.082] <0.001 −0.482 [−0.561, −0.403] <0.001 Age 60–70, older Direct effect of VA on cognition −0.951 [−1.067, −0.835] <0.001 −0.027 [−0.066, 0.011] 0.163 0.059 [0.048, 0.07] <0.001 −0.35 [−0.428, −0.272] <0.001 indirect effect through depression −0.024 [−0.032, −0.017] <0.001 0 [−0.001, 0.002] 0.79 0.0015 [0.001, 0.002] <0.001 −0.015 [−0.019, −0.01] <0.001 Indirect effect through social isolation −0.011 [−0.015, −0.006] <0.001 0.002 [0.001, 0.004] 0.001 0.0005 [0.0001, 0.0009] 0.007 −0.005 [−0.008, −0.002] <0.001 Total effect direct plus indirect effect −0.986 [−1.102, −0.87] <0.001 0.025 [−0.063, 0.014] 0.2 0.061 [0.05, 0.072] <0.001 −0.37 [−0.448, −0.292] <0.001 Open in a new tab * The odds ratio for prospective memory was obtained by exponentiating the coefficient. Table 4. The direct, indirect, and total effect of visual acuity on cognitive outcomes by sex. Verbal numeric reasoning 95% Confidence Interval P value Pair match in log scale 95% Confidence Interval P value Reaction time in log scale 95% Confidence Interval P value Prospective memory * 95% confidence interval P value Male Direct effect of VA on cognition −0.987 [−1.11, −0.864] <0.001 0.042 [0.003, 0.081] 0.035 0.065 [0.054, 0.076] <0.001 −0.407 [−0.488, −0.326] <0.001 indirect effect through depression −0.029 [−0.039, −0.02] <0.001 0.001 [0, 0.002] 0.113 0.002 [0.001, 0.003] <0.001 −0.015 [−0.02, −0.01] <0.001 Indirect effect through social isolation −0.005 [−0.009, −0.001] 0.023 0.0026 [0.0012, 0.0041] <0.001 0.0007 [0.0003, 0.0011] <0.001 −0.004 [−0.007, −0.001] 0.003 Total effect −1.021 [−1.144, −0.898] <0.001 0.046 [0.007, 0.085] 0.022 0.068 [0.057, 0.079] <0.001 −0.427 [−0.508, −0.345] <0.001 Female Direct effect of VA on cognition −0.971 [−1.078, −0.863] <0.001 0.001 [−0.034, 0.037] 0.947 0.061 [0.051, 0.072] <0.001 −0.388 [−0.464, −0.313] <0.001 indirect effect through depression −0.045 [−0.055, −0.036] <0.001 0.0024 [0.001, 0.004] 0.004 0.0022 [0.0016, 0.0027] 0.001 −0.027 [−0.032, −0.021] <0.001 Indirect effect through social isolation −0.003 [−0.005, 0] 0.049 0.001 [0, 0.001] 0.12 0.0002 [−0.0005, 0.00043] 0.118 −0.001 [−0.003, 0] 0.124 Total effect −1.018 [−1.126, −0.9111 <0.001 0.004 [−0.031, 0.041 0.815 0.064 [0.054, 0.0741 <0.001 −0.416 [−0.492, −0.341 <0.001 Open in a new tab * The odds ratio for prospective memory was obtained by exponentiating the coefficient. Figure 2. Open in a new tab Mediation effect of vision on cognition through social isolation. Figure 3. Open in a new tab Mediation effect of vision on cognition through depressive symptoms. Sex differences were also apparent in these mediating pathways. In men, poor vision mediated more through impacting on social isolation (β for prospective memory −0.004 [−0.007, −0.001], p=0.003 for men vs. a statistically non-significant effect in women β −0.001, p=0.1). Conversely, VA had a stronger mediating effect via depressive symptoms in women (β for prospective memory: −0.027 [−0.032, −0.021], p<0.001) than in men (β −0.015 [−0.02, −0.01], p<0.001) with no overlap in 95% confidence intervals. These differences by sex were evident in all four cognitive outcomes. ( Tables 3 and 4 , Figures 2 and 3 ). The mediating effect of poor vision on cognition through social isolation was the largest in the older male subgroup (ages 60–70), β for reasoning −0.013 [−0.02, −0.005], p < 0.001, compared to all other groups ( Figure 2 ). The age and sex differences in mediating effects are illustrated in Figures 2 and 3 and Tables 3 and 4 . Discussion Our study examined the comprehensive relations among vision, social isolation, depressive symptoms, and various cognitive outcomes in a large middle-aged and older adult population. We demonstrated that VA not only had a direct effect on cognition, but VA also influenced cognition indirectly through affecting social isolation and depressive symptoms. Importantly, the mediating effects differed by sex and age. Poor vision influences cognition more through increased social isolation in men and older adults, whereas poor vision mediates cognition more via exacerbating depressive symptoms in women and middle-aged persons. The mediating effect of vision on cognition through increased social isolation was the largest in older male adults. To our knowledge, such age and sex differences in mediating effects of vision on cognition have not been reported before. We compared the influence of VA on cognitive outcomes across different domains using standardized coefficients, which were expressed in a common metric of standard deviation unit and are directly comparable. VA exhibited the strongest association with reasoning ability (fluid intelligence), followed by prospective memory, and processing speed. While advancing in age is commonly associated with a decline in cognitive performance, particularly fluid intelligence, 40 – 42 poor vision adds another layer to the association. Interestingly, although VA was not directly associated with visual memory, it had an indirect effect on visual memory through affecting social isolation and depressive symptoms. However, the total effect of VA on visual memory didn’t reach statistical significance in this study. ( Table 2 ). Depression and social isolation have been hypothesized as the pathways through which poor vision affects cognitive function in older adults. 