Thinning of retinal nerve fiber layer (RNFL) may reflect neurodegeneration of the central nervous system, which has been reported as part of the neuropathogenesis of Alzheimer's disease (AD). Specifically, AD patients have thinner RNFL as compared to age-matched normal controls. However, whether reduction of RNFL over time can predict those at higher risk to develop cognitive deterioration remains unknown. We therefore set out a prospective clinical investigation to determine both the reduction of RNFL thickness and the deterioration of cognitive function over a period of 25 months in 78 participants (mean age 72.31±3.98 years, 52% men). The participants were categorized as stable participants whose cognitive status remained unchanged (n= 60) and converted participants whose cognitive status deteriorated, which was diagnosed by DSM-VI (for AD) and Petersen's definition (for mild cognitive impairment)(n= 18). Here we show for the first time that the converted participants had greater reduction of RNFL thickness than the stable participants. Specifically, the reduction in the thickness of the inferior quadrant RNFL in the converted participants was greater than that in stable participants [− 11.0±12.8 (mean±standard deviation) μm versus 0.4±15.7 μm, p= 0.009]. These data showed that greater reduction in the inferior quadrant of RNFL thickness might indicate a higher risk for the old adults to develop cognitive deterioration. These findings have established a system to embark on a larger scale study to further test whether changes in RNFL thickness can serve as a biomarker of AD.