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Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D'Orazio LM, Buennagel DP, Harrington MG, Benzinger TL, Fagan AM, Ringman JM, Schneider LS, Morris JC, Reiman EM, Caselli RJ, Chui HC, Tcw J, Chen Y, Pa J, Conti PS, Law M, Toga AW, Zlokovic BV. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020 May;581(7806):71-76. Epub 2020 Apr 29 PubMed.
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University of Southampton School of Medicine
University of Southampton School of Medicine
In this paper, the authors used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 245 humans to demonstrate that there was breakdown of the blood-brain barrier (B4) in the hippocampi and parahippocampal gyri in cognitively normal APOE4 individuals and the degree of B4 increased with the decline in cognition. The breakdown was not observed in other areas of the brain. These findings could be relevant to the pathogenesis of Amyloid-Related-Imaging Abnormalities-E (ARIA-E), where there is evidence of sulcal hyperintensities that were presumed to be vasogenic edema, especially in APOE4 individuals. The present study suggests that the areas susceptible for B4 are different from those observed in ARIA and consistent with a hypothesis that impaired intramural periarterial drainage (IPAD) is a key pathogenic factor (Weller et al., 2005; Sperling et al., 2012).
Another major strength of the paper is the observation that PDGFRβ is a reliable predictor of cognitive impairment in APOE4 carriers, suggesting a key role for pericytes in cognition. Previous studies from the Zlokovic lab using APOE3/4 knock-in mice showed that APOE4 activates CypA via low-density lipoprotein receptor-related protein-1, followed by activation of MMP9 (Halliday et al., 2015) in pericytes. Inhibiting CypA may be an exciting therapeutic option to improve the function of pericytes in the aging brain, which may improve cerebral blood flow as well as facilitate IPAD and reduce expression of MMP9 (Roth et al., 2019; Carare et al., 2020).
References:
Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 2015 Jan;25(1):63-78. PubMed.
Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, Fox NC, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Lieberburg I, Arrighi HM, Morris KA, Lu Y, Liu E, Gregg KM, Brashear HR, Kinney GG, Black R, Grundman M. Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol. 2012 Mar;11(3):241-9. PubMed.
Halliday MR, Rege SV, Ma Q, Zhao Z, Miller CA, Winkler EA, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab. 2015 Mar 11; PubMed.
Roth M, Gaceb A, Enström A, Padel T, Genové G, Özen I, Paul G. Regulator of G-protein signaling 5 regulates the shift from perivascular to parenchymal pericytes in the chronic phase after stroke. FASEB J. 2019 Aug;33(8):8990-8998. Epub 2019 May 2 PubMed.
Carare RO, Aldea R, Bulters D, Alzetani A, Birch AA, Richardson G, Weller RO. Vasomotion Drives Periarterial Drainage of Aβ from the Brain. Neuron. 2020 Feb 5;105(3):400-401. PubMed.
View all comments by Roy WellerGeorgetown University
This work greatly builds the literature of amyloid-independent effects of APOE4 in AD pathogenesis. Using diverse imaging and CSF analyses, Montagne et al. show that blood-brain barrier (BBB) leakage in humans is more pronounced in APOE4 individuals with and without AD, and does not correlate with in vivo markers of Aβ or tau. Indeed, over all individuals, BBB breakdown was not linked to the accumulation of amyloid (although their measures would not preclude some amyloid angiopathy).
These data suggest that BBB breakdown may be linked to other AD risk processes, such as inflammation. Indeed, CSF signs of neuroinflammation (CypA, sPDGFRβ, and MMP9) were elevated in the CSF of APOE4 individuals at the early stages of AD. BBB breakdown in APOE3 individuals with AD did not correlate with elevation of these biomarkers, suggesting that neuroinflammation is more pronounced in APOE4 individuals. These exciting in vivo findings provide important support for the hypothesis that APOE4 increases risk of AD at least partially by increasing neuroinflammation.
View all comments by G. William RebeckUniversity of Edinburgh
This is a very important paper because it provides yet more evidence for the crucial role that vascular dysfunction seems to play in Alzheimer’s disease, and also provides a plausible mechanism by which the vascular dysfunction damages the hippocampus. These findings help explain why Alzheimer’s disease shares so many risk factors with stroke and they should encourage researchers to pay more attention to the vasculature in their experiments, and encourage clinicians to identify and manage vascular risk factors such as hypertension and diabetes when treating patients with or at risk of Alzheimer’s disease and encourage them to reduce dietary salt intake and stop smoking.
View all comments by Joanna WardlawUniversity of British Columbia
University of British Columbia
University of British Columbia
University of British Columbia
Here, Montagne et al. present an elegant study that brings together elements from much of their previous work, ultimately culminating in a strong case for an APOE4-specific effect on blood-brain barrier (BBB) integrity. In this paper, they reported significant BBB breakdown in the hippocampi and parahippocampal gyri in cognitively normal APOE4 carriers compared to APOE3 homozygotes. The BBB breakdown was further increased with cognitive decline and was independent of Aβ and p-tau status. They then went on to investigate pericyte loss as a potential mechanism of this disparity and found that elevated levels of CSF sPDGFRβ predicted cognitive decline in APOE4 carriers only, and that the CypA-MMP9 pathway may be the underlying mechanism.
