Effect of Low-Dose Aspirin on the Course of Age-Related Macular Degeneration: A Secondary Analysis of the ASPREE Randomized Clinical Trial.

Importance: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. Objective: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. Design, Setting and Participants: The Aspirin in Reducing Events in the Elderly-AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. Interventions: Aspirin (100 mg daily, enteric coated) or placebo. Main Outcomes and Measures: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. Results: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). Conclusions and Relevance: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. Trial Registration: anzctr.org Identifier: ACTRN12613000755730.

Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration.

PURPOSE: A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. METHODS: We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. MAIN OUTCOME MEASURES: Association of PRS2023 and PRS2016 with AMD risk at baseline. RESULTS: At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41-7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%-95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). CONCLUSIONS: A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The ASPREE Healthy Ageing Biobank: Methodology and participant characteristics.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

DNA methylation analysis of candidate genes associated with dementia in peripheral blood.

Aim: To investigate whether genes implicated in dementia pathogenesis are differently methylated in peripheral blood. Materials & methods: Participants included 160 cognitively healthy individuals aged 70+ years: 73 who were subsequently diagnosed with dementia and 87 controls matched on age, gender, education, smoking and baseline cognition. A total of 49 participants also provided blood samples at diagnosis. Blood DNA methylation of APOE, APP, BDNF, PIN1, SNCA and TOMM40 was examined. Results: A total of 56 of 299 probes were differentially methylated in dementia compared with controls and 39 probes prior to diagnosis. The greatest effect size was in APP (cg19423170, Δ-8.32%, adjusted p = 0.009 at diagnosis; cg19933173, Δ-4.18%, adjusted p < 0.0001 prediagnosis). Conclusion: Genes implicated in dementia pathogenesis show differential blood methylation in dementia, even prior to diagnosis.

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

PURPOSE: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression. METHODS: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants. RESULTS: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors. CONCLUSIONS: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.

Blood DNA methylation signatures to detect dementia prior to overt clinical symptoms.

INTRODUCTION: This study determined whether blood DNA methylation (DNAm) patterns differentiate individuals with presymptomatic dementia compared to controls. METHODS: DNAm was measured in 73 individuals prior to dementia diagnosis and 87 cognitively healthy controls matched for age, sex, smoking, education, and baseline cognition. DNAm was also measured at 3 years follow-up in 25 dementia cases, and 24 controls. RESULTS: Cases and controls differed in DNAm (unadjusted P < .01) at the time of diagnosis (n = 28,787 probes), and pre-diagnosis (n = 15,111 probes), with cg01404610 (General transcription factor IIA subunit 1 gene) significant after correction for multiple testing. Overall, 1150 probes overlapped between analyses (methylation differences from -10.6% to +11.0%), and effect sizes increased from pre-diagnosis to diagnosis. DISCUSSION: Discernible blood DNAm signatures are in dementia cases before the appearance of overt clinical symptoms. Blood-based methylation may serve as a potential biomarker of dementia, but further investigation is needed to determine their true clinical utility.

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

PURPOSE: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. METHODS: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. RESULTS: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. CONCLUSION: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

Testosterone and Estrone Increase From the Age of 70 Years: Findings From the Sex Hormones in Older Women Study.

CONTEXT: There is a lack of understanding of what is normal in terms of sex steroid levels in older women. OBJECTIVE: To determine whether sex steroid levels vary with age in and establish reference ranges for women >70 years of age. DESIGN AND SETTING: Cross-sectional, community-based study. PARTICIPANTS: Included 6392 women ≥70 years of age. MAIN OUTCOME MEASURES: Sex steroids measured by liquid chromatography-tandem mass spectrometry. A reference group, to establish sex steroid age-specific reference ranges, excluded women using systemic or topical sex steroid, antiandrogen or glucocorticoid therapy, or an antiglycemic agent. RESULTS: The reference group of 5326 women had a mean age of 75.1 (±4.2) years, range of 70 to 94.7 years. Median values (range) were 181.2 pmol/L (3.7 to 5768.9) for estrone (E1), 0.38 nmol/L (0.035 to 8.56) for testosterone (T), 2.60 nmol/L (0.07 to 46.85) for dehydroepiandrosterone (DHEA), and 41.6 nmol/L (2.4 to 176.6) for SHBG. Estradiol and DHT were below method sensitivity in 66.1% and 72.7% of the samples, respectively. Compared with women aged 70 to 74 years, women aged ≥85 years had higher median levels of E1 (11.7%, P = 0.01), T (11.3%, P = 0.02), and SHBG (22.7%, P < 0.001) and lower DHEA (30% less, P < 0.001). Women with overweight and obesity had higher E1 (P < 0.001) and T (P < 0.03) and lower SHBG (P < 0.001) than did women with normal body mass index. Smokers had 17.2% higher median T levels (P = 0.005). CONCLUSION: From the age of 70 years, T and E1 increase with age, despite a steady decline in DHEA. Whether E1 and T are biomarkers for longevity or contribute to healthy aging merits investigation.

