APOE-ε4 is not associated with pure-tone hearing thresholds, visual acuity or cognition, cross-sectionally or over 3 years of follow up in the Canadian Longitudinal Study on Aging

Background Hearing loss and vision loss are independently and jointly associated with faster rates of cognitive decline. Identifying mechanisms underlying sensory-cognitive associations is a research priority and is needed to inform public health efforts to reduce cognitive decline. Sensory impairment is highly prevalent and treatable, and if a cause-and-effect relationship exists with cognitive decline, treating sensory impairments could reduce rates of cognitive decline with age. On the other hand, if sensory-cognitive associations are the result of a common cause (e.g., a genetic predisposition for both sensory and cognitive impairment), then interventions aimed at reducing sensory loss would not be expected to have beneficial effects on cognition. The apolipoprotein E ( APOE )-ε4 allele variant is associated with age-related neurological diseases (e.g., Alzheimer’s disease) and non-neurological diseases (e.g., atherosclerosis). APOE -ε4 could be a common factor underlying associations between sensorineural losses and cognitive decline, but links between APOE -ε4 and both hearing and vision in the general population remain under-studied. Furthermore, the association between APOE -ε4 and cognition in healthy individuals is not as clear as the link between APOE -ε4 and Alzheimer’s disease. Therefore, we aimed to determine if APOE -ε4 allele count (the explanatory variable) was associated with differences in baseline and 3-year change in executive function, memory, pure-tone hearing thresholds, and visual acuity (the outcome variables). Methods A secondary analysis of data collected in the Canadian Longitudinal Study on Aging (CLSA) was performed using data from two time points 3 years apart. Participants, aged 45-85 years, were recruited from 11 cities across Canada. Composite scores for executive function and memory were developed from five tests of cognition. Bilateral air-conduction pure-tone threshold averages and pinhole-corrected visual acuity in the better-seeing eye were used to measure hearing and vision, respectively. Linear mixed regression models assessed associations between APOE -ε4 allele count (as a categorical variable with 0 as the reference) and a.) baseline differences and b.) 3-year declines in each of the four outcome variables. Multivariable models adjusted for age, education, sex, race, heart disease, stroke, hypertension and diabetes. Interactions between APOE -ε4 and age group (45-54, 55-64, 65-74, and 75-85 years) and APOE -ε4 sex were tested. Results There were 27,765 participants in the CLSA comprehensive cohort but only 11,296 had complete data and were included. Individuals with complete data were more likely to be younger and healthier than those with partially missing data. In main effects models, APOE -ε4 was not associated with any of the sensory or cognitive outcome measures, either in terms of differences in baseline values or change over time. Regression models including the APOE -ε4*age interaction term (but not the APOE -ε4*sex interaction term) better fit the data than the corresponding main effects models. In age-stratified analyses most associations between APOE -ε4 and the outcome variables were still not significant. The exceptions were as follows: Twoε4 alleles predicted better baseline executive function in the 55-64 year old age group, and better baseline pure-tone average in the 45-54 year old age group. In the 65-74 year-old age group, one ε4 allele predicted worsening in visual acuity over time, whereas two ε4 alleles predicted improvements. Discussion APOE- ε4 allele count was not associated with poorer executive function, memory, pure-tone hearing thresholds or visual acuity, at baseline or over 3 years of follow-up, among a population-based sample of healthy 45-85 year old Canadians. Thus, the study does not support the hypothesis that APOE- ε4 is a common cause underlying associations between hearing or vision loss (respectively) and declines in each of executive function and memory. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was made possible using the data/biospecimens collected by the Canadian Longitudinal Study on Aging (CLSA). Funding for the Canadian Longitudinal Study on Aging (CLSA) is provided by the Government of Canada through the Canadian Institutes of Health Research (CIHR) under grant reference: LSA 94473 and the Canada Foundation for Innovation. This research has been conducted using the CLSA Baseline Comprehensive Dataset version 4.1, Follow-up 1 Comprehensive Dataset version 3.0, and the Vital Status files for both Tracking and Comprehensive cohorts, under Application Number 20CA007. The CLSA is led by Drs. Parminder Raina, Christina Wolfson and Susan Kirkland. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval for the secondary analysis of CLSA data was obtained from the University of Saskatchewan Biomedical Research Ethics Board (application ID: 1656) and data access was approved by the CLSA data access committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data are available from the Canadian Longitudinal Study on Aging ([www.clsa-elcv.ca][1]) for researchers who meet the criteria for access to de-identified CLSA data. [1]: http://www.clsa-elcv.ca