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Implicated in ARIA: Perivascular Macrophages and Microglia

Series - Alzheimer's Association International Conference (AAIC) 2024:

As more people are treated with lecanemab and donanemab in clinical care, the risk of serious reactions due to ARIA grows. At AAIC, held July 28 to August 1 in Philadelphia, clinicians discussed how to avoid those by screening patients better. The first report of deaths due to lecanemab use in primary care, in two APOE4 carriers who developed inflammatory ARIA-E and seizures, only made this more urgent (see previous story). 

  • Inflammatory mechanisms drive ARIA.
  • Perivascular macrophages and microglia both contribute to vascular damage.
  • Should steroids be brought to bear sooner?

Risk assessment is complicated, and not the same for all groups. Participants in the Dominantly Inherited Alzheimer Network carry AD mutations that spur massive plaque deposition and lead to memory problems in mid-life. Randall Bateman of Washington University in St. Louis, who leads the DIAN Trials Unit, said clinicians were able to relax the entry criteria for middle-aged participants in the DIAN secondary prevention trial, relative to the more stringent standards used in late-onset AD trials. Alireza Atri of the Banner Sun Health Research Institute in Sun City, Arizona, said the decade-long DIAN trial taught scientists a great deal about ARIA, including that it can occur late in treatment and recur multiple times in the same patient.

Others in Philadelphia focused on the mechanisms underlying ARIA. Inflammation is emerging as a key culprit, with microglia and perivascular macrophages both playing a role. The latter pump out free radicals and inflammatory cytokines that damage blood vessels, leading to the leakiness that causes edema and brain bleeds. While scientists are trying to develop ways to target these cells, so far steroids remain the only treatment for severe ARIA. Some clinicians argued for using these drugs even in mild cases to prevent worse outcomes.

Younger Patient, Sturdier Brain?
Unlike older AD patients, many of whom have cerebrovascular pathology and other co-morbidities, DIAN participants tend to have overall healthy brains and blood vessels. Perhaps for this reason, they tolerate amyloid immunotherapy particularly well.

Scientists know that in LOAD trials, the biggest risk for ARIA came from APOE4, more than one microhemorrhage, or superficial siderosis on baseline MRI (Nov 2023 conference news). These trials excluded people with more than four microhemorrhages. Appropriate Use Recommendations for lecanemab stress this restriction (Apr 2023 conference news). Microhemorrhages can be a sign of cerebral amyloid angiopathy, which is closely linked with ARIA.

For the DIAN trial, clinicians did enroll people who had more than four microhemorrhages. These families, who have watched many of their relatives die of dementia in middle age, are willing to accept more risk to find a treatment. They supported tripling the dose of gantenerumab from that in LOAD trials to try to curb their rapid plaque growth, even though higher doses hike the risk of ARIA (see related AAIC news).

Despite this, DIAN participants had about the same ARIA incidence as seen in LOAD trials. In Philadelphia, Jorge Llibre Guerra of WashU said 22 of the 73 participants, or about one-third, developed ARIA-E. This was mostly occipital and cleared up after two months on average. Eight people had recurrent ARIA episodes. These were typically asymptomatic, with six of 32 total episodes causing noticeable symptoms. ARIA-H was seen in 37 percent of people, more commonly as disease progressed. No one in the trial had a macrohemorrhage, and no one died due to ARIA. Importantly, neither type of ARIA was associated with greater cognitive decline. Nick Fox of University College London called these clinical data reassuring.

Atri offered some detail by showing case studies. One participant had six recurrent episodes of ARIA-E over six years. The first one was mildly symptomatic, with dizziness and balance problems, the others were asymptomatic. Three of the episodes were moderately severe on MRI, involving multiple foci. Each time, dosing was suspended until the edema went away. The participant stayed in the study and is still cognitively well, with a CDR of 0 and MMSE of 30, six years past his or her estimated year of symptom onset.

In another case, a participant developed a single episode of mild, asymptomatic ARIA after a year and a half on drug. This shows that ARIA can pop up late in treatment, Atri said, cautioning clinicians to be on the watch for this. Indeed, about 10 percent of the ARIA in this study occurred after one year, he added.

Atri believes ARIA should be treated with steroids more often than is current practice. He described another case where the participant had severe ARIA on MRI, with seven foci, and complained of headaches and brain fog. Clinicians treated the patient with IV steroids but tapered off quickly, causing the edema to come back. They moved to high-dose oral steroids with a long taper to completely clear up ARIA, and the participant remains cognitively healthy. Atri believes the aggressive treatment potentially headed off worse problems. “We should have a lower threshold for giving steroids,” he said.

Are Bam Bad? In one model of ARIA, Aβ released from plaques acts on perivascular macrophages (lilac), a type of border-associated macrophage. BAMs then release free radicals and inflammatory cytokines that damage blood vessels, causing leakage. [Courtesy of Costantino Iadecola.]

Homing in on Inflammatory Pathways
Other speakers in Philadelphia focused on why steroids may help, presenting new evidence of inflammatory involvement. Steven Greenberg of Massachusetts General Hospital, Boston, summarized the two main hypotheses for what causes ARIA. Initially, scientists thought that Aβ, mobilized from plaques, floods the perivascular space, clogging it and worsening CAA. This is plausible, but still lacks a clear mechanism for how this leads to ARIA, Greenberg said. ARIA representing an inflammatory response to CAA is a newer idea that has caught on in the field (Aug 2023 conference news). One sign of this: Pathology from fatal ARIA cases resembles that from CAA-related inflammation (CAA-ri) (Jan 2024 news).

