Lower thickness of inner retinal layers is associated with an increased risk of incident dementia and Alzheimer’s disease – an individual participant data analysis of four prospective cohort studies (69,955 participants)
Authors: van der Heide Frank , Khawaja Anthony , Berendschot Tos T.J.M. , Littlejohns Thomas J , Kuzma Elzbieta , Foster Paul J , Patel Praveen , Bertelsen Geir , von Hanno Therese , Johnsen Bente , Schirmer Henrik , Rebou Sara Cristina Lima , Grasset Leslie , Delcourt Cécile , Helmer Catherine , Webers Carroll , Kroon Abraham A , van der Kallen Carla J.H. , Eussen Simone J.P.M. , van Dongen Martien , Schalkwijk Casper , Bosma Hans , Köhler Sebastian , Schram Miranda T. , Blokland Gabriella , Linden David , Wesselius Anke , Stehouwer Coen D.A. ,   European Eye Epidemiology consortium, UK Biobank Eye & Vision Consortium
Published: December 2023

Background

Retinal imaging tools may be biomarkers for the early identification of individuals at risk for dementia. Currently, it remains unclear whether retinal neurodegeneration precedes the onset of clinical dementia as few prospective data have been published. The objective To investigate whether retinal neurodegeneration, estimated from lower thickness of inner retinal layers, was associated with incident all‐cause dementia and Alzheimer’s disease.

Method

We performed an individual participant data meta‐analysis using data from four prospective cohort studies with a total of 69,955 participants (n = 1,087 cases of incident all‐cause dementia; n = 520 cases incident Alzheimer’s disease; follow‐up time median [interquartile range; IQR] 11.3 [8.8 ‐ 11.5] years). We investigated the associations of baseline macular retinal nerve fiber layer (mRNFL) thickness and ganglion cell‐inner plexiform layer (mGCIPL) thickness (expressed per standard deviation lower thickness) with incident dementia. We used Cox proportional hazards models adjusted for age, sex, educational level, and other key dementia risk factors. Missing data for covariables were imputed. We tested for interaction with age, sex, apolipoprotein E (APOE) genotype status, and educational level.

Result

After adjustment for age, sex, educational level, and key dementia risk factors, lower baseline mRNFL thickness was significantly associated with higher incidence of all‐cause dementia and Alzheimer’s disease (per SD lower mRNFL thickness, hazard risk [95% confidence interval], 1.10 [1.02; 1.17] and 1.11 [1.001; 1.23], respectively); and lower mGCIPL thickness was not significantly associated with these outcomes (per SD lower mGCIPL thickness, 1.04 [0.99; 1.10] and 1.01 [0.94; 1.09], respectively). Age, sex, apolipoprotein E (APOE) genotype status, and educational level did not (consistently) modify these associations.

Conclusion

This individual participant data meta‐analysis found that lower baseline thickness of inner retinal layers was associated with up to approximately 10% higher risk of incident all‐cause dementia and Alzheimer’s disease. These findings suggest that retinal neurodegeneration precedes the onset of clinical dementia and that retinal imaging tools may be biomarkers for the early identification of individuals at risk for dementia.