In our study, BG-EPVS had a significant negative association with cerebral tau deposition, even after controlling for other small vessel disease markers. Further exploratory analyses showed that the association between increased BG-EPVS and lower tau deposition was prominent in CI, APOE4-positive, or Aβ-positive individuals, but not in CN, APOE4-negative, or Aβ-negative individuals. In contrast to BG-EPVS, CSO-EPVS did not have any relationship with cerebral tau deposition. In addition, neither BG-EPVS nor CSO-EPVS were associated with cerebral Aβ deposition.
The findings of this study on the relationship between increased BG-EPVS and lower cerebral tau deposition is a novel one, in contrast to the finding of no association between BG-EPVS and Aβ level. The contrast between tau and Aβ deposition in relation to BG-EPVS may be explained by the different clearance systems of the brain for the two proteins. Aβ is cleared from the brain via blood brain barrier (BBB) transport, degradation, ISF bulk flow to the perivascular space, and CSF absorption [4]. In particular, BBB transport and the perivascular ISF pathway are responsible for the clearance of Alzheimer’s disease-related Aβ from the brain, covering 80–85% and 15–20%, respectively [4, 35]. In contrast, tau is removed mainly via degradation, the perivascular ISF pathway, and CSF absorption because it cannot be transported across the BBB [4]. The role of the glymphatic system, which includes drainage of ISF to the perivascular space, is increasingly recognized for the clearance of these proteins [4, 36]. When BBB permeability or transport is impaired by the neurodegenerative process of Alzheimer’s disease [37], the compensatory role of the perivascular ISF pathway might increase with the enlargement of perivascular spaces to improve fluid flow. As BBB transport is not related to tau removal, compensatory facilitation of perivascular ISF drainage accompanying EPVS may increase tau clearance, which results in lower tau deposition levels in the brain. In contrast, given that Aβ proteins are cleared via both BBB transport and the perivascular ISF pathway, the compensatory facilitation of the perivascular ISF pathway in response to BBB damage is not likely to significantly change the overall brain Aβ clearance and eventually Aβ deposition in the brain. We observed a significant negative association between EPVS and tau deposition only in BG-EPVS, but not in CSO-EPVS. A recent neuroimaging study provides a possible clue for the explanation of our results [38]. The study showed that compromised BBB integrity, measured using dynamic contrast-enhanced-MRI, was associated with the severity of BG-EPVS but not with that of CSO-EPVS. These findings suggest that BBB dysfunction may be involved in the pathogenesis of BG-EPVS, but not CSO-EPVS.
Only a couple of studies have previously investigated the association between EPVS and cerebral tau pathology. In contrast to our results, Gertje et al [13] reported no significant association between BG-EPVS and CSF tau levels. Besides the discrepancy in the measurement method for tau pathology, that is, measurement of tau level in CSF vs. measurement of tau deposition by PET, the differences in the study participants may explain the discordant results. The previous study by Gertje et al [13] included only CN (67.5%) and MCI (22.5%) individuals, but not patients with dementia, to analyze the relationship between EPVS and CSF tau levels, while we included individuals with a diverse cognitive spectrum (CN [41.7%], MCI [27.6%], and Alzheimer’s disease dementia [30.7%]). Our additional exploratory analysis for the moderation of the cognitive status showed that the relationship between BG-EPVS and lower tau deposition was prominent in the CI but not in the CN. Given this, the null finding from the previous study might be related to the fact that more than two-thirds of the participants were CN individuals, and less than one-third were MCI individuals with no dementia. Similarly, another study on only CN individuals also reported no significant association between BG-EPVS and tau deposition on PET [14]. The association between more BG-EPVS and lower tau pathology specifically observed only in the CI status may be explained by the fact that BBB integrity, related to BG-EPVS [38], is more impaired in Alzheimer’s disease dementia or MCI [37, 39–41], compared to the cognitively intact state.
Similarly, a significant association between BG-EPVS and tau was observed only in the Aβ or APOE4-positive subgroup. Aβ deposition is the upstream pathology of Alzheimer’s disease-specific neurodegeneration and cognitive impairment [42]. APOE4, a major genetic risk of Alzheimer’s disease dementia [43] and Aβ deposition [28, 44], is known to accelerate BBB breakdown and degeneration of pericytes that maintain BBB integrity [45]. Taken together, the significant association between BG-EPVS and tau observed only in Aβ-positive or APOE4-positive cases can possibly be explained by BBB breakdown and related compensatory enlargement of the BG perivascular space as described above.
The CI individuals had more prevalent BG-EPVS than the CN individuals in the present study, in line with previous reports that showed increased overall EPVS [7] or BG-EPVS [8] in Alzheimer’s disease dementia and MCI [7]. Given this, together with the association between more BG-EPVS and lower tau deposition, especially in CI or Aβ-positive individuals, our results suggest that, while overall BG-EPVS burden increases with cognitive decline or progression of Alzheimer’s disease, elevated BG-EPVS themselves may reduce tau pathology by facilitating clearance of tau proteins under CI conditions.
Our finding on the relationship between high BG-EPVS and reduced cerebral tau burden is a novel observation. Nevertheless, some limitations of the current study need to be mentioned. First, as this was a cross-sectional study, it was not possible to infer a causal relationship between EVPS and in vivo AD pathology. Further investigations are needed to clarify the mechanism underlying the association between increased BG-EPVS and low tau deposition. Although a compensatory increase in the perivascular ISF pathway for tau elimination in response to compromised BBB permeability might be a possible explanation for the mechanism, we did not evaluate BBB permeability. Large longitudinal studies including dynamic contrast-enhanced MRI for the measurement of BBB permeability can be helpful in overcoming the limitations of the present study.
In conclusion, our findings suggest that brain tau pathology appears to be reduced with increased BG-EPVS, especially in individuals with cognitive impairment, pathological amyloid burden, or genetic Alzheimer’s disease risk. Further investigations on the mechanism underlying the relationship between high BG-EPVS and lower tau pathology is needed.