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Advanced Neurology Insights on ARIA

A diagnosis of ARIA depends on both clinical and 13.4%, and 19.9% for the 0.5 mg/kg, 1.0 mg/kg, and 2.0 mg/
imaging findings. It is generally easy for researchers kg groups, respectively, compared with 0.6% in the placebo
to identify ARIA using the standardized protocols group [32,33] . In the EMERGE study of aducanumab, the
of clinical trials such as those of aducanumab ; the incidence rates of ARIA-E in the low-dose and high-dose
[24]
rigorous monitoring of MRI and new-onset symptoms groups were 25.7% and 34.0%, respectively; very similar
during the titration period largely ensure the early results were reported in the ENGAGE study, with rates of
recognition of ARIA. However, it should be noted that 25.4% and 35.5%, respectively . Researchers have also
[25]
some individuals have spontaneous vasogenic edema at observed a dose-dependent effect of gantenerumab; the
baseline, although the proportion is very low (typically incidence rates of ARIA-E were 0.8%, 6.6%, and 13.65% in
<0.1%) . Furthermore, as age increases, the probability the placebo, 105 mg, and 225 mg groups, respectively .
[27]
[34]
of spontaneous superficial siderosis and microhemorrhage Similar results have been reported for other monoclonal
also increases; specifically, the incidence rate of antibodies, such as lecanemab . In contrast, the
[35]
spontaneous superficial siderosis increases from 0.21% incidence rate of ARIA-H does not significantly increase
at 50 to 69 years old to 1.43% at >69 years old , and the with a higher therapeutic dose. In one study, participants
[28]
rate of spontaneous microhemorrhage increases from without the APOE ε4 allele had an incidence rate of
18% at 60 to 69 years old to 38% at >80 years old . These ARIA-H of 12.3% for the 105 mg gantenerumab group
[29]
spontaneous events need to be differentiated from drug- and 11.0% for the 225 mg gantenerumab group; among
induced events. In addition, radiologists should be trained subjects with one APOE ε4 allele, the rates were 19.8% and
to ensure diagnostic reliability. In a retrospective study, 19.4%, respectively . In aducanumab Phase III studies,
[34]
compared with judgment by professional radiologists, 84% although ARIA-H (superficial siderosis) showed a dose-
of cases were missed at an initial audit by local radiologists, dependent effect in the high- and low-dose groups (13.3%
whereas only 14% were missed after training . vs. 9.2% in EMERGE, 15.4% vs. 8.8% in ENGAGE), there
[30]
3. Risk factors for ARIA was no clear difference in the incidence rate of ARIA-H
(microhemorrhage) between the two groups (18.6% vs.
We should first clarify whether all amyloid-targeting 16.2% in EMERGE, 17.6% vs. 15.5% in ENGAGE) . In
[25]
monoclonal antibodies can lead to ARIA. Integrated addition, mounting evidence has confirmed that carrying
data from aducanumab Phase III studies (EMERGE and the APOE ε4 allele also significantly increases ARIA-E
ENGAGE) suggest that ARIA (both ARIA-E and ARIA-H) incidence. For example, compared with an occurrence
occurred in 35.2% of patients taking high-dose aducanumab rate of 20.3% in APOE ε4 noncarriers, 43% of patients
compared with 2.7% of the placebo group, indicating that with the APOE ε4 allele developed ARIA-E with high-
aducanumab is associated with a substantially increased dose aducanumab treatment . Furthermore, among
[24]
rate of ARIA compared with that observed in natural participants receiving lecanemab, ARIA-E was observed
history studies or trial placebo groups . In addition, an most commonly in participants who were APOE ε4
[24]
important meta-analysis recently suggested that amyloid- carriers, and least often in those who were noncarriers
targeting therapy indeed increases the risk of ARIA by a (14.3% vs. 8.0% in the 10 mg/kg biweekly group; 10.2% vs.
large effect size, with a relative risk of 4.30 (95% confidence 7.1% in the 10 mg/kg monthly group) . Comparatively
[35]
interval: 2.39 – 7.77). Further subgroup analysis revealed few studies have analyzed the correlation between
that all drugs were responsible for this increase except for ARIA-H and APOE ε4 status, but there is evidence that
solanezumab, whose low ARIA risk may be attributed to ARIA-H incidence is also likely to occur in an APOE
its preferential targeting of monomeric Aβ (rather than Aβ ε4 genotype-dependent manner [34-36] . For example,
species deposited in plaques) . APOE ε4 allele frequency, the pre-existence of small
[31]
The present evidence suggests that the clearest and microhemorrhages, treatment with bapineuzumab, and
most important factors for ARIA occurrence are a high the use of antithrombotic agents are all associated with
[36]
therapeutic dose and being a carrier of apolipoprotein an increased risk of ARIA-H . Furthermore, integrated
E (APOE) ε4 allele. In a retrospective analysis of three data from aducanumab studies have suggested that
bapineuzumab Phase II studies, researchers found that ARIA-E and ARIA-H are highly correlated. Specifically,
ARIA-E incidence increased with bapineuzumab dose ARIA-H microhemorrhage and superficial siderosis were
(hazard ratio: 2.24/mg/kg increase in dose) and with both more common in participants with ARIA-E (40.3%
APOE ε4 allele number (hazard ratio: 2.55/allele) using and 38.7%, respectively) than in participants without
Cox proportional hazards models . In bapineuzumab ARIA-E (7.6% and 1.6%, respectively); moreover, among
[26]
Phase III studies, the incidence proportions of treatment- participants with both ARIA-E and ARIA-H, these two
emergent ARIA-E in APOE ε4 non-carriers were 5.6%, events frequently overlapped temporally .
[37]

Volume 1 Issue 1 (2022) 4 https://doi.org/10.36922/an.v1i1.2