ApoE4 weakens the blood-brain barrier in the hippocampus, and in this way takes its toll on cognition, according to a study published April 29 in Nature. Researchers led by Berislav Zlokovic of the University of Southern California in Los Angeles reported that ApoE4 carriers sprang more leaks in their hippocampal blood-brain barriers (BBBs) than did noncarriers, and that this permeability was even worse if carriers were cognitively impaired. Surprisingly, the cognitive impairment occurred regardless of Aβ or tau pathology—the hallmarks of Alzheimer’s disease. Markers of BBB damage soared in the cerebrospinal fluid of E4 carriers and predicted subsequent slippage on cognitive tests. In all, the findings suggest that apart from stoking Alzheimer’s protein pathology, ApoE4 also harms the brain by eroding its border.
- Blood-brain barrier appears disrupted in hippocampi of ApoE4 carriers.
- Barrier breakdown correlates with cognitive decline independently of Aβ or tau pathology.
- Pericyte protein in CSF potential marker of BBB damage.
“These observations cast new light on APOE4 that runs contrary to the widely held idea that this gene variant contributes to Alzheimer’s disease solely by promoting Aβ and tau accumulation,” wrote Makoto Ishii and Costantino Iadecola of Weill Cornell Medical College in New York in an editorial. “Instead, it seems that BBB dysfunction might explain why APOE4 carriers are susceptible to Alzheimer’s disease.” They write that Aβ and tau pathology come later as the disease progresses, exacerbating cognitive decline, and that ApoE contributes to their accumulation also.
Zlokovic’s group had previously reported that the hippocampal BBB grows leakier with age, and might even trigger cognitive decline (Jan 2015 webinar; Jan 2019 news). Other groups have reported that the integrity of this cellular barrier wanes in the early stages of AD, though this claim is not universally accepted (Nov 2015 news; van de Haar et al., 2016; van de Haar et al., 2016). At the same time, the strongest genetic risk factor for AD, ApoE4, has been tied to a damaged cerebrovasculature, including injury to the pericytes that form part of the blood-brain barrier (Halliday et al., 2016; May 2012 news). However, it was unclear if ApoE4’s toxic relationship with the brain vasculature itself causes cognitive decline.
Lead authors Axel Montagne, Daniel Nation, Abhay Sagre, Giuseppe Barisano, and Melanie Sweeney investigated. They used dynamic-contrast-enhanced magnetic resonance imaging (DCE-MRI) to gauge the permeability of the BBB in a cohort of 245 participants averaging 69 years of age, including 101 who carried at least one copy of ApoE4, and 144 noncarriers who had two copies of ApoE3. DCE-MRI uses a contrast agent to measure leakage of a tracer through blood vessels in the brain. Based on their clinical dementia rating scale scores of 0 and 0.5, volunteers were deemed cognitively normal or mildly impaired. Compared with noncarriers, ApoE4 carriers had a disrupted BBB in their hippocampi and parahippocampal gyri (see image below).
BBB Breakdown. Maps of BBB permeability generated by DCE-MRI (left) revealed leakage in the hippocampi of ApoE4 carriers (right), and even more so in those with cognitive impairment. Permeability increases from blue to red. [Courtesy of Montagne et al., Nature, 2020.]
This BBB breakdown was worse in ApoE4 carriers who were cognitively impaired. In noncarriers, cognitive impairment came with a compromised barrier, as well, but the effect was smaller than in carriers.
Did the presence of plaques or tangles influence the relationships among ApoE4, the BBB, and cognition? Not according to CSF or PET imaging. The researchers report that among ApoE4 carriers, BBB disruption came with cognitive impairment regardless of CSF Aβ42 or p-tau. In a subset of 74 and 96 cognitively normal participants who underwent PET scans for brain amyloid or tau, respectively, plaques and tangles accumulated in different regions than those whose BBB looked disrupted. While ApoE4 carriers had more cortical plaques, with the orbital frontal cortex bearing the brunt, the cortex had but sparse signs of a disrupted BBB. Tangles were detected in the inferior temporal gyri of some participants, which is common during normal aging, but levels were not influenced by ApoE genotype.
Together, the findings suggested that while ApoE4 did bring a greater amyloid burden, it did so independently of docking BBB integrity in the medial temporal lobe. Furthermore, this erosion of the barrier associated with poorer cognition, regardless of AD pathology.