Fabrizio Piazza of the University of Milano-Bicocca, Italy, is a proponent of this latter hypothesis. He previously reported that in patients with CAA-ri and parenchymal amyloid plaques, microglia activate in regions with ARIA-E. Curiously, microglia did not activate in areas of edema in people with CAA-ri alone (Piazza et al., 2022). What explains this?

In Philadelphia, Piazza noted that people with CAA-ri make auto-antibodies to Aβ, and the concentration of these antibodies correlates with ARIA-E. He believes that, just as in amyloid immunotherapy, these auto-antibodies mobilize Aβ from plaques to blood vessels, thickening the CAA. At the same time, Aβ-antibody complexes trigger microglia, prompting inflammation and ARIA-E. Steroid treatment calms microglia, and this correlates with lessened ARIA-E. He believes this is similar to what happens with antibody therapy.

If microglia activation helps drive ARIA, then this may explain why antibodies against the microglial receptor TREM2 were associated with ARIA in a recent trial, Piazza speculated (Aug 2023 conference news).

Because the leaky vessels of ARIA-E can cause brain bleeds, aka ARIA-H, early steroid treatment may head off this vascular damage, Piazza said. Like Atri, he believes steroids should be given even for mild ARIA cases.

Costantino Iadecola of Weill Cornell Medical College, New York, points the finger at a different brain immune cell, the perivascular macrophages that nestle up to small blood vessels. Iadecola previously reported that APOE4 from perivascular macrophages slows cerebral blood flow (Apr 2023 conference news). In parallel, Aβ acts directly on these cells via their CD36 receptor, instigating them to spew free radicals and inflammatory cytokines that damage blood vessels and make them leaky (May 2017 news).

CAA Away. In Tg2576 mice (left), blood vessels (pink) are coated with amyloid (blue), but when the CD36 receptor is deleted from perivascular macrophages (right), this vascular amyloid goes away. [Courtesy of Uekawa et al., 2023, Molecular Neurodegeneration.]

In Philadelphia, Iadecola added functional data, reporting that knocking out CD36 only in perivascular macrophages of 15-month-old Tg2576 mice rescued cerebral blood flow. The vessels looked healthier, CAA cleared up, and the mice’s memories returned to normal, even though parenchymal plaques did not budge (Uekawa et al., 2023). “Perivascular macrophages are a hub for free radical production and neuroinflammation, and may be a therapeutic target in CAA and ARIA,” Iadecola said. Others have come to similar conclusions. Scientists at Eli Lilly reported that antibody treatment in amyloidosis mice activated perivascular macrophages to express matrix remodeling genes such as matrix metalloprotease 9, resulting in leakier vessels (Taylor et al., 2023). 

Do microglial and perivascular macrophage dysfunction go hand in hand? Addressing this question, Donna Wilcock of Indiana University in Indianapolis reported at AAIC that within 24 hours after injecting an anti-amyloid antibody into Tg2576 mice, microglia released TGFβ, which signaled to other immune cells such as perivascular macrophages. Next, Wilcock will examine the effects of chronic immunotherapy on this cell-to-cell communication, and what its consequences are for blood vessels.

This mechanistic research may eventually yield better biomarkers of CAA and ARIA, and potentially treatments to prevent or resolve the latter. Other approaches are trying to circumvent ARIA entirely. Roche’s new antibody trontinemab, which conjugates the business end of gantenerumab to a brain shuttle, allows the antibody to enter the brain through capillaries, bypassing most vascular amyloid. In Phase 1/2, the highest dose tested, 3.6 mg/kg, cleared amyloid completely in three months, with no ARIA in the eight patients who have reached this timepoint so far (Mar 2024 conference news). In Philadelphia, Geoffrey Kerchner of Roche presented these data again, sparking excitement among attendees.

Kerchner promised new data at the upcoming Clinical Trials on Alzheimer’s Disease conference, to be held October 29 to November 1 in Madrid.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Gantenerumab
  4. Trontinemab

News Citations

  1. Two New Deaths on Leqembi Highlight Need to Better Manage ARIA
  2. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
  3. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
  4. Living Among Us: People Whose Alzheimer’s Is Already Being Prevented
  5. Is ARIA an Inflammatory Reaction to Vascular Amyloid?
  6. Brain of Woman Who Died on Leqembi Shows Worst-Case Scenario
  7. Macrophages Blamed for Vascular Trouble in ApoE4 Carriers
  8. Do Perivascular Macrophages Mediate Aβ Pathology?
  9. Fast Plaque Clearance with Little ARIA? So Teases Trontinemab at AD/PD 2024

Research Models Citations

  1. Tg2576

Paper Citations

  1. Piazza F, Caminiti SP, Zedde M, Presotto L, DiFrancesco JC, Pascarella R, Giossi A, Sessa M, Poli L, Basso G, Perani D. Association of Microglial Activation With Spontaneous ARIA-E and CSF Levels of Anti-Aβ Autoantibodies. Neurology. 2022 Sep 20;99(12):e1265-e1277. Epub 2022 Aug 8 PubMed.
  2. Uekawa K, Hattori Y, Ahn SJ, Seo J, Casey N, Anfray A, Zhou P, Luo W, Anrather J, Park L, Iadecola C. Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress. Mol Neurodegener. 2023 Oct 3;18(1):73. PubMed. Correction.
  3. Taylor X, Clark IM, Fitzgerald GJ, Oluoch H, Hole JT, DeMattos RB, Wang Y, Pan F. Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice. Mol Neurodegener. 2023 Aug 30;18(1):59. PubMed.

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