Associations between dementia and exposure to topical glaucoma medications

Abstract

Background

Some studies have suggested that glaucoma may be associated with neurodegeneration and a higher risk of dementia.

Objective

To evaluate whether exposure to different categories of topical glaucoma medications is associated with differential dementia risks in people with glaucoma.

Methods

We used data from Adult Changes in Thought, a population-based, prospective cohort study that follows cognitively normal older adults from Kaiser Permanente Washington (KPWA) until Alzheimer's disease (AD) and related dementia development. We included participants with a diagnosis of glaucoma, KPWA pharmacy records of filling topical glaucoma medication (alpha-adrenergic agonists [AAA], beta-adrenergic antagonists, miotics, carbonic anhydrase inhibitors [CAI], and prostaglandins) and at least 10 years of pharmacy records. Eight-year sliding windows were derived for each medication class by computing days on each medication starting 10 years earlier and excluding the most recent 2 years. Cox regression used all 5 classes of medication simultaneously to predict AD and all-cause dementia.

Results

We included 521 participants (mean age 78 [range 65–96], 62% female) with APOE genotype data. Beta-adrenergic antagonists were the most frequently prescribed (n = 431) followed by prostaglandins (351), AAA (239), CAI (162), and miotics (142). Adjusting for time-varying exposure to other glaucoma medications, APOE, demographics, and smoking, each year of use of alpha-adrenergic agonists in an 8-year window was associated with a higher risk of developing dementia (HR = 1.33, 95% CI = 1.03–1.72).

Conclusions

Among older adults with treated glaucoma, exposure to alpha-adrenergic agonists appears to be associated with risk for developing all-cause dementia.

Keywords

Adult Changes in Thought Alzheimer's disease Cognitive Abilities Screening Instrument score contrast sensitivity Eye Adult Changes in Thought (Eye ACT)glaucoma ophthalmology optical coherence tomography measurement prospective study visual acuity

Introduction

Dementia affects an estimated 55 million people globally, while Alzheimer's disease (AD), the most common type of dementia, accounts for 60–70% of these cases. There are many theories about the pathogenesis of dementia, but the modern consensus is that degenerative changes may begin decades before the onset of clinically relevant symptoms.^1,2 Understanding the risk factors of dementia may provide tremendous economic and quality-of-life value to aging populations. Currently theorized risk factors for dementia include genetic variants, lifestyle factors, and medication exposures such as anticholinergics.^2–7

Sensory impairment has been discussed as a potential source of modifiable dementia risk.^8–13 One common cause of visual impairment in older adults is glaucoma, a multifactorial disease leading to degeneration of the optic nerve. Although there is conflicting literature, several studies suggest that glaucoma may be associated with neurodegeneration and a higher risk of dementia.^12,14,15 Both glaucoma and dementia may share molecular pathways and clinical features related to neurodegeneration.¹⁶ Prevailing theories for a common pathway are multifactorial and implicate immunodysregulation, disruption in microcirculation, autonomic dysregulation, genetics, or a combination of these factors.^17–19 While investigating the role of retinal biomarkers in the evaluation of AD, several have found Aβ and tau deposition in the retina but the frequency of their presence or their locations in the retina vary significantly.^20–22

Medical management of glaucoma is focused on reducing intraocular pressure (IOP) with daily administration of topical eye drops.¹⁴ Several classes of medications are used to reduce IOP including alpha-adrenergic agonists (AAA), which have been associated with neuroprotection²³ and are known to have systemic effects.²⁴ Given the high prevalence of glaucoma in older adults²⁵ who are also at risk of dementia, it is important to examine the potential relationships between exposure to glaucoma medications and the development of dementia. Preventing glaucoma-related sensory impairment may help reduce the risk of dementia, and gaining insights into potential associations between glaucoma treatments and dementia risk could have a significant impact on our healthcare system. In this study, we used data available from the Adult Changes in Thought (ACT) study to examine risks associated with exposure to different classes of glaucoma medications and the development of all-cause dementia as well as AD-type dementia.

