The relationship between retinal layers and brain areas in asymptomatic first-degree relatives of sporadic forms of Alzheimer’s disease: an exploratory analysis

Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia [1]. The progressive accumulation of amyloid-beta (Aβ) protein (plaques) outside the neurons [2] and the accumulation of tau protein (tangles) within the neurons [1] are the hallmarks of this disease. Aβ aggregation starts in the anterior cingulate cortex and the precuneus [3, 4], while tau tangles are located in the entorhinal cortex, the hippocampus, and adjacent limbic structures in milder cases [5]. The use of biomarkers such as quantification of Aβ and tau levels in cerebrospinal fluid (CSF) or the increased deposition of tau tangles and accumulation of Aβ plaques revealed by positron emission tomography (PET) are biomarkers that help determine the clinical stage of AD; however, they are limited because they require invasive techniques and expensive diagnostic tools [6].

The retina and the brain are part of the central nervous system, and both have a common embryological origin [7]. Currently, it is known that there is a relationship between age-related retinal neurodegenerative diseases and brain neurodegenerative diseases, including AD [8]. In addition, in the retina, protein deposits have been detected in both AD animal models and in vivo and postmortem eyes from human AD patients [9‐11], with the retina having important diagnostic implications in this disease. Through optical coherence tomography (OCT), a reliable non-invasive diagnostic tool that is commonly used in ophthalmology to visualize and analyze the retinal layers, retinal changes have been observed in different stages of AD. In a previous work using OCT, we have demonstrated that, in preclinical stages, participants with a high genetic risk of developing AD show a significant thinning in several retinal layers in the macular region [12]. In patients with mild AD, thinning also occurs principally in the macular region [13‐15]; when the disease progresses to a moderate stage, these changes are reflected in the peripapillary region [16].

A direct correlation has been observed between the volumes of brain areas measured by magnetic resonance imaging (MRI) and the thickness of specific retina regions using OCT in nondemented older adults [6, 17]. In addition, both family history of the disease (FH+) and ApoE ɛ4 genotype (ApoE ɛ4+) potentiate each other, contributing to the thinning of the cortex in the hippocampal region [18]. The purpose of our study was to analyze the correlations between the macular volumes of all the retinal layers and the thickness of the peripapillary retinal nerve fiber layer (pRNFL) measured by OCT, with the volumes and thickness of different brain areas measured by MRI in participants at high genetic risk of developing AD (FH+ ApoE ɛ4+) compared with a control group (FH− ApoE ɛ4−).

To our knowledge, no previous study has studied the relationships between the retina and different brain structures in cognitively healthy participants but with two main genetic risk factors for developing the disease: (i) having a family history of sporadic senile form of AD and (ii) carrying at least one ɛ4 allele for the allele of the ApoE gene. One of the chief assets of this study was the careful selection of cases. Only family members of people diagnosed with sporadic senile AD were selected, and participants were free of ocular pathology and mental or cognitive disorders that could mask the results. We analyzed both macular and peripapillary areas of the retina in correlation with 20 brain structures, making this one of the studies that analyzed the correlation of the largest number of structures.

The higher number of female participants in the FH+ ApoE ɛ4+ group in comparison with male participants is due to the fact that women are more involved in caring for sick parents [26]. They are also more aware that participating in the studies will further advance the knowledge of Alzheimer’s disease to help both patients and their descendants [27].

Regarding the brain structural cortical thickness and volume, we did not find any correlation with the risk of developing an Alzheimer’s dementia based on familiar history or ApoE ɛ4 phenotype, except for the right cingulate isthmus, which almost reached a statistical difference between both study groups. Although this region is classically involved in AD degeneration, we cannot assess its significance as it is itself affected by all the other regions in our research. In the present study, a trend of a larger volume, without reaching statistical significance, was observed in different brain areas in the FH+ ApoE ɛ4+ group compared with the FH− ApoE ɛ4− group. Classically, it has been reported that subjects carrying at least one E4 allele for ApoE, throughout the temporal continuum of the disease and from several decades before, present a reduction of hippocampal volume [28‐31] or a focal atrophy of this area [32, 33]. Nevertheless, an inflammatory reaction mediated by progranulin has been described in patients in early stages of the disease, who already present positive markers for amyloid, which also contributes to producing neuroinflammatory structural changes in preclinical stages of the disease [34].

