Clinical Review & Education

JAMA Neurology | Review

Amyloid-Related Imaging Abnormalities

and β-Amyloid–Targeting Antibodies
A Systematic Review
Massimo Filippi, MD; Giordano Cecchetti, MD; Edoardo Gioele Spinelli, MD; Paolo Vezzulli, MD; Andrea Falini, MD;
Federica Agosta, MD, PhD

Supplemental content
IMPORTANCE After more than a decade of research and development of clinical trials testing
anti–β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained
regarding the effects of these treatments in patients with Alzheimer disease (AD). On the
verge of an expected large-scale introduction in the clinical setting after the recent US Food
and Drug Administration approval of aducanumab, shared knowledge regarding
amyloid-related imaging abnormalities (ARIAs) is of paramount importance.

OBJECTIVE To summarize available evidence on ARIAs from randomized clinical trials (RCTs)
testing anti–β-amyloid mAbs in patients with AD and to provide a comprehensive update
about risk factors, clinical correlates, and implications for withholding and reinitiating
treatment.

EVIDENCE REVIEW In this systematic review, a literature search of MEDLINE/PubMed,

Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through
September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case
reports of ARIAs were included. Strengths of clinical data were graded according to the
Oxford Centre for Evidence-Based Medicine.

FINDINGS Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in
total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were
selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion
leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted
sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including
parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed
ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types;
ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4
carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early
during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases
at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic.
Most ARIA-E cases resolved with treatment withholding, although corticosteroid
administration was required anecdotally. ARIA-E recurrence after dose reinitiation or
adjustment varied from 13.8% to 25.6% across RCTs.

CONCLUSIONS AND RELEVANCE Evidence suggests that ARIAs are frequent, mostly
asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for
standardized clinical and neuroradiological management protocols in real-world clinical
settings.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Massimo
Filippi, MD, Neuroimaging Research
Unit, Division of Neuroscience, IRCCS
San Raffaele Scientific Institute,
JAMA Neurol. doi:10.1001/jamaneurol.2021.5205 Via Olgettina, 60, 20132 Milan, Italy
Published online January 31, 2022. (filippi.massimo@hsr.it).

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 Clinical Review & Education Review
B
y 2050, more than 150 million people will have dementia
worldwide.1 Alzheimer disease (AD) is the most frequent
cause of cognitive decline in elderly people, accounting for
as many as 70% to 75% of all dementia cases.2,3 Considering the high
prevalence of AD and the related high economic burden,4 during the
last decade, efforts have addressed development of monoclonal an-
tibodies (mAbs) that could effectively remove β-amyloid from the
brain and slow down the progression of cognitive impairment.
Since the first AD clinical trials testing anti–β-amyloid agents,5
the observation of magnetic resonance imaging (MRI) abnormali-
ties required a crucial consideration from the scientific community.
In 2011, after an Alzheimer Association Research Roundtable Work-
group, the term amyloid-related imaging abnormalities (ARIAs) was
coined to encompass such a spectrum of MRI findings.6 ARIA is a
general term, which covers 2 classes of MRI signal alterations (Figure 1
and Table 1).7-10 ARIA-E refers to parenchymal edema and sulcal ef-
fusion, which commonly manifest as transient hyperintensities on
fluid-attenuated inversion recovery or T2-weighted MRI se-
quences, with no restricted diffusion abnormalities.6,11 ARIA-H re-
fers to deposits of hemosiderin (ie, a blood degradation product),
including parenchymal microhemorrhages (<10 mm or <5 mm ac-
cording to different studies) 6 and leptomeningeal superficial
siderosis.6,12 ARIA-H manifests as very low-intensity signals, de-
Figure 1. Magnetic Resonance Imaging Features of Amyloid-Related Imaging Abnormalities (ARIAs)
A ARIA-E
A, For ARIAs with signal alterations that included parenchymal edema and sulcal
effusion (ARIA-E), axial fluid-attenuated inversion recovery (FLAIR) images
show ARIA-E features in a woman in her early 70s diagnosed with prodromal
Alzheimer disease and enrolled in a clinical trial testing an anti–β-amyloid agent.
The FLAIR images show parenchymal and sulcal hyperintensities (yellow and
pink arrowheads, respectively) involving subcortical and deep white matter in
occipital and parietal lobes, associated with gyral swelling (blue arrowheads).
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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
Key Points
Question What is the association of amyloid-related imaging
abnormalities (ARIAs) with treatment regimens consisting of
anti–β-amyloid monoclonal antibodies in patients with Alzheimer
disease?
Findings In this systematic review of 34 studies and 15 508
patients, ARIAs were a frequent finding of randomized clinical
trials, prompting centralized and structured magnetic resonance
imaging reporting, and incidence of ARIAs was associated with
apolipoprotein E ε4 genotype and antibody dosage. In most cases,
ARIAs were asymptomatic and resolved with dose adjustment or
withdrawal; in some cases, severe neurological symptoms
occurred, requiring hospitalization and specific treatments (eg,
corticosteroids).
Meaning These findings suggest that there is still a need for
information about whether specific components of ARIAs are
associated with clinical management and treatment response.
tected on gradient echo or susceptibility-weighted imaging MR
sequences.6
ARIA-E and ARIA-H are thought to be expressions of an in-
creased vascular fragility and leakage of proteinaceous fluid and
B ARIA-H
Findings on corresponding diffusion-weighted imaging sequences were normal.
B, For ARIAs with signal alterations that included hemosiderin deposits
(ARIA-H), axial susceptibility-weighted images (SWI) (upper line) and FLAIR
images (lower line) in the same patient. The SWI images show hypointense
dotted areas consistent with microhemorrhages (black arrowheads) and a
hypointense subarachnoid signal (white arrowhead) consistent with superficial
siderosis.
jamaneurology.com
 Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies Review Clinical Review & Education