Next, Montagne and colleagues checked if CSF markers of BBB damage track with ApoE genotype and cognitive decline by measuring soluble platelet-derived growth factor receptor-β. sPDGFRβ sheds from stressed pericytes and has been tied to BBB damage and cognitive decline (Miners et al., 2019; Nation et al., 2019). The group recently developed an assay to detect the biomarker in CSF (Sweeney et al., 2020), and found that among 350 participants, those with higher baseline CSF sPDGFRβ slipped faster on cognitive tests over two to four years of follow-up—but only if they carried ApoE4. This remained significant regardless of amyloid or tau biomarkers. CSF sPDGFRβ correlated with BBB permeability in the medial temporal lobe detected by DCE-MRI.
Montagne found that ApoE4 carriers who were cognitively impaired also had more cyclophilin A (CypA) and metalloproteinase 9 (MMP9) in their CSF than did normal carriers. Previous studies reported that stressed pericytes pump out CypA, which prompts endothelial cells to crank expression of MMP9, a protease that digests the BBB (Jin et al., 2004; Bell et al., 2012). Cognitively impaired E4 carriers also had elevated CSF concentrations of neuron-specific enolase (NSE), a marker of neuronal stress. The researchers did not measure neurofilament light (NfL), a marker of neurodegeneration that rises early in AD.
Finally, the researchers report that pericytes derived from induced pluripotent stem cells from ApoE4 homozygotes expressed much more CypA and MMP9 than pericytes derived from ApoE3 homozygotes. This suggested that, in agreement with animal data, ApoE4 may ramp up the CypA-MMP9 pathway in human pericytes (Bell et al., 2012).
All told, Zlokovic believes the findings link ApoE4 to BBB breakdown and implicate the pro-inflammatory CypA-MMP9 pathway as part of the mechanism. How ApoE4 trips off this pathway, or why the BBB damage happens only in the medial temporal lobe, is unclear.
Also unexplained is whether the cognitive impairment associated with this barrier breakdown represents AD. Zlokovic said it will be interesting to monitor the ApoE4 carriers who tested negative for AD biomarkers and were cognitively impaired, to see if they develop AD. Overall, Zlokovic argues that vascular dysfunction and Aβ accumulation are two distinct pathways, both of which are exacerbated by ApoE4. While some studies place vascular dysfunction among the earliest pathological changes on the AD trajectory, others have reported that vascular damage puts people at risk for dementia, though not necessarily for Alzheimer’s (Jul 2016 news; Nov 2019 news; Jan 2020 news).
In their editorial, Ishii and Iadecola called it striking that the drivers of cognitive impairment would differ between ApoE4 and ApoE3 carriers. “Montagne and colleagues’ findings indicate that activation of the CypA pathway and pericyte damage might not be involved in cognitive impairment in people who carry the most common APOE variant, APOE3,” they wrote. The possibility remains that a leaky BBB caused by other factors—such as Aβ-inflicted damage to endothelial cells—might contribute to cognitive impairment in ApoE3 carriers, they added.
“This work greatly builds the literature of amyloid-independent effects of APOE4 in AD pathogenesis,” wrote Bill Rebeck of Georgetown University in Washington, D.C. “These exciting in vivo findings provide important support for the hypothesis that APOE4 increases risk of AD at least partially by increasing neuroinflammation,” he wrote, interpreting CypA, sPDGFRβ, and MMP9 as inflammatory markers.
“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,” commented Joanna Wardlaw of the University of Edinburgh.
Roy Weller and Roxana Carare of the University of Southampton in England called out the observation that PDGFRβ predicts cognitive impairment in ApoE4 carriers. Together with the linkage of the CypA-MMP9 pathway to BBB damage, the study implicates pericytes in cognition, they noted. “Inhibiting CypA may be an exciting therapeutic option to improve the function of pericytes in the aging brain,” they wrote.—Jessica Shugart
- Absent Aβ, Blood-Brain Barrier Breakdown Predicts Cognitive Impairment
- Does the Blood-Brain Barrier Stand Up to Alzheimer’s? Study Finds No Breach
- ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage
- LOAD of Data Place Vascular Malfunction as Earliest Event in Alzheimer’s
- Already in Mid-30s, Poor Vascular Health Means Small Brain at 70
- Vascular Dysfunction Taxes Cognition, but Not Via Amyloid, AD
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- Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012 May 24;485(7399):512-6. PubMed.
No Available Further Reading
- 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.
- Ishii M, Iadecola C. Risk factor for Alzheimer's disease breaks the blood-brain barrier. Nature. 2020 May;581(7806):31-32. PubMed.