From another point of view, our group has demonstrated previously that, when compared with the healthy control group, mild cognitive impairment patients exhibited a marked decrease in functional connectivity over posterior areas accompanied by an increased in anteriorventral regions of the brain, representing the common feature of the network failure starting in the pre-dementia stages of the disease, as a compensatory mechanism [35]. Although this increased connectivity has not been shown to require an increase in volume, it remains plausible that the increase in neuronal plasticity required to produce it would carry a transient physical increase in networks structures.

Both considering the compensatory or inflammatory hypothesis, a final possible explanation for this slight not significant increase in volume in our participants could be due to a statistical artifact being necessary to verify it in more extensive and longitudinal studies.

In our study, the FH+ ApoE ɛ4+ group showed a statistically significant volume decrease in the macular area in different retinal sectors compared with the FH− ApoE ɛ4− group. These results are in agreement with our previous study, in which we observed that there is a thinning of certain retinal sectors in relatives at high genetic risk for the development of AD [12].

It has been observed that family history of AD and the ApoE ɛ4 gene were associated with a thinning in the entorhinal cortex, subiculum, and medial temporal lobe, with these factors being additive to each other [18] and these structures the first to show signs of AD [36]. However, in our work, no statistically significant brain changes were observed between participants with FH+ ApoE ɛ4+ and FH− ApoE ɛ4−. This result is supported by previous studies that showed that retinal changes appear earlier than brain changes [13, 37‐39]. Also, these retinal alterations, which could occur through retrograde transneuronal neurodegeneration [40], may be associated with atrophic brain changes already present before the appearance of clinical cognitive symptoms [17, 41].

The relationship between the brain and retina has been analyzed in other populations without a family history of AD and ApoE ɛ4 gene. There are previous studies that analyzed these correlations in normal older adults with mean ages of 68.0 ± 5.3 years, in which pRNFL thickness in the temporal quadrant was associated with temporal medial lobe volume and hippocampus volume, while the inferior quadrant was significantly associated with occipital lobe volume and selectively associated with the substructure of lingual gyrus volume [6]. In our work, in contrast to Shi et al., we did not find a correlation between the inferior quadrants of the pRNFL and the volume of the occipital lobe.

In a recent work undertaken in an older population (mean age: 65.1 ± 9.0 years), a positive correlation was observed between the pRNFL thickness and right and left hippocampal thickness [42]. Also, Méndez-Gómez et al., in an older population of 80.8 ± 3.9 years, found a direct correlation between pRNFL and the hippocampal fraction [43]. In agreement with these authors, we found a direct correlation in the FH+ ApoE ɛ4+ group between the thickness of the inferotemporal region of the pRNFL with (i) the thickness of right and left posterior cingulate; (ii) the right and left isthmus cingulate, being these, hippocampal areas; and (iii) the volume of right ventral diencephalon. The association between the retina and medial temporal lobe volume may indicate a degeneration in both tissues at the same time, preceding clinical cognitive changes in cognitively healthy participants at risk of AD [17].

In a 12-month longitudinal study, with participants with a mean age of 71.8 ± 3.9 years, an inverse association between the mean reduction in pRNFL thickness and the decrease in central cingulate cortex volume was observed. In addition, the reduction of pRNFL thickness in the inferior quadrants was associated with the decrease of central cingulate cortex volume [44]. We found the same correlation between inferotemporal pRNFL thickness with posterior cingulate thickness in our FH+ ApoE ɛ4+ participants. One possible explanation of the differences between previous studies and our work could be that our participants are young elder people with a mean age of 58.8 ± 6.0 years and we only accepted MMSE values > 26, whereas in Shi and colleagues’ studies, they accepted values for the Chinese version of the Mini-Mental State Examination (CMMSE) of ≥24. This issue is important, because normal cognitive values are above 26, and lower values could mask previous stages of the disease such as subjective memory complaints or mild cognitive impairment. Furthermore, we found no significant differences in pRNFL thickness between our study groups. Altered pRNFL thickness is known to be a good marker of disease progression [16]. On the other hand, changes in this retinal layer are associated with increased susceptibility to accumulation of neurofibrillary tangles and deposition of amyloid plaques in the occipital lobe and inferior temporal lobe, which are a part of the visual association cortex [45, 46].