Methods

ACT cohort and the study population with medically treated glaucoma

Other studies have used data from the ACT study cohort and described their methods in detail.^26–29 The ACT study is a population-based longitudinal study of aging and dementia. The study began recruiting in 1994 and is designed to evaluate risk factors associated with cognitive impairment, AD-type dementia, and other forms of dementia. Participants are cognitively normal older adults (≥65 years old) at risk for dementia at the time of enrollment who are randomly selected and recruited from the Kaiser Permanente Washington (KPWA) population. Participants are followed until they develop Alzheimer's disease and related dementia (ADRD) as detailed below.²⁷ Our study analysis includes data from the Original Cohort (participants recruited from 1994 to 1996), the Expansion Cohort (recruited from 2000 to 2003), and the Replacement Cohort, who were followed from 2004 to the 3/5/2020 data freeze. At enrollment and during biennial visits, participants receive standardized cognitive screening tests, brief physical evaluations, and medical history and risk factor assessments.^26,30 This study was approved by the institutional review boards of KPWA and the University of Washington and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent. This report is based on the 2020 ACT data freeze.

All-cause dementia and AD-type dementia evaluation

At biennial ACT visits, participants were screened with the Cognitive Abilities Screening Instrument (CASI). The CASI results range from 0–100 with higher scores indicating better cognition.³¹ Participants with CASI scores ≤ 85 underwent a standardized diagnostic evaluation, including physical and neurologic examinations and a neuropsychological test battery.³² Dementia diagnoses were determined at consensus conferences using Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, and probable and possible AD-type dementia diagnoses were determined using the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.^33,34 Our primary outcome was the development of all-cause dementia and our secondary outcome was the development of AD-type dementia, defined as NINCDS-ADRD probable and possible AD.

Study variables

Ophthalmic care was performed by KPWA staff and unrelated to enrollment in the ACT study. Glaucoma medical history was extracted from associated participant medical records, which were available from 1993 onwards. The diagnosis of glaucoma was based on the International Classification of Disease Ninth (ICD-9) and Tenth (ICD-10) Revision codes and was broad, encompassing primary open-angle, low-tension, pigmentary, capsular, and pseudoexfoliation glaucomas (Supplemental Table 1). Our analytic cohort was limited to people who had a glaucoma diagnosis based on the above-mentioned ICD codes and were on medical management confirmed by a history of glaucoma medication fill in the KPWA pharmacy data. A system for calculating exposure history based on the medication records was developed after a manual review of selected medical fill records by a board-certified glaucoma specialist (JPK, Supplemental Methods). Topical glaucoma medication classes included AAA, beta-adrenergic antagonists, miotics, carbonic anhydrase inhibitors (CAI), and prostaglandins (Supplemental Table 1). Patients without available medication data for at least a 10-year period, APOE genotype, or smoking history data were excluded from the analyses.

Statistical analysis

ACT participants with a glaucoma diagnosis, at least one glaucoma prescription, and 10 years of KPWA enrollment were analyzed by creating a sliding window for each medication class. On a given day, the exposure was the number of days in the previous 10 years on a drug in that medication class, a “10-year window” that varied over time. For our primary analysis, we used an “8-year window” that excluded the most recent 2 years because recent exposure to glaucoma medication is unlikely to be a strong factor in disease manifestation, given the long duration of preclinical dementia.³⁵ We used time-varying medication exposure windows, converted to years, as predictors of all-cause dementia and AD-type dementia in Cox survival models. Age was used as the time axis, with the dementia risk period starting at glaucoma diagnosis (ICD code diagnosis and first glaucoma medication fill) or ACT enrollment, whichever was later. Outcomes were censored at death, loss to follow-up, disenrollment from KPWA, the end of the study period, and diagnosis of AD-type dementia or other dementia. All models were adjusted for years of education, self-reported race (White versus all others), the presence of any APOE ε4 alleles, time-dependent smoking status (ever/never), and ACT enrollment cohort. Fewer years of education, APOE ε4, and smoking are associated with increased risks of dementia.^36–38 Secondary models also included a pre-selected list of self-reported medical history variables that are known cardiometabolic risk factors of dementia including heart disease (history of myocardial infarction, angina, coronary artery bypass graft, or angioplasty), hypertension, diabetes, and cerebrovascular disease (history of stroke, transient ischemic attack, or carotid endarterectomy).^39–42 Additional secondary analyses examined (1) the full 10-year window as opposed to the oldest 8 years in each 10-year window which was the primary analysis_, (2) the risk of each medication class without including the other classes in the model, and (3) risk for non-AD-type dementia, defined as all DSM-IV dementia cases minus all NINDS-ADRDA probable or possible AD-type dementia cases. To assess the possibility of unmeasured confounding, we computed the E-value.^43,44 To meet proportional hazards assumptions, we allowed the baseline hazards to differ by sex, which means a hazard ratio for sex is not in the tables. Other model assumptions were tested and found tenable. All analyses were done in Stata 18.0.

