Dataset Information

Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife.

ABSTRACT:

Background

Identification of at-risk individuals who would benefit from early intervention for Alzheimer's disease and related dementias (ADRD) is critical as new treatments are developed. Measures of retinal health could offer accessible and low-cost indication of pre-morbid disease risk, but their association with ADRD risk is unknown.

Objective

To determine whether midlife retinal neuronal and microvascular measures are associated with ADRD risk-index scores and individual domains of ADRD risk.

Methods

Data were from the Dunedin Multidisciplinary Health and Development Study, a population-representative longitudinal New Zealand-based birth cohort study. 94.1% (N = 938) of living Study members were seen at age 45 (2017-2019). Retinal neuronal (retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL)) and microvascular (arterioles and venules) measures were used as predictors. Outcome measures were four top ADRD risk indexes (CAIDE, LIBRA, Lancet, and ADU-ADRI), and a comprehensive midlife ADRD risk index, the DunedinARB.

Results

Poorer retinal microvascular health (narrower arterioles and wider venules) was associated with greater ADRD risk (βs = 0.16-0.31; ps < 0.001). Thinner RNFL was modestly associated with higher ADRD risk (βs = 0.05-0.08; ps = 0.02-0.13). Follow-up tests of distinct domains of ADRD risk indicated that while RNFL associations reflected cardiometabolic risk only, microvascular measures were associated with diverse ADRD risk factors.

Conclusions

Measures of retinal health, particularly microvascular measures, successfully capture ADRD risk across several domains of known risk factors, even at the young midlife age of 45 years. Retinal microvascular imaging may be an accessible, scalable, and relatively low-cost method of assessing ADRD risk among middle-aged adults.

SUBMITTER: Barrett-Young A

PROVIDER: S-EPMC12371708 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature

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Publications

Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife.

Barrett-Young Ashleigh A Reuben Aaron A Caspi Avshalom A Cheyne Kirsten K Ireland David D Kokaua Jesse J Ramrakha Sandhya S Tham Yih-Chung YC Theodore Reremoana R Wilson Graham G Wong Tien Yin TY Moffitt Terrie T

Journal of Alzheimer's disease : JAD 20250303 1_suppl

BackgroundIdentification of at-risk individuals who would benefit from early intervention for Alzheimer's disease and related dementias (ADRD) is critical as new treatments are developed. Measures of retinal health could offer accessible and low-cost indication of pre-morbid disease risk, but their association with ADRD risk is unknown.ObjectiveTo determine whether midlife retinal neuronal and microvascular measures are associated with ADRD risk-index scores and individual domains of ADRD risk.M ...[more]

PMID: 40033783

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Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

Dataset Information

Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife.

Background

Objective

Methods

Results

Conclusions

Publications

Measures of retinal health successfully capture risk for Alzheimer's disease and related dementias at midlife.

Similar Datasets

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