Ong et al. observed, in a group of 164 patients aged 40–85 years including patients with cognitive impairment without dementia (n = 125), cognitively healthy participants (n = 36), and people with dementia (n = 3), that GCL-IPL thinning is associated with a reduction of gray matter in occipital and temporal lobe volume [47]. In another study performed on 79 neurologically normal adults with a mean age of 76.0 ± 5.5 years, the pRNFL reduction and the decline in total macular volume and GCL volume were significantly associated with a decrease in the medial temporal volumes of the hippocampus, the parahippocampal region, and the entorhinal region [17]. In a study carried out by Mutlu and colleagues, as part of the Rotterdam Study, older patients (67 ± 9.8 years old) with MMSE values of 28 ± 1.7, only the data of GCL, IPL, and pRNFL thickness measurements in relation to brain volume and hippocampal volume were analyzed [48]. In this study, it was found that the thinning of these retinal layers was significantly associated with lower brain volume and lower hippocampal volume, finding that this retinal thinning was associated with the thinning of both gray and white matter in the brain [48]. Chua et al., in a large population-based study (2131 participants) aged between 40 and 69 years old, also found that GCL thinning and total macular thickness were significantly associated with smaller hippocampal volume [49]. These findings are consistent with another study in 20 cognitively healthy, younger patients (50.5 ± 14.1 years old), where it was found that entorhinal gray matter volume was correlated with the GC-IPL complex [50]. In our FH− ApoE ɛ4− group, there was a significantly inverse correlation in the IPL between the volumes of the outer nasal macular sector and the volumes of the left parahippocampal region, the right entorhinal region, the right and left medial temporal lobule, the right and left hippocampus, the right lingual gyrus, the left cuneus, the right ventral diencephalon, and the left amygdala (Table 7). In addition, there was a significant inverse correlation in this retinal layer between the outer inferior macular sector and the right entorhinal, right medial temporal lobe, right ventral diencephalon, right hippocampus, and right and left amygdala (Table 7).

Carriers of the ApoE ɛ4 gene have a thinning of the entorhinal cortex in the left hemisphere compared with the right hemisphere, regardless of age or cognitive status [51]. In our FH− ApoE ɛ4− participants, there was a significant correlation between the left entorhinal thickness with the C0 retinal volume in the INL. Asymmetry of cerebral cortex thickness in the entorhinal region associate to the presence of an ApoE ɛ4 allele [52], may in itself reflect pathology, but could lead to future spatial and temporal distribution patterns of pathological changes [51]. This fact may explain, why in our participants with ApoE ɛ4+, the correlation between the nasal sector of the pRNFL with the right entorhinal volume was stronger than in ApoE ɛ4– participants.

As can be seen in the tables, most of the correlations found between the macular sectors and brain structures in FH− ApoE ɛ4− participants are inverse, while in participants with a high genetic risk for sporadic senile form of AD (FH+ ApoE ɛ4+), they were mostly direct. This could be due to the presence or not of the ApoE ɛ4 gene, as we have already seen in the retina [12], as well as to different behaviors in the central nervous system generated by the presence of this gene [51]. When the ApoE ɛ4 gene is present, changes could occur at the same time in the retina and in different brain areas, either due to the accumulation of Aβ or tau protein, or to structural brain changes that would be concomitant with retinal changes. However, the absence of the ApoE ɛ4 gene could generate different behavior as the correlations are inverse and a change in brain structures would not be accompanied by retinal changes, because they would not be related to it or would not be concomitant in their genesis.

In conclusion, these results demonstrate that there is a correlation between changes in the retina and various brain structures in participants at high genetic risk for developing sporadic senile forms of AD. In these cognitively healthy participants, there is already a significant correlation between pRNFL thickness and the volume of brain areas closely related to AD such as the entorhinal cortex, the lingual gyrus, and the hippocampus. Moreover, with the recent approval by the Food and Drug Administration (FDA) of the first treatment capable of modifying the pathophysiology of AD, the search for cheap, non-invasive, and readily available biomarkers will be mandatory given the need for early diagnosis in participants at high risk of a pathology whose incidence will increase exponentially in the near future worldwide [53]. Therefore, OCT volume measurements and their correlations with brain area volumes could be a biomarker of AD, even in the preclinical stages of AD, and longitudinal studies are needed to really know how many of these participants eventually develop the disease.