Results

Analytic sample

A total of 989 out of 5763 eligible dementia-free ACT participants were diagnosed with glaucoma prior to the ACT study start or during follow-up (17% of the entire cohort). Out of the 989 participants with glaucoma, 819 had a record of glaucoma medication use, but only 595 had at least 10 years of pharmacy data available for analysis (73% of those with a history of glaucoma medication use). Within this group, 522 had APOE genotype data for analysis but one person was missing smoking history data, so the final analysis cohort included 521 participants (Figure 1). Participants within the analytic cohort were at risk for dementia for a median of 8.1 years since ACT study enrollment, a number less than 10 years because many participants had medical records preceding ACT enrollment while time at risk started at ACT enrollment. By the end of follow-up, 115 (115/521, 22.1%) were diagnosed with all-cause dementia, and 92 (92/521, 17.7%) were classified as AD-type dementia. Baseline characteristics of our cohort are shown in Table 1.

Figure 1.

Flow diagram of Adult Changes in Thought (ACT) patient inclusion criteria.

Table 1.

Self-reported demographics and smoking history, and glaucoma medication use from electronic medical records, as of the last Adult Changes in Thought (ACT) study visit.

Characteristic	Mean (SD) or n (%)
N	521
Age at first glaucoma medication	78.0 (6.6)
Age at ACT study entry	75.8 (6.6)
Female	325 (62.4%)
Greater than high school education	264 (50.7%)
Race
American Indian or Alaskan Native	2 (0.4%)
Asian	14 (2.7%)
Black	29 (5.6%)
White	461 (88.5%)
Other, including mixed	15 (2.9%)
Any APOE ε4 alleles	129 (24.8%)
Ever smoked	262 (50.3%)
Prostaglandin analogs^a
Last 8-year window^b	1.1 (1.5)
Last 10 years	1.5 (1.8)
Miotics^a
Last 8-year window^b	0.2 (0.7)
Last 10 years	0.2 (0.8)
Carbonic anhydrase inhibitors^a
Last 8-year window^b	0.3 (0.9)
Last 10 years	0.4 (1.1)
Beta-adrenergic antagonists^a
Last 8-year window^b	1.4 (1.5)
Last 10 years	1.7 (1.8)
Alpha adrenergic agonists^a
Last 8-year window^b	0.3 (0.8)
Last 10 years	0.4 (1.0)

Mean exposure in years.

Mean years of medication use starting 10 years before the last visit but excluding the most recent 2 years.

Glaucoma medication exposure

The 521 participants had a mean age of 78 (range 65–96) when they were first prescribed glaucoma medication, and 62% were female. Of these participants, beta-adrenergic antagonists were the most frequently prescribed (n = 431) followed by prostaglandins (351), AAA (239), CAI (162), and miotics (142). Looking at the last 8-year windows for each person, the mean exposure to beta-adrenergic antagonists was 1.4 years, 1.1 years for prostaglandin analogs, 0.3 years for AAA, 0.2 years for miotics, and 0.3 years for CAI (Table 1).

Risks of dementia

In our primary analyses with the 8-year time-dependent window, each year of AAA use was associated with a 33% higher risk of dementia (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.03, 1.72), adjusting for medications in other classes, demographics, APOE and ACT enrollment cohort (Table 2). The AAA risk is based on fairly short exposure periods. Of those who ever took AAA, the maximum years of exposure in any of their 8-year windows were less than one year for 68%, 1–2 years for 17%, and 2–6 years for 16%. Total lifetime exposure to AAA was over 5 years in 7 people, and over 8 years in 2 people. Those who had ever used AAA, on average, had greater exposure to prostaglandin analogs, miotics, and CAI in their last 8-year window as well (Supplemental Table 2). AAA associations with higher risk of developing all-cause dementia remained significant (HR = 1.35 (1.04, 1.74); p = 0.026) even after adding hypertension, diabetes, heart disease and cerebrovascular disease (Supplemental Tables 3 and 4).