erythrocytes caused by the therapeutic effect of mAbs. At present,

Table 1. Main Characteristics of Amyloid-Related Imaging Abnormalities
the continued need for understanding the impact of ARIAs on amy-
loid-modifying treatments and standardized protocols of MRI sur- Characteristic ARIA-E ARIA-H

veillance and clinical management is gaining even more attention Primary MRI FLAIR hyperintense GRE and/or T2-weighted
features hypointense
due to the recent approval from the US Food and Drug Administra- DWI negative SWI hypointense
tion of the first mAb (aducanumab) for the treatment of AD.13 This No contrast enhancement
systematic review summarizes published data on ARIAs from ran-
Nature of Proteinaceous fluids Blood degradation
domized clinical trials (RCTs) of mAbs targeting β-amyloid and from leakage products products
studies performing secondary analyses of RCT data. Location of Parenchyma: vasogenic Parenchyma:
increased edema (parenchymal microhemorrhages
vascular hyperintensities and gyral (<10 mm) and macro-
permeability swelling) hemorrhages (≥10 mm)
Leptomeninges: sulcal Leptomeninges: superficial
Methods effusion/exudate (sulcal hemosiderin deposits
hyperintensities) (superficial siderosis)
This systematic review was conducted according to the updated Pre- Frequently unilateral, Frequently developed in
ferred Reporting Items for Systematic Reviews and Meta-analyses involving occipital, the context of an ARIA-E
frontal, and temporal
(PRISMA) guidelines.14 The literature search was conducted using regions
MEDLINE/PubMed, Embase, and the Cochrane Library. We opted Evaluation of Barkhof MRI severity No. of hemosiderin
severity scale7 deposits and superficial
for the following combination of terms: Alzheimer* or mild cognitive siderosis
impairment and ponezumab or PF-04360365 or solanezumab or 3-Point and 5-point Microbleed Anatomical
LY2062430 or bapineuzumab or AAB-003 or AAB-003 or scales8,9 Rating Scale10
PF-05236812 or crenezumab or MABT5102A or RG7412 or Abbreviations: ARIA-E, amyloid-related imaging abnormalities with edema and
gantenerumab or RO4909832 or aducanumab or BIIB037 or effusion; ARIA-H, ARIAs with hemosiderin deposit; DWI, diffusion-weighted
imaging; FLAIR, fluid-attenuated inversion recovery; GRE, gradient-recalled
donanemab or LY3002813 or lecanemab or BAN2401 or mAb158 or
echo; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.
passive immunotherapy or monoclonal antibod* and amyloid related
imaging abnormalit* or ARIA or ARIA-E OR ARIA-H OR gyral swelling
or sulcal effusion or parenchymal hyperintensit* or microbleed* or
microhemorrhage* or superficial siderosis or vasogenic edema. Our Ponezumab
search strategy included studies published in any language from Ponezumab (Pfizer Inc) is a humanized IgG2 mAb engineered to mini-
2009 to September 15, 2021. We also searched ClinicalTrials.gov and mize its ability to activate complement and cellular immunity. Pon-
conference presentations for safety results of RCTs unavailable in ezumab is unique in that it binds to β-amyloid 40. In a phase 2 study
peer-reviewed publications. Randomized clinical trials, relevant (increasing the dose from 0.1 to 8.5 mg/kg every 60 days)16 includ-
studies performing secondary analyses of RCT data, and case reports ing 194 patients with mild to moderate AD, ARIA-E occurred in
were included if they were published in English. Phase 1 RCTs were 1 patient.
excluded if peer-reviewed data from phase 2 and/or phase 3 RCTs
were available for the same mAb; we also excluded studies Solanezumab
presenting only partial safety results or duplicated patient data and Solanezumab (Eli Lilly & Company) is a humanized IgG1 mAb that
animal studies. Data including study design, participants’ binds to β-amyloid monomers. In the EXPEDITION (Effect of
demographics and stage of AD, treatment regimens and durations, LY2062430 on the Progression of Alzheimer's Disease) 1 and EX-
and safety results regarding ARIA occurrence were extracted by PEDITION 2 phase 3 studies (400 mg intravenously every 4 weeks)17
coauthors and recorded. The strength of clinical data and subsequent that included 2052 patients with mild to moderate AD, solan-
evidence of ARIA incidence and clinical features in patients with AD ezumab showed a favorable safety profile. ARIA-E occurred only in
treated with β-amyloid–targeting mAbs were graded according to 0.9% of the active treatment and 0.4% of the placebo groups. In
the Oxford Centre for Evidence-Based Medicine levels of evidence the EXPEDITION 3 study18 including 2129 patients with mild AD,
by 2 authors (G.C. and E.G.S.) independently.15 ARIA-E occurred in 0.1% of the active treatment and 0.2% of the pla-
cebo groups.