43 , 44 This theory proposes that impaired visual function reduces older adults’ ability to participate in activities and social engagement, and becomes a risk factor for cognitive decline. 43 , 44 However, this hypothesis has rarely been confirmed in large epidemiological studies. Using data from a large middle-aged and older adult population, we demonstrate that social isolation and depressive symptoms both mediate the vision-cognition relationship. It is important to note that the mediation effect sizes of the two are small and account for only a small portion of the total effect compared to the direct effect of VA on cognition. This suggests other important pathways (i.e. vascular process, etc.) or mediating factors (i.e. physical activity) may exist between vision and cognition. However, a small effect size at the population level that accumulates over time can have significant public health implications. VI has substantial health consequences, such as increased risk of injuries and reduced independence. 45 – 47 VI also profoundly affects communication, social life, and psychological well-being of individuals 48 – 50 and can exacerbate the negative effects of social isolation and depression, especially in older adults. With the fast aging of the US population 51 and the high prevalence of VI in older adults, 52 we anticipate an increased impact of VI on cognitive health and dementia in aging adults. Notably, the Lancet Commission recently included untreated visual loss as a modifiable risk factor for dementia in older adults. 53 Our finding that social isolation exerts a larger mediating effect on the vision-cognition relationship in older adults is supported by the literature. 12 , 54 Older people are more likely to experience social isolation due to lifestyle factors such as living alone, deceased friends and partners, chronic illnesses, and disability. 54 The prevalence of VI also increases rapidly with age. 52 VI and social isolation together increase the risk of dementia and other negative health outcomes in older adults. 55 , 56 Research also suggests gender differences in social connections, particularly during adulthood, with men being more isolated than women. 22 Adult men are less likely than women to have close ties outside their spouse/partner relationship. 22 , 57 Following widowhood or divorce, women may be less isolated than men due to their stronger ties with family and friend networks. 58 , 59 This may contribute to a larger mediating effect of social isolation for men on the vision-cognition relationship. It is noteworthy that the mediation effects via depressive symptoms were stronger in women than men in our analyses. ( Figure 3 ) Women are more likely than men to report experiencing depressive symptoms. 60 Factors contributing to this difference include female hormonal changes, gender differences in coping style, stressful life events, and the joint effects of biological and environmental factors. 61 Other studies have explored the mediating effect of hearing and visual impairment on cognitive function. However, these studies relied on self-reported measures of hearing and vision, which are prone to bias and may not accurately represent actual sensory status. 15 , 16 , 62 For example, studies utilizing self-reported hearing status and objectively measured pure tone audiometry to examine the relationships between hearing impairment and cognitive function yielded different results. 63 Additionally, our project focused specifically on exploring the mechanisms linking VA and cognitive function. While both hearing and vision impairments share similar mechanisms in their impact on cognitive function in aging adults, the extent to which each pathway influences cognition may differ. 63 Therefore, it is valuable to investigate the specific mechanisms through which vision affects cognition. Our findings align with previous research using self-reported VI, indicating that social isolation is a pathway through which vision difficulty is associated with decreased cognitive function. 