Table 2.

Risks for all-cause dementia from 8-year sliding windows for glaucoma medication, in a multivariable Cox survival model with age as the time axis.

	Hazard Ratio (95% confidence interval)	p
Glaucoma Medications (y)
Alpha-adrenergic agonists	1.33 (1.03, 1.72)	0.031
Beta-adrenergic antagonists	1.11 (0.98, 1.26)	0.11
Miotics	1.09 (0.87, 1.37)	0.47
Carbonic anhydrase inhibitors	0.81 (0.59, 1.13)	0.22
Prostaglandins	0.97 (0.81, 1.13)	0.61
Demographic and Clinical Characteristics^a
Education (per year)	0.98 (0.93, 1.04)	0.57
Self-reported race (White versus all other)	1.04 (0.52, 2.09)	0.92
Any APOE ε4 alleles	1.88 (1.25, 2.82)	0.002
Ever smoked	1.12 (0.75, 1.66)	0.59
Adult Changes in Thought Cohort^b
2000–2003	1.05 (0.64, 1.70)	0.86
2004–2020	0.96 (0.52, 1.75)	0.89

To meet proportional hazards assumptions, we allowed the baseline hazards to differ by sex, so sex does not appear in this Table.

Reference cohort is participants who were recruited between 1994–1996.

No other medication class was associated with dementia or AD-type dementia (Tables 2 and 3).

Table 3.

Risks for Alzheimer's disease-type dementia from 8-year sliding windows for glaucoma medication, in a multivariable Cox survival model with age as the time axis.

	Hazard Ratio (95% confidence interval)	p
Glaucoma Medications (y)
Alpha-adrenergic agonists	1.10 (0.77, 1.58)	0.60
Beta-adrenergic antagonists	1.11 (0.96, 1.28)	0.16
Miotics	1.12 (0.86, 1.45)	0.39
Carbonic anhydrase inhibitors	0.84 (0.58, 1.20)	0.34
Prostaglandins	0.97 (0.81, 1.17)	0.78
Demographic and Clinical Characteristics^a
Education (per year)	0.99 (0.92, 1.05)	0.69
Self-reported race (White versus all other)	1.45 (0.58, 3.65)	0.43
Any APOE ε4 alleles	1.95 (1.23, 3.07)	0.004
Ever smoked	0.98 (0.63, 1.54)	0.94
Adult Changes in Thought Cohort^b
2000–2003	1.19 (0.70, 2.04)	0.52
2004–2020	1.12 (0.58, 2.16)	0.74

To meet proportional hazards assumptions, we allowed the baseline hazards to differ by sex, so sex does not appear in this output.

Reference cohort is participants who were recruited between 1994–1996.

There was minimal confounding by the self-reported health measures for any of the medication classes for risk of AD-type dementia (Supplemental Table 5). The full 10-year window showed a smaller risk for all-cause dementia associated with AAA (HR 1.22, CI 1.00, 1.50) compared to the 8-year window (Supplemental Table 6), and the associations with AD-type dementia remained non-significant (Supplemental Table 7). None of the medication classes were significant predictors of dementia or AD-type dementia when considering each medication class independently (Supplemental Table 8). Post-hoc analyses that included 23 non-AD-type dementia cases, 14 of whom had vascular dementia, showed that AAA use was associated with a two-fold higher risk of non-AD-type dementia (HR 2.04, CI 1.38, 3.02) (Supplemental Table 9). For the primary analysis, the E-value for the association between AAA and dementia was 1.73, meaning that there would need to be an unmeasured covariate having a hazard ratio of at least 1.73 with both AAA and dementia to fully explain away the association (Supplemental Figure 1).

Discussion

Based on 4690-person-years of follow-up data from a total of 521 ACT participants with glaucoma, the exposure to AAA was associated with a 33% increased risk of all-cause dementia per year, but not AD-type dementia. Other glaucoma medications including beta-adrenergic antagonists, miotics, carbonic-anhydrase inhibitors, and prostaglandins were not associated with an increased risk for all-cause dementia or AD-type dementia.