This work highlights the potential impact of personalized medicine in the treatment of dementia and raises many broad questions for the field of AD research. Given that the APOE4-specific phenotypes presented here occur prior to AD pathology, could it be that we are considering AD as we once considered cancer—with a blanket diagnosis covering multiple distinct etiologies? Where do APOE3 homozygotes who develop AD fit into this proposed paradigm? Are they completely unaffected by this pathway or is there some sort of continuum? For instance, do APOE3 homozygotes with high barrier permeability function similarly to APOE4 carriers and do they also have higher CSF sPDGFRβ levels? The potential for a protective effect of APOE2 on this pathway also remains to be seen, although the rarity of the allele makes it difficult to power human studies to answer APOE2-related questions. Needless to say, there is still much work to do to define the relationship between the APOE gene and AD.
Given the links between vascular risk factors and dementia, APOE4 and cardiovascular disease risk, and the protective effect of peripheral ApoE on coronary heart disease (Qi et al., 2018), we found it surprising that this study found no significant contributions of vascular risk factors to BBB breakdown. The effect of vascular risk factors was evaluated by comparing BBB breakdown in subjects with at least two risk factors to subjects with fewer than two risk factors. Although the authors provided a rationale for this strategy, it may have been more informative to parse apart individual vascular risk factors and include others, such as HDL-C levels, in their analysis.
Other questions raised by this study include how ApoE from different cell types may contribute to this mechanism, as there is evidence for cell-specific effects of APOE4 on other cellular functions (Lin et al., 2018). Further, many questions remain to be answered by longitudinal studies of BBB breakdown in APOE4 carriers. For example, does BBB breakdown predict future Aβ and p-tau positivity? Do all of those with BBB breakdown go on to develop cognitive impairment? And what other factors explain why some APOE4 carriers develop BBB breakdown and cognitive impairment while others do not? Is CypA-MMP9-mediated BBB breakdown reversible and could thus be a targetable pathway for cognitive decline?
Overall, this paper was a very thought-provoking and enticing read. It undoubtedly deepens our understanding of the APOE4 risk allele and opens up many new avenues for investigation.
References:
Qi Y, Liu J, Wang W, Wang M, Zhao F, Sun J, Liu J, Zhao D. Apolipoprotein E-containing high-density lipoprotein (HDL) modifies the impact of cholesterol-overloaded HDL on incident coronary heart disease risk: A community-based cohort study. J Clin Lipidol. 2018 Jan - Feb;12(1):89-98.e2. Epub 2017 Nov 14 PubMed.
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1294. PubMed.
View all comments by Cheryl WellingtonOHSU
University of Washington
VA/U of Washington
In this elegant study, the authors used dynamic-contrast-enhanced magnetic resonance imaging (DCE-MRI) in 245 people to provide evidence that apolipoprotein E4 contributes to BBB breakdown in specific brain regions, specifically the hippocampi and para-hippocampal gyri, in older individuals without cognitive impairments. Furthermore, BBB breakdown is worsened in older individuals with cognitive impairment, independent of pathological hallmarks of AD. In E4 carriers, platelet-derived growth factor receptor beta (PDGFRβ) was a reliable predictive biomarker of cognitive impairment. These results raise the following important questions:
Our studies in ApoE targeted replacement (TR) mice generated by Patrick Sullivan suggest that the impact of E4, compared to E3, on the BBB begins early on in young adulthood (at 2 to 4 months of age) (Rhea et al., 2020; Rhea et al., 2020). At this age, insulin interactions with the BBB are already altered due to ApoE isoform and sex.
In the frontal cortex, E4 females have higher levels of vascular insulin binding than E3 females. In the hypothalami of E3 mice, males have higher levels of vascular insulin binding than females. There are no significant effects in the hippocampus. These findings occurred in the absence of human Aβ or human tau in the model.
The results from the current human study, combined with our mouse studies in young mice, also bring up the question of whether, in E4 individuals, the BBB alterations seen in young adulthood contribute to neurological conditions other than AD later in life. For a review on E4 being a risk factor for other neurological conditions, such as stroke, vascular dementia, multiple sclerosis, and Parkinson’s disease, please see Verghese et al., Lancet Neurology 2011, and Giau et al, Neuropsychiatr Dis 2015, and even in long-term effects following exposure to SARS-CoV-2.
Clearly, increased efforts are warranted to address these timely questions.
References:
Rhea EM, Torres ER, Raber J, Banks WA. Insulin BBB pharmacokinetics in young apoE male and female transgenic mice. PLoS One. 2020;15(1):e0228455. Epub 2020 Jan 31 PubMed.
Rhea EM, Raber J, Banks WA. ApoE and cerebral insulin: Trafficking, receptors, and resistance. Neurobiol Dis. 2020 Apr;137:104755. Epub 2020 Jan 21 PubMed.
Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011 Mar;10(3):241-52. PubMed.
Giau VV, Bagyinszky E, An SS, Kim S. Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat. 2015;11:1723-37. Epub 2015 Jul 16 PubMed.
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