Results
Two hundred eighty-four relevant studies were screened and as-
sessed for eligibility. After applying inclusion and exclusion criteria
(eFigure in the Supplement), 22 publications of RCTs (evidence level
1B), 5,16-36 11 secondary analyses of RCT data (evidence level
2B),7,11,12,37-44 and 1 clinical case report (evidence level 4),45 includ-
ing in total 15 508 adult patients (7025 men [45.3%] and 8483
women [54.7%]; mean [SD] age, 69.6 [8.3] years), were selected
for inclusion. Table 2 summarizes findings of the included RCTs,
whereas eTable 1 in the Supplement reports findings from second-
ary analyses of RCT data and the case report.
Bapineuzumab
Bapineuzumab (Janssen Pharmaceuticals/Pfizer Inc) is a human-
ized IgG1 mAb binding both fibrillar and soluble β-amyloid species.
In studies 201, 202, and 251 (2 phase 2 RCTs5,37,38 and an open-
label extension study38) (increasing dosage to 2.0 mg/kg intrave-
nously every 13 weeks),5,37,38 13% of patients receiving active treat-
ment exhibited incident microhemorrhages (ARIA-H), and 26.7% of
patients receiving high-dose bapineuzumab developed ARIA-E. One
case with symptomatic ARIA-E also required dexamethasone ad-
ministration. In 49% of cases with ARIA-E, associated ARIA-H find-
ings were detected, whereas only 4% of patients developed ARIA-H
without ARIA-E.12 Monthly subcutaneous bapineuzumab in a phase

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Table 2. Characteristics of Included Clinical Trials
No. of patients in
Source Time range Study MRI exclusion treatment/placebo Study treatment Incident ARIA-E, Incident ARIA-H,
(study code) (phase) population criteria groups regimen Dose % of patientsa % of patientsa Clinical correlates Notes
Landen et al,16 2008- Mild-to- Evidence of 138/56 Ponezumab, IV every 0.1 mg/kg 0 16.0 NA NA
2017 2011 (2) moderate AD; cortical stroke 60 d for 18 mo 0.5 mg/kg 4.0 24.0
MMSE score, or strategic
16-26 subcortical 1.0 mg/kg 0 4.0
stroke, 3.0 mg/kg 0 6.3
>2 mHs
8.5 mg/kg 0 19.4
Placebo 0 19.3
Clinical Review & Education Review