15 , 62 Another study utilizing VA found that social factor was not a statistically significant mediator in healthy people but had slightly higher effects in females and older adults. 17 This study utilized broadly defined social factors, e.g., social network index and social support, which differed from our definition of social isolation and may contribute to the differences in findings. Our results indicated that social isolation is a mediator with a stronger mediating effect in older adults and men. Additionally, VA had the strongest mediating effect through social isolation in older males. The limitations of our study include the age range of our study population extends only up to 70. As a result, the prevalence of VI and CI was relatively low. We anticipate that the mediating effect of social isolation would be even stronger in individuals aged 70 and above. However, the vision-cognition relationships are rarely examined in middle-aged adults, which can be considered a strength of our study. The majority of participants were White (81%), which may limit the generalizability of findings to other racial and ethnic groups. Additionally, we didn’t utilize the cognition data for multiple rounds due to the “practice effect” phenomenon observed in the data. Participants performed better in the later round of assessment than in baseline because they became more familiar with the tests. Additionally, our study is a cross-sectional analysis; therefore, reverse causation cannot be ruled out. Nevertheless, our study includes a large sample size and objectively measured visual function, which provides excellent statistical power and ensures the accuracy and robustness of findings. Our study highlights the importance of maintaining good vision in middle-aged and older adults. The leading causes of VI include refractive error, cataracts, glaucoma, and age-related macular degeneration (AMD). 64 Ensuring correct prescription glasses and timely treatment of conditions like cataracts, glaucoma, and AMD is important in preserving cognitive function in aging adults. Furthermore, We provide insight into the potential exacerbation of social isolation and depressive symptoms on cognition in aging adults with impaired vision. Understanding the difference in the mediating effect of impaired vision on cognition for different age and gender groups will help provide targeted intervention to slow cognitive decline and prevent dementia. Our findings underscore the value of staying socially connected and maintaining good mental health. Encouraging male and older adult patients with visual difficulties to stay socially connected and participate in social activities, as well as urging women and middle-aged patients with vision problems to be mindful of their mental health and seek professional help, if needed, can mitigate these risks. Addressing these issues can reduce the negative impact of VI and lower the risk of cognitive decline and dementia, ultimately enhancing overall well-being. Conclusion We demonstrated that poor vision not only directly impacts cognitive function but also operates through social isolation and depressive symptoms to influence cognitive function, with the mediating effects varying across age and gender groups. These findings have important public health implications for mitigating the adverse effects of visual impairment and preserving cognitive function in aging adults. Given the limited treatment options for dementia, treating modifiable factors such as visual impairment, social isolation, and depressive symptoms offers a promising strategy to slow cognitive decline, prevent dementia, and improve the quality of life for many aging adults. Highlights. Vision had direct and indirect effects on cognition via social isolation and depressive symptoms. The mediating effect via social isolation was stronger in older adults than middle-aged and in men than women. Vision had the largest influence via social isolation in older men. The mediating effect of vision via depressive symptoms was stronger in women and middle-aged. Findings will guide targeted intervention to reduce the impact of VI, slow cognitive decline, & improve quality of life. ACKNOWLEDGEMENTS Sources of funding: National Institute on Aging K01AG080120 and 1R01AG077677. Role of the Sponsor: The organization that provided funding had no role in the design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Footnotes Declaration of interests: None of the authors of this manuscript had any potential conflicts of interest, including relevant financial interests, activities, relationships, and affiliations to disclose. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. References: 1. 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