Some previous studies have reported an increased risk of dementia in patients with glaucoma, while other large population studies have not found an association. One study of 6509 individuals with glaucoma from Taiwan (3304 primary open-angle glaucoma [POAG] and 3205 primary angle-closure glaucoma [PACG]) found an increased risk of dementia in patients with POAG but not PACG when compared to age and sex-matched individuals without glaucoma.⁴⁵ Another retrospective study from Taiwan found an increased risk of AD development in 15,317 patients with normat tension glaucoma compared to 61,268 matched subjects.⁴⁶ Notably, both of these studies relied on ICD-9 codes rather than research criteria diagnoses for dementia. In contrast, a large record linkage study performed using English National Health Service data followed more than 85,000 people with a diagnosis of POAG and did not find an increased risk of AD in the POAG group, though there was a small increased risk of vascular dementia (HR 1.10, CI: 1.05, 1.16), which they attributed to shared vascular risk factors.⁴⁷ Our previous study in ACT participants did show an increased risk of AD associated with glaucoma (HR 1.46, CI: 1.08, 1.91), but only in those patients with a recent glaucoma diagnosis (within 5 years of AD diagnosis) and not with chronic glaucoma (over 5-year duration).¹²

Exposure to glaucoma medication use has not been well-studied, and to our knowledge, the use of AAA for glaucoma has not previously been shown to be associated with an increased risk for dementia. In the Taiwan study mentioned above, the use of AAA was associated with increased AD risk in a univariate analysis but no longer significantly associated with AD in the multivariate analysis which included age, sex, and co-morbidities.⁴⁶ In fact, some studies have demonstrated the potential for AAA to be neuroprotective.²³ In animal models of glaucoma and retinal ischemia, Dong et al. reported that alpha2-adrenergic agonists protect retinal ganglion cells⁴⁸ and suggested that brimonidine likely modulates the N-methyl-D-aspartate (NMDA) receptor, an important player in memory formation.^49,50 It is possible we found a lower risk for AD than for all-cause dementia because of potentially beneficial effects of AAA that affect AD specifically.

Some studies have also implicated adrenergic dysregulation as part of the mechanism for cognitive changes.^51–53 Topical ophthalmic instillation of AAA drops is known to induce central adrenergic activity in some patients, providing a mechanism through which the drops may result in adrenergic dysregulation. Brimonidine is contraindicated in children under the age of 2 and used cautiously in older children due to the risk of central nervous system side effects including somnolence and respiratory depression. Drowsiness and fatigue are known side effects in adults. However, it is unclear how the short-term exposures to AAA seen in our study would ultimately contribute to the onset of dementia manifestation through this mechanism. The 10-year window adjusted model had a lower hazard ratio for AAA medication (HR 1.22 [1.00, 1.50]) than the 8-year model (HR 1.33 [1.03, 1.72]). We suspect that by including the 2 most recent years, the power to estimate the effect of AAA medication on dementia risk is lower because dementia disease development has a long time course, making recent exposures not as impactful. We found strong associations between AAA exposure and all-cause dementia but not AD-type dementia. Our post hoc analyses showed that the AAA use was associated with a two-fold increased risk of non-AD-type dementia. Small numbers require cautious interpretation, but given that vascular dementia comprises the majority of non-AD-type dementia, this association may suggest the shared role of vascular disease in glaucoma and dementia risks.

Our findings on associations between the topical AAA and increased risk of dementia were unexpected. We cannot fully rule out that the association is related to patients receiving AAA having more severe glaucoma than those who did not receive AAA. We did not have sufficient information on the severity of glaucoma by ICD codes. All our participants received care from the same healthcare delivery system but many different providers. There was no unified policy regarding which agents to use first in our system, but common practice is to administer beta blockers and/or prostaglandins, and if the glaucoma treatment is not effective, to then add AAA and CAI class medications. In our cohort, AAA was the third most commonly prescribed medication. It is important to note that our model did control for all other glaucoma medication use, thus if the number of the medications is a good indicator of glaucoma severity then we would have accounted for glaucoma severity in the model.⁵⁴ Given that relatively few people were exposed to AAA over multiple years (only 2 for >5 years in any 8-year window), our finding of significant associations from this small sample was again unexpected.

Our study limitations include the possibility for unmeasured and residual confounding as in any observational studies, relying on the accuracy of medical records, and the study population being limited to one institution, which may not be representative of the broader US population. There remains the possibility of an unmeasured confounder that would explain the association between AAA and dementia. However, it seems unlikely because the E-value was 1.73, and one of the strongest known predictors of dementia in the literature, the presence of any APOE ε4 alleles, had an HR of 1.88 in these data. Additionally, adding other health variables essentially did not change the risk estimates. We used pharmacy records as a surrogate indicator of participants’ medication exposure, but cannot rule out poor compliance. People at the preclinical dementia stage may have lower adherence, resulting in protopathic bias. If they were initially started with either beta antagonists or prostaglandins for glaucoma and forgot to take drops, it would lead to worsening glaucoma, and then the doctor would add another medicine such as AAA. We did not have a sufficient number to stratify analysis by each glaucoma subtype. Given glaucoma subtypes have different mechanisms of action, treatments may have led to different interactions creating potentially confounding variables, which we are not able to evaluate in this study. In addition, we did not evaluate the use of concurrent systemic medications which may impact risk of dementia development, including exposure to systemic alpha adrenergic agonists, due to lack of reliable exposure data in our cohort, potential confounding by different indications, and small sample size, Our study however did possess many valuable strengths including large population size with reliable records from a comprehensive medical system, long-term follow-up, and conservative estimates of exposure by using medication fill duration.

In summary, exposure to AAA was associated with risks of developing all-cause dementia, though not Alzheimer's disease, in older adults with glaucoma. Further studies are needed to validate these findings and to further investigate medication exposure time and other factors such as concurrent systemic medications. Nevertheless, the association between exposure to AAA and dementia may offer insight for starting points to research the pathophysiology of dementia and its connections with glaucoma.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241305745 - Supplemental material for Associations between dementia and exposure to topical glaucoma medications

Supplemental material, sj-docx-1-alz-10.1177_13872877241305745 for Associations between dementia and exposure to topical glaucoma medications by Oliver Davidson, Michael L Lee, Jason P Kam, Michael Brush, Anand Rajesh, Marian Blazes, David E Arterburn, Eric Duerr, Laura E Gibbons, Paul K Crane, Cecilia S Lee and in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

We thank the participants of the Adult Changes in Thought (ACT) study for the data they have provided and the many ACT investigators and staff who steward that data. You can learn more about ACT at: .

ORCID iDs

Oliver Davidson

Cecilia S Lee

Author contributions

Oliver Davidson (Writing – original draft; Writing – review & editing); Michael L Lee (Formal analysis; Methodology; Writing – review & editing); Jason P Kam (Data curation; Formal analysis; Methodology; Writing – review & editing); Michael Brush (Methodology); Anand Rajesh (Writing – original draft; Writing – review & editing); Marian Blazes (Writing – original draft; Writing – review & editing); David Arterburn (Conceptualization; Writing – review & editing); Eric Duerr (Methodology); Laura E Gibbons (Formal analysis; Methodology; Writing – original draft; Writing – review & editing); Paul K Crane (Conceptualization; Funding acquisition; Methodology; Writing – review & editing); Cecilia Lee (Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Supervision; Writing – original draft; Writing – review & editing).

Funding

This research was funded by the National Institute on Aging (U19AG066567). Data collection for this work was additionally supported, in part, by prior funding from the National Institute on Aging (U01AG006781). All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of the National Institute on Aging or the National Institutes of Health. This research was also funded by National Institute on Aging grant R01AG060942, National Institutes of Health grant OT2OD032644, the Alzheimer's Drug Discovery Foundation, the Latham Vision Research Innovation Award (Seattle, WA), the Klorfine Family Endowed Chair, the Karalis Johnson Retina Center, and by an unrestricted grant from Research to Prevent Blindness. The sponsors or funding organizations had no role in the design or conduct of this research.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

Data from this analysis cannot be made publicly available for ethical and legal reasons. In order to replicate our findings, a researcher may need access to personal health identifiers (PHI) Version 2/24/2023 including dates of birth and death, dates of diagnoses, and ages over 89. These are required variables for the analysis, and we cannot publicly release this information without IRB approval and a Data Use Agreement with interested researchers. However, the datasets used and/or analyzed in the current study are available upon reasonable request and execution of appropriate human subjects review and data sharing agreements by following the process described on the Adult Changes in Thought (ACT) website: actagingresearch.org.

Supplemental material

Supplemental material for this article is available online.

References

Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 280–292.

Gauthier

Webster

Servaes

, et al. World Alzheimer Report 2022. Life after diagnosis: Navigating treatment, care and support. London, UK: Alzheimer’s Disease International, 2022.

Coupland

CAC

Hill

Dening

, et al. Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA Intern Med 2019; 179: 1084–1093.

Omura

McGuire

Patel

, et al. Modifiable risk factors for Alzheimer disease and related dementias among adults aged ≥45 years - United States, 2019. MMWR Morb Mortal Wkly Rep 2022; 71: 680–685.

Aiello Bowles

Crane

Walker

, et al. Cognitive resilience to Alzheimer’s disease pathology in the human brain. J Alzheimers Dis 2019; 68: 1071–1083.

Gatz

Reynolds

Fratiglioni

, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006; 63: 168–174.

Dourlen

Kilinc

Malmanche

, et al.

The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis?

Acta Neuropathol 2019; 138: 221–236.

Paulsen

Schubert

Pinto

, et al. Associations of sensory and motor function with blood-based biomarkers of neurodegeneration and Alzheimer’s disease in midlife. Neurobiol Aging 2022; 120: 177–188.

Livingston

Sommerlad

Orgeta

, et al. Dementia prevention, intervention, and care. Lancet 2017; 390: 2673–2734.

10.

Hwang

Longstreth

Jr Thielke

, et al. Longitudinal changes in hearing and visual impairments and risk of dementia in older adults in the United States. JAMA Netw Open 2022; 5: e2210734.

11.

Ehrlich

Goldstein

Swenor

, et al. Addition of vision impairment to a life-course model of potentially modifiable dementia risk factors in the US. JAMA Neurol 2022; 79: 623–626.

12.

Lee

Larson

Gibbons

, et al. Associations between recent and established ophthalmic conditions and risk of Alzheimer’s disease. Alzheimers Dement 2019; 15: 34–41.

13.

Shang

Zhu

Wang

, et al. The association between vision impairment and incidence of dementia and cognitive impairment: a systematic review and meta-analysis. Ophthalmology 2021; 128: 1135–1149.

14.

Sharif

. Degeneration of retina-brain components and connections in glaucoma: disease causation and treatment options for eyesight preservation. Curr Res Neurobiol 2022; 3: 100037.

15.

Ward

Petersen

. Glaucoma and dementia: more than meets the eye? Ann Neurol 2013; 74: 155–157.

16.

Mancino

Martucci

Cesareo

, et al. Glaucoma and Alzheimer disease: one age-related neurodegenerative disease of the brain. Curr Neuropharmacol 2018; 16: 971–977.

17.

Liu

Tian

. Hypothesis of optineurin as a new common risk factor in normal-tension glaucoma and Alzheimer’s disease. Med Hypotheses 2011; 77: 591–592.

18.

Choi

. An altered neurovascular system in aging-related eye diseases. Int J Mol Sci 2022; 23: 14104.

19.

Jain

Aref

. Senile dementia and glaucoma: evidence for a common link. J Ophthalmic Vis Res 2015; 10: 178–183.

20.

Tang

Blazes

Lee

. Imaging amyloid and tau in the retina: current research and future directions. J Neuroophthalmol 2023; 43: 168–179.

21.

Lee

Jiang

McIlmoyle

, et al. Amyloid beta immunoreactivity in the retinal ganglion cell layer of the Alzheimer’s eye. Front Neurosci 2020; 14: 758.

22.

den Haan

Morrema

THJ

Verbraak

, et al. Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s disease retinas. Acta Neuropathol Commun 2018; 6: 147.

23.

Nizari

Guo

Davis

, et al. Non-amyloidogenic effects of α2 adrenergic agonists: implications for brimonidine-mediated neuroprotection. Cell Death Dis 2016; 7: e2514.

24.

Inoue

. Managing adverse effects of glaucoma medications. Clin Ophthalmol 2014; 8: 903–913.

25.

Tham

Wong

, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 2014; 121: 2081–2090.

26.

Larson

Wang

Bowen

, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 2006; 144: 73–81.

27.

Kukull

Higdon

Bowen

, et al. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 2002; 59: 1737–1746.

28.

Wang

van Belle

Kukull

, et al. Predictors of functional change: a longitudinal study of nondemented people aged 65 and older. J Am Geriatr Soc 2002; 50: 1525–1534.

29.

Lee

Gibbons

, et al. Associations between retinal artery/vein occlusions and risk of vascular dementia. J Alzheimers Dis 2021; 81: 245–253.

30.

Crane

Gibbons

McCurry

, et al. Importance of home study visit capacity in dementia studies. Alzheimers Dement 2016; 12: 419–426.

31.

Teng

Hasegawa

Homma

, et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994; 6: 45–58; discussion 62.

32.

Crane

Trittschuh

Mukherjee

, et al. Incidence of cognitively defined late-onset Alzheimer’s dementia subgroups from a prospective cohort study. Alzheimers Dement 2017; 13: 1307–1316.

33.

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. (DSM-IV). Washington, DC: American Psychiatric Publishing, Inc., 1994.

34.

McKhann

Knopman

Chertkow

, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7: 263–269.

35.

Vermunt

Sikkes

SAM

van den Hout

, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer’s disease in relation to age, sex, and APOE genotype. Alzheimers Dement 2019; 15: 888–898.

36.

Belloy

Napolioni

Greicius

. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 2019; 101: 820–838.

37.

Livingston

Huntley

Liu

, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet 2024; 404: 572–628.

38.

Zhong

Wang

Zhang

, et al. Smoking is associated with an increased risk of dementia: a meta-analysis of prospective cohort studies with investigation of potential effect modifiers. PLoS One 2015; 10: e0118333.

39.

Tai

Veldsman

Lyall

, et al. Cardiometabolic multimorbidity, genetic risk, and dementia: a prospective cohort study. Lancet Healthy Longev 2022; 3: e428–e436.

40.

Kuźma

Lourida

Moore

, et al. Stroke and dementia risk: a systematic review and meta-analysis. Alzheimers Dement 2018; 14: 1416–1426.

41.

Dove

Shang

, et al. The impact of diabetes on cognitive impairment and its progression to dementia. Alzheimers Dement 2021; 17: 1769–1778.

42.

Sierra

. Hypertension and the risk of dementia. Front Cardiovasc Med 2020; 7: 5.

43.

Mathur

Ding

Riddell

, et al. Web site and R package for computing E-values. Epidemiology 2018; 29: e45–e47.

44.

VanderWeele

Ding

. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med 2017; 167: 268–274.

45.

Lin

Kao

, et al. Association between glaucoma and the risk of dementia. Medicine 2016; 95: e2833.

46.

Chen

Lai

Yen

, et al. Association between normal tension glaucoma and the risk of Alzheimer’s disease: a nationwide population-based cohort study in Taiwan. BMJ Open 2018; 8: e022987.

47.

Keenan

TDL

Goldacre

. Associations between primary open angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage study. Br J Ophthalmol 2015; 99: 524–527.

48.

Dong

Guo

Agey

, et al. Alpha2 adrenergic modulation of NMDA receptor function as a major mechanism of RGC protection in experimental glaucoma and retinal excitotoxicity. Invest Ophthalmol Vis Sci 2008; 49: 4515–4522.

49.

Newcomer

Farber

Olney

. NMDA Receptor function, memory, and brain aging. Dialogues Clin Neurosci 2000; 2: 219–232.

50.

Liu

Chang

Song

, et al. The role of NMDA receptors in Alzheimer’s disease. Front Neurosci 2019; 13: 43.

51.

Karczewski

Hempel

Kunze

, et al. Agonistic autoantibodies to the α(1)-adrenergic receptor and the β(2) -adrenergic receptor in Alzheimer’s and vascular dementia. Scand J Immunol 2012; 75: 524–530.

52.

Karczewski

Hempel

Bimmler

. Role of alpha1-adrenergic receptor antibodies in Alzheimer’s disease. Front Biosci 2018; 23: 2082–2089.

53.

Slater

Wang

. Alzheimer’s disease: an evolving understanding of noradrenergic involvement and the promising future of electroceutical therapies. Clin Transl Med 2021; 11: e397.

54.

Michelessi

Lindsley

, et al. Combination medical treatment for primary open angle glaucoma and ocular hypertension: a network meta-analysis. Cochrane Database Syst Rev 2014; 2014: CD011366.

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