Doody et al,17 2009- Mild-to- NA 1027/1025 Solanezumab, IV Q4W 400 mg 0.9 4.9 NA NA
2014 2012 (3) moderate AD; for 18 mo Placebo 0.4 5.6
(EXPEDITION 1 MMSE score,
and 16-26
EXPEDITION 2)
Honig et al,18 2013- Mild AD; >4 mHs 1057/1072 Solanezumab, IV Q4W 400 mg 0.1 NA NA NA
2018 2017 (3) MMSE score, for 76 wk Placebo 0.2 NA
(EXPEDITION 3) 20-26
Salloway et al,5 2005- Mild-to- NA 124/110 Bapineuzumab, IV 0.15 mg/kg 3.2 NA 50% of ARIA-E 83.3% of ARIA-E
2009 (Study 2008 (2) moderate AD; every 13 wk for 18 mo 0.5 mg/kg 0 NA cases asymptomatic cases in ApoE ε4
201) MMSE score, and 50% carriers; 13.5% of

JAMA Neurology Published online January 31, 2022 (Reprinted)

16-26 1.0 mg/kg 10.0 NA symptomatic ApoE ε4 carriers and

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2.0 mg/kg 26.7 NA (headache, 4.3% of ApoE ε4
confusion, noncarriers
Placebo NA NA vomiting, gait developed ARIA-E;
disturbances) 1 symptomatic
ARIA-E case required
dexamethasone
Brody et al,19 2010- Mild-to- ≥4 mHs 109/37 Bapineuzumab, SC 2 mg 2.7 2.7 Asymptomatic NA
2016 2013 (2) moderate AD; Q4W for 24 mo 7 mg 0 0
MMSE score,
18-26 20 mg 2.7 0
Placebo NA NA
Salloway et al,21 2007- Mild-to- Prior Study 301 (ApoE ε4 Bapineuzumab, IV Study 301, Study 301, 4.2 NA ARIA-E, 84.5% The 2.0-mg/kg dose
2014 (Study 301 2012 (3) moderate AD; hemorrhagic noncarriers): every 13 wk for 78 wk 0.5 mg/kg (0.5 mg/kg) of was discontinued
and Study 302) MMSE score, or ischemic 807/524; Study 302 Study 301, Study 301, 9.4 NA ApoE ε4 carriers early owing to the
16-26 stroke >1 cm3, (ApoE ε4 carriers): 1.0 mg/kg and 64.3% high rate of
≥2 lacunar 673/448 (0.5 mg/kg) and symptomatic ARIA-E
infarcts, ≥2 Study 301, Study 301, 14.2 NA 83.9% (1.0 mg/kg) (55% of

© 2022 American Medical Association. All rights reserved.

mHs 2.0 mg/kg of ApoE ε4 cases); as per
Study 301, Study 301, 0.2 NA noncarriers were protocol, occurrence
Placebo asymptomatic of ARIA-E required
Study 302, Study 302, 15.3% NA interruption of
0.5 mg/kg (0, 11.4, and 27.3 dosing, and
ApoE ε4 carriers) participants had the
option of
Study 302, Study 302, 0.2 NA
redosing at
Placebo
a lower dose after
MRI resolution

(continued)

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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
 Table 2. Characteristics of Included Clinical Trials (continued)
No. of patients in
Source Time range Study MRI exclusion treatment/placebo Study treatment Incident ARIA-E, Incident ARIA-H,
(study code) (phase) population criteria groups regimen Dose % of patientsa % of patientsa Clinical correlates Notes
Salloway et al,23 2009- NA NA 1462 (688 ApoE ε4 Bapineuzumab, IV 0.5 mg/kg ApoE ε4 carriers, NA Symptomatic cases: ApoE ε4 carriers and

jamaneurology.com
2018 2012 carriers and 774 ApoE every 13 wk placebo to ApoE ε4 carriers, those who
(Study 351) (3 [OLE]) ε4 noncarriers) bapineuzumab: 11.8; 2.7% of placebo to experienced ARIA-E
bapineuzumab to bapineuzumab and in Study 301 were
bapineuzumab: 5.1; 1 patient in assigned to
ApoE ε4 noncarriers, bapineuzumab to bapineuzumab,
placebo to bapineuzumab 0.5 mg/kg
bapineuzumab: 5.4; groups (after first
bapineuzumab to 3 doses); ApoE ε4
bapineuzumab: 1.3 noncarriers, after
1.0 mg/kg ApoE ε4 noncarriers: NA first bapineuzumab
placebo to dose
bapineuzumab: 7.6;
bapineuzumab to
bapineuzumab: none
Vandenberghe 2008- Mild-to- Prior Study 3000 (ApoE ε4 Bapineuzumab, IV Study 3000, Study 3000, NA NA 2.0-mg/kg Dose was
et al,22 2016 2012 (3) moderate AD; hemorrhagic noncarriers): every 13 wk for 18 mo 0.5 mg/kg 4.9 discontinued early
(Study 3000 MMSE score, or ischemic 541/344; Study 3001 Study 3000, Study 3000, NA owing to the high
and Study 3001) 16-26 stroke >1 cm3, (ApoE ε4 carriers): 1.0 mg/kg 11.8 rate of symptomatic
≥2 lacunar 654/439 ARIA
infarcts, ≥2 Study 3000, Study 3000, NA

