The association between retina thinning and hippocampal atrophy in Alzheimer's disease and mild cognitive impairment: a meta-analysis and systematic review

Introduction: The retina is the "window" of the central nervous system. Previous studies discovered that retinal thickness degenerates through the pathological process of the Alzheimer's disease (AD) continuum. Hippocampal atrophy is one of the typical clinical features and diagnostic criteria of AD. Former studies have described retinal thinning in normal aging subjects and AD patients, yet the association between retinal thickness and hippocampal atrophy in AD is unclear. The optical coherence tomography (OCT) technique has access the non-invasive to retinal images and magnetic resonance imaging can outline the volume of the hippocampus. Thus, we aim to quantify the correlation between these two parameters to identify whether the retina can be a new biomarker for early AD detection.Methods: We systematically searched the PubMed, Embase, and Web of Science databases from inception to May 2023 for studies investigating the correlation between retinal thickness and hippocampal volume. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the study quality. Pooled correlation coefficient r values were combined after Fisher's Z transformation. Moderator effects were detected through subgroup analysis and the meta-regression method.Results: Of the 1,596 citations initially identified, we excluded 1,062 studies after screening the titles and abstract (animal models, n = 99; irrelevant literature, n = 963). Twelve studies met the inclusion criteria, among which three studies were excluded due to unextractable data. Nine studies were eligible for this meta-analysis. A positive moderate correlation between the retinal thickness was discovered in all participants of with AD, mild cognitive impairment (MCI), and normal controls (NC) (r = 0.3469, 95% CI: 0.2490-0.4377, I-2 = 5.0%), which was significantly higher than that of the AD group (r = 0.1209, 95% CI:0.0905-0.1510, I-2 = 0.0%) (p < 0.05). Among different layers, the peripapillary retinal nerve fiber layer (pRNFL) indicated a moderate positive correlation with hippocampal volume (r = 0.1209, 95% CI:0.0905-0.1510, I-2 = 0.0%). The retinal pigmented epithelium (RPE) was also positively correlated [r = 0.1421, 95% CI:(-0.0447-0.3192), I-2 = 84.1%]. The retinal layers and participants were the main overall heterogeneity sources. Correlation in the bilateral hemisphere did not show a significant difference.Conclusion: The correlation between RNFL thickness and hippocampal volume is more predominant in both NC and AD groups than other layers. Whole retinal thickness is positively correlated to hippocampal volume not only in AD continuum, especially in MCI, but also in NC.