A new study led by researchers at National Taiwan University (NTU) reveals that subtle differences in retinal thickness between the eyes—known as inter-eye retinal asymmetry—may serve as an early and accessible biomarker for cognitive frailty, a high-risk condition combining mild cognitive impairment with physical frailty.
The study reveals that uneven buildup of amyloid beta between the eyes may cause thinning differences in the retina, appearing early in cognitive decline. This eye-based asymmetry could offer a simple, noninvasive way to detect cognitive frailty at its earliest stages.
Often called "the window to the brain," the retina offers a unique opportunity to study brain health through the eye. This research, published in Alzheimer's & Dementia, has attracted global attention, including at the 19th International Congress of the Asian Society Against Dementia held in Seoul (May 2025).
Cognitive frailty is a potentially reversible condition associated with elevated risks of dementia, disability, and mortality. While earlier studies have primarily examined how the average thickness of retinal markers relates to overall cognitive function—typically using cross-sectional designs—none have investigated the role of retinal asymmetry with cognitive impairment or cognitive frailty. Furthermore, longitudinal studies exploring related topics are still limited.
The NTU-led study addresses this gap, showing that greater ganglion cell–inner plexiform layer (GC-IPL) asymmetry between the eyes at baseline is significantly associated with worsening memory-related cognitive frailty over four years—but not with physical frailty alone.
These findings suggest that GC-IPL asymmetry may be a sensitive, structural biomarker for early-stage cognitive decline as well as cognitive frailty.
The study was led by Professor Yen-Ching Karen Chen from the Institute of Epidemiology and Preventive Medicine, NTU College of Public Health, and Dr. Jen-Hau Chen, Director of the Department of Geriatrics and Gerontology at NTU Hospital Yunlin Branch, under the framework of the Taiwan Initiative for Geriatric Epidemiological Research (TIGER).
Launched in 2011, the TIGER study is a nationally supported longitudinal cohort that follows older adults every two to three years to identify early risk factors for dementia and frailty. For this study, 222 community-dwelling older adults (average age: 75) were assessed from 2015 to 2022, with cognitive and frailty evaluations conducted biennially. Among them, 158 participants completed the four-year follow-up.
To measure retinal asymmetry, the team used optical coherence tomography (OCT)—a noninvasive imaging tool—to assess the retinal nerve fiber layer (RNFL) and GC-IPL thickness.
"Compared with expensive brain imaging or invasive blood tests, OCT offers a quick, widely available, and painless alternative, making it well-suited for early screening among older adults," said Prof. Yen-Ching Karen Chen, an epidemiologist specializing in preventive medicine and population-based dementia prevention strategies.
"To truly protect cognitive health in aging, we need screening tools that are both accurate and practical in real-world clinical settings," added Dr. Jen-Hau Chen, a geriatrician dedicated to advancing early detection and care strategies for older adults.
The research team also included Dr. Yi-Ting Hsieh (NTU Hospital), Director Yung-Sung Lee (Linkou Chang Gung Memorial Hospital), and Director Jeng-Min Chiou (NTU Institute of Statistics and Data Science).
Earlier research by Professor Chen's team in 2019 identified a U-shaped relationship between GC-IPL thickness and cognitive decline, with both thinning and thickening linked to elevated risk. The current study builds on this by showing that asymmetric amyloid beta accumulation between eyes may drive GC-IPL thickness asymmetry, which emerges in the early stages of cognitive impairment.
Moreover, GC-IPL asymmetry may be detectable earlier than RNFL asymmetry. Age-related thinning and structural differences in the optic nerve head make RNFL asymmetry harder to observe in older adults, especially compared to macular GC-IPL measurements. These anatomical insights support the potential of GC-IPL asymmetry as a more precise early indicator of brain–eye changes related to dementia.
"Additionally, Asian populations have a high prevalence of high myopia. Using GC-IPL thickness as an indicator is more suitable for Asians because RNFL thickness often shows image artifacts and measurement errors in myopic eyes," added Director Yung-Sung Lee, an ophthalmologist with expertise in ocular imaging analysis.
The Taiwan Initiative for Geriatric Epidemiological Research (TIGER) is a pioneering, longitudinal aging study that integrates epidemiology, geriatric medicine, and biomedical imaging to identify early markers of aging-related diseases.
Led by NTU's multidisciplinary team, TIGER aims to advance preventive strategies and promote healthy aging for older adults in Taiwan and beyond.
More information: Yung‐Sung Lee et al, Interocular retinal asymmetry and cognitive frailty: A prospective cohort study, Alzheimer's & Dementia (2024). DOI: 10.1002/alz.14437
Journal information: Alzheimer's & Dementia
Provided by National Taiwan University