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mHs placebo 0.6
Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies

Study 3001, Study 3001, NA

0.5 mg/kg 16.7
Study 3001, Study 3001, NA
placebo 2.1
Ivanoiu et al,24 2009- MMSE score Prior Study 3002 (ApoE ε4 Bapineuzumab, IV Study 3002, Study 3002, placebo Study 3002, 0 Study 3002: 1 NA
2016 (Study 2012 ≥10 hemorrhagic noncarriers): 202; every 13 wk 0.5 mg/kg to bapineuzumab: 7.7 symptomatic
3002 and (3 [OLE]) or ischemic Study 3003 (ApoE ε4 Study 3002, Study 3002, 1.5 ARIA-E case in
Study 3003) stroke >1 cm3, carriers): 492 bapineuzumab to placebo to
≥2 lacunar bapineuzumab: 3.0 bapineuzumab
infarcts, ≥4 0.5 mg group; study
mHs Study 3002, Study 3002, placebo Study 3002, 0 3003: >70% of
1.0 mg/kg to bapineuzumab: ARIA-E cases were
16.2 asymptomatic
Study 3002, Study 3002, 5.4
bapineuzumab to
bapineuzumab: 5.4

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Study 3003, Study 3003, placebo Study 3003, 9.3
0.5 mg/kg to bapineuzumab:
10.7
Study 3002, Study 3002, 5.5
bapineuzumab to
bapineuzumab: 3.6
Delnomdedieu 2010- Mild-to- Prior ischemic 69/19 AAB-003, IV every 0.5 mg/kg 0 0 All ARIA cases were No clear link between
et al,20 2016 2013 (1) moderate AD; stroke >1 cm3, 13 wk for 26 wk asymptomatic ApoE status and
1.0 mg/kg 0 0
MMSE score, >1 lacunar ARIA-E; 52 patients
16-26 infarcts, >1 2.0 mg/kg 0 6.3 entered a 52-wk OLE
mHs 4.0 mg/kg 0 0 study, and no ARIA
cases were reported
8.0 mg/kg 8.3 12.5
Placebo 0 0

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Table 2. Characteristics of Included Clinical Trials (continued)
No. of patients in
Source Time range Study MRI exclusion treatment/placebo Study treatment Incident ARIA-E, Incident ARIA-H,
(study code) (phase) population criteria groups regimen Dose % of patientsa % of patientsa Clinical correlates Notes
Cummings 2011- Mild-to- 287/146 Crenezumab, 68 wk 300 mg SC Q2W 0 13.1 ARIA-E cases were NA
et al,25 2018 2014 (2) moderate AD; 15 mg/kg IV 0.6 9.1 asymptomatic; 2
(ABBY) MMSE score, Q4W cases of ARIA-H in
18-26 the placebo group
Placebo 0 14.6 were symptomatic
Guthrie 2015- Mild-to- NA 61/14 Crenezumab, IV Q4W 30 mg/kg 0 0 NA Patients were
et al,26 2020 2019 (1b) moderate AD; for 13 wk 45 mg/kg 0 18.2 discontinued if >10
MMSE score, treatment-emergent
Clinical Review & Education Review

18-28 60 mg/kg 0 4.8 ARIA-H or ≥3

120 mg/kg 0 0 symptomatic ARIA-E;
71 patients entered a
Placebo 0 0 120-wk OLE study,
with no ARIA-E cases
and 7 ARIA-H cases
reported
Ostrowitzki 2010- Prodromal ≥3 mHs, ≥2 531/266 Gantenerumab, SC 105 mg 6.6 22.9 (12.3%/ >80% of ARIA-E With new ARIA-E,
et al,27 2018 2014 (3) AD; MMSE lacunar Q4W for 24 mo (1.8%/5.4%/10.7% 19.8%/32% ApoE ε4 were asymptomatic treatment was
(Scarlet Road) score, ≥24 infarcts, ApoE ε4 carriers) carriers) and resolved with withheld and
confluent 225 mg 13.5 16.2 (11%/19.4%/0 dose adjustment restarted at half