Development and validation of a deep-learning algorithm for the detection of neovascular age-related macular degeneration from colour fundus photographs.

IMPORTANCE: Detection of early onset neovascular age-related macular degeneration (AMD) is critical to protecting vision. BACKGROUND: To describe the development and validation of a deep-learning algorithm (DLA) for the detection of neovascular age-related macular degeneration. DESIGN: Development and validation of a DLA using retrospective datasets. PARTICIPANTS: We developed and trained the DLA using 56 113 retinal images and an additional 86 162 images from an independent dataset to externally validate the DLA. All images were non-stereoscopic and retrospectively collected. METHODS: The internal validation dataset was derived from real-world clinical settings in China. Gold standard grading was assigned when consensus was reached by three individual ophthalmologists. The DLA classified 31 247 images as gradable and 24 866 as ungradable (poor quality or poor field definition). These ungradable images were used to create a classification model for image quality. Efficiency and diagnostic accuracy were tested using 86 162 images derived from the Melbourne Collaborative Cohort Study. Neovascular AMD and/or ungradable outcome in one or both eyes was considered referable. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC), sensitivity and specificity. RESULTS: In the internal validation dataset, the AUC, sensitivity and specificity of the DLA for neovascular AMD was 0.995, 96.7%, 96.4%, respectively. Testing against the independent external dataset achieved an AUC, sensitivity and specificity of 0.967, 100% and 93.4%, respectively. More than 60% of false positive cases displayed other macular pathologies. Amongst the false negative cases (internal validation dataset only), over half (57.2%) proved to be undetected detachment of the neurosensory retina or RPE layer. CONCLUSIONS AND RELEVANCE: This DLA shows robust performance for the detection of neovascular AMD amongst retinal images from a multi-ethnic sample and under different imaging protocols. Further research is warranted to investigate where this technology could be best utilized within screening and research settings.

Age-related macular degeneration in a randomized controlled trial of low-dose aspirin: Rationale and study design of the ASPREE-AMD study.

PURPOSE: Although aspirin therapy is used widely in older adults for prevention of cardiovascular disease, its impact on the incidence, progression and severity of age-related macular degeneration (AMD) is uncertain. The effect of low-dose aspirin on the course of AMD will be evaluated in this clinical trial. DESIGN: A sub-study of the 'ASPirin in Reducing Events in the Elderly' (ASPREE) trial, ASPREE-AMD is a 5-year follow-up double-blind, placebo-controlled, randomized trial of the effect of 100 mg daily aspirin on the course of AMD in 5000 subjects aged 70 years or older, with normal cognitive function and without cardiovascular disease at baseline. Non-mydriatic fundus photography will be performed at baseline, 3-year and 5-year follow-up to determine AMD status. PRIMARY OUTCOME MEASURES: The incidence and progression of AMD. Exploratory analyses will determine whether aspirin affects the risk of retinal hemorrhage in late AMD, and whether other factors, such as genotype, systemic disease, inflammatory biomarkers, influence the effect of aspirin on AMD. CONCLUSION: The study findings will be of significant clinical and public interest due to a potential to identify a possible low cost therapy for preventing AMD worldwide and to determine risk/benefit balance of the aspirin usage by the AMD-affected elderly. The ASPREE-AMD study provides a unique opportunity to determine the effect of aspirin on AMD incidence and progression, by adding retinal imaging to an ongoing, large-scale primary prevention randomized clinical trial.