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deep white (11.0%/15.0%/0 ApoE ε4 carriers) dose at resolution;
matter lesions with a second

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ApoE ε4 carriers)
ARIA-E, treatment
Placebo 0.8 (2.5%/0/0 ApoE 13.2 (5.1%/14.2%/ permanently
ε4 carriers) 22.6% ApoE ε4 discontinued; with
carriers) >4 treatment-
emergent ARIA-H,
treatment
discontinued; if >2
and ≤4 new ARIA-H,
dose was halved
Klein et al,30 2016- NA >5 mHs, 379 Gantenerumab, 1200 mg NA NA 25% of ARIA-E in A trend toward
2019 (Scarlet 2020 recurrent SC Q4W PET substudy was slightly higher
Road and (3 [OLE]) ARIA-E in symptomatic reduction of amyloid
Marguerite placebo- load in patients who
Road) controlled had ARIA-E; 41.8%
study of patients (28/67)
in amyloid PET
substudy

© 2022 American Medical Association. All rights reserved.

experienced ARIA-E
Andjelkovic 2016- NA >5 mHs, 154 Gantenerumab, SC 1200 mg 28.6 17.4 84% of ARIA-E were To reduce ARIA-E
et al,29 2018 2020 recurrent Q4W asymptomatic; the risk, gantenerumab
(Scarlet Road) (3 [OLE]) ARIA-E in results refer to 2 y doses were increased
double-blind of study duration slowly using a 6- or
study 10-mo titration
scheme based on
ApoE genotype and
last double-blind
dose

(continued)

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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
 Table 2. Characteristics of Included Clinical Trials (continued)
No. of patients in
Source Time range Study MRI exclusion treatment/placebo Study treatment Incident ARIA-E, Incident ARIA-H,
(study code) (phase) population criteria groups regimen Dose % of patientsa % of patientsa Clinical correlates Notes
Abi-Saab et al,28 2016- NA >5 mHs, 225 Gantenerumab, SC 1200 mg 29.2 23.2 76.5% of ARIA-E To reduce ARIA-E

jamaneurology.com
2018 2020 recurrent Q4W were asymptomatic; risk, gantenerumab
(Marguerite (3 [OLE]) ARIA-E in the results refer to doses were increased
Road) double-blind 2 y of study slowly using a 6- or
study duration 10-mo titration
scheme based on
ApoE genotype and
last double-blind
dose
Sevigny et al,32 2012- Prodromal to >4 mHs, >1 125/40 Aducanumab, IV Q4W 1 mg/kg 3.2 (0/5.3%) 6.5 (8.3%/5.3%) NA Patients developing
2016 (PRIME) 2014 (2b) mild AD; lacunar for 12 mo 3 mg/kg 6.3 (9.1%/4.8%) 9.4 (9.1%/9.5%) mild ARIA-E or ≤4
MMSE score, infarct, ARIA-H without
≥20 cortical 6 mg/kg 37.0 (22.2%/43.0%) 0 symptoms could
infarct 10 mg/kg 40.6 (16.7%/55.0%) 6.3 (0/10.0%) continue at same
dose; with moderate
Placebo 0 5.3 (0/8.3%) or severe ARIA-E
without symptoms
or ARIA-E with mild
symptoms, treatment
was withheld and
restarted at a lower

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dose at resolution; in
case of moderate or
Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies

severe symptoms,
treatment was
discontinued
ClinicalTrials.gov 2015- Prodromal to >4 mHs, >1 2192/1093 Aducanumab, Low dose, Placebo-controlled, Placebo-controlled, ARIA events were Patients developing
(ENGAGE and 2019 mild AD; lacunar (1623 in OLE) IV Q4W 6 mg/kg in ApoE 26.1 (17.8%/29.3%) 16.4 symptomatic in mild ARIA-E or ≤4
EMERGE)35,36 (3 [OLE]) MMSE score, infarct, ε4 noncarriers; OLE, placebo to OLE, 19.2% and in 24.4% ARIA-H without
≥24 cortical 3 mg/kg in ApoE aducanumab, 20.5 placebo to of cases at low and symptoms could
infarct, ε4 carriers aducanumab, 14.9 high dose, continue at same
superficial respectively; dose; with moderate
siderosis, OLE, aducanumab to OLE, aducanumab to symptoms reported or severe without
diffuse white aducanumab, 5.4 aducanumab, 5.1 in patients with symptoms or with
matter disease High dose, Placebo-controlled, Placebo-controlled, ARIA include ARIA-E with mild to
10 mg/kg (6 35.7 (20.3%/42.2%) 19.3 headache, dizziness, moderate symptoms,
mg/kg in ApoE OLE, placebo to OLE, placebo to visual disturbances, treatment was
ε4 carriers aducanumab, 27.0 aducanumab, 11.8 nausea and withheld and
before protocol

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vomiting; most restarted at a lower
version 4) OLE, aducanumab to OLE, aducanumab to
patients with ARIA dose at resolution;
aducanumab, 8.5 aducanumab, 7.7
continued in case of severe
Placebo Placebo-controlled, Placebo-controlled, 6.6 investigational symptoms and/or
2.7 (3.6%/2.2%) treatment ≥10 microbleeds
and/or
>2 superficial
siderosis, treatment
was discontinued

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Table 2. Characteristics of Included Clinical Trials (continued)
No. of patients in
Source Time range Study MRI exclusion treatment/placebo Study treatment Incident ARIA-E, Incident ARIA-H,
(study code) (phase) population criteria groups regimen Dose % of patientsa % of patientsa Clinical correlates Notes
Swanson et al,33 2012- Prodromal to NA 609/245 Lecanemab, 2.5 mg/kg 2.0 (0/2.6%) 3.8 60% ARIA-E A protocol
2021 2017 (2b) mild AD; IV Q2W or Q4W Biweekly occurred within the amendment during
(Study 201) MMSE score, for 18 mo 5.0 mg/kg 2.0 (0/2.5%) 13.7 first 3 mo of the study course
≥22 Monthly treatment, and 89% requested that ApoE
were mild to ε4 carriers no longer
5.0 mg/kg 3.3 (0/3.6%) 18.5 moderate in receive the
Biweekly radiological 10-mg/kg biweekly
10 mg/kg 9.9 (7.1%/10.2%) 11.1 severity; 11% of dose due
Clinical Review & Education Review

Monthly ARIA-E cases were to the higher risk of

10 mg/kg 9.9 (8.0%/14.3%) 6.8 symptomatic developing ARIA-E;
Biweekly (headache, visual all patients with
disturbances, ARIA-E were
Placebo 0.8 (0/1.1%) 5.3
confusion); ARIA-H discontinued per
cases were protocol, regardless
asymptomatic of radiological
severity or
symptoms; ARIA-H
was seen in 13.1% of
ApoE ε4 carriers and
in 4.6% of ApoE ε4

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noncarriers

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Mintun et al,34 2017- Prodromal to NA 131/126 Donanemab, 700 mg for the 27.5 (11.4%/ 30.5 Symptomatic Eligibility criteria
2021 (TRAIL- 2021 (2) mild AD; IV Q4W for 72 wk First 3 doses; 30.9%/ ARIA-E, 6.1% of all required a positive
BLAZER-ALZ) MMSE score, 1400 mg 44.0%) participants in flortaucipir PET scan
20-28 subsequently donanemab group; finding with an SUVR
Placebo 0.8 (0/0/3.6%) 7.2 serious of 1.10 to 1.46 and a
symptomatic positive florbetapir
ARIA-E, 1.5% PET scan finding
(confusion, aphasia)
Salloway et al,31 2012- Patients with NA 52/52/40 Gantenerumab, SC Gantenerumab, 19.2 42.3 NA In August 2016,
2021 (DIAN-TU) 2019 (2-3) no symptoms Q4W; solanezumab, IV 1200 mg gantenerumab dose
(CDR 0), Q4W; placebo Solanezumab, 0 12.5 was gradually
carrying a 1600 mg increased from 225
mutation to 1200 mg Q4W and
Placebo 2.5 NA solanezumab from
400 to 1600 mg
Q4W; 36% of ARIA-H
in gantenerumab

© 2022 American Medical Association. All rights reserved.

Abbreviations: ABBY, A Study to Evaluate the Efficacy and Safety of MABT5102A in Patients With Mild to
Moderate Alzheimer's Disease; AD, Alzheimer disease; ARIA, amyloid-related imaging abnormality; ARIA-E, ARIAs
with edema/effusion; ARIA-H, ARIAs with hemosiderin deposits; CDR, Clinical Dementia Rating; DIAN-TU,
Dominantly Inherited Alzheimer Network–Trials Unit; EMERGE, 221AD302 Phase 3 Study of Aducanumab
(BIIB037) in Early Alzheimer’s Disease; ENGAGE, 221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early
Alzheimer’s Disease; EXPEDITION, Effect of LY2062430 on the Progression of Alzheimer’s Disease; IV,
intravenous infusion; Marguerite Road, A Study of Gantenerumab in Participants With Mild Alzheimer Disease;
mHs, microhemorrhages; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; NA, not
group were
superficial siderosis
available; OLE, open-label extension; PET, positron emission tomography; PRIME, Multiple Dose Study of
Aducanumab (BIIB037) Participants With Prodromal or Mild Alzheimer’s Disease; Q2W, every 2 weeks; Q4W,
every 4 weeks; SC, subcutaneous injection; Scarlet Road, Study of Gantenerumab in Participants With Prodromal
Alzheimer’s Disease; SUVR, standardized value uptake ratio; TRAILBLAZER-ALZ, A Study of LY3002813 in
Participants With Early Symptomatic Alzheimer’s Disease.
a
Parenthetical data are calculated as percentage of patients with 0/1/2 Ԑ4 alleles or percentage of Ԑ4
noncarriers/Ԑ4 carriers where indicated.

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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
 Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
2 study19 and intravenous AAB-OO3 (a modified version of bap-
ineuzumab) in a phase 1 study20 revealed instead a better safety pro-
file (Table 2).
Due to growing awareness about the need for expertise in ARIA
evaluation, during the conduction of phase 3 studies,21-24 report-
ing of safety MRI scans was gradually transferred from local respon-
sibility to central readers (safety read). In a central MRI second re-
view (final read) of the more than 2000 patients who had completed
their participation in phase 3 studies,39 ARIA-E was detected in 13%
of patients receiving active treatment. The 2.0-mg/kg dosage was
discontinued early due to the high rate of symptomatic ARIA-E (see
below), reducing the total rate of ARIAs relative to phase 2 RCTs. In-
cidence of ARIA-E was higher in bapineuzumab-treated ApoE ε4 car-
riers (21% in active treatment vs 1% in placebo groups) than in non-
carriers (11% in active treatment vs 0.6% in placebo groups).
Incidence, duration, and radiological severity of ARIA-E decreased
during study treatment, with the highest frequency occurring after
the first infusion.39,40 Recurrence rate was 25.6% after reinitiation
of treatment.39 A clinical review of the high-dose bapineuzumab
phase 3 studies revealed that symptomatic cases with ARIA-E ac-
counted for the 39.3% of cases among ApoE ε4 noncarriers (2.0 mg/
kg) and for the 11% of cases in ApoE ε4 carriers (0.5 mg/kg).40 Treat-
ment-emergent adverse events among patients experiencing ARIA-E
were mainly neuropsychiatric (headache, cognitive dysfunction, and
agitation). None of the cases were fatal.
In terms of risk factors, bapineuzumab dosage, absence of car-
diac disorders, lower baseline cerebrospinal fluid levels of β-amy-
loid (but not baseline amyloid uptake on positron emission tomog-
raphy), female sex, 2 copies of the ApoE ε4 allele, and presence of
microhemorrhages at baseline were associated with an increased
risk for ARIA-E development (eTable 1 in the Supplement).40,41 Ex-
posure to drug treatment (but not bapineuzumab dosage), base-
line ARIA-H, and antithrombotic use were instead associated with
incident microhemorrhages (eTable 1 in the Supplement).38
In terms of longitudinal changes, bapineuzumab-treated par-
ticipants with ARIA-E had a greater reduction in amyloid uptake on
positron emission tomography, which appeared temporally and to-
pographically correlated with ARIA occurrence, and in phosphory-
lated and total tau levels in cerebrospinal fluid (eTable 1 in the
Supplement).37 Participants with ARIA-E also had a greater reduc-
tion in total hippocampal volume and a significantly greater ven-
tricular volume increase. No differences in clinical outcomes be-
tween groups with and without ARIA-E were detected.
Crenezumab
Crenezumab (Genentech, Inc) is a humanized IgG4 mAb that binds
multiple conformations of β-amyloid (monomers, oligomers, and fi-
brils) and collaterally reduces the activation of microglia and the re-
lease of proinflammatory cytokines. In the phase 1 study (ⱕ120
mg/kg intravenously every 4 weeks)26 and phase 2 trials (testing 300
mg subcutaneously every 2 weeks and 15 mg/kg intravenously ev-
ery 4 weeks)25 including 75 and 431 patients with mild to moderate
AD,25,26 only 1 patient (ApoE ε4/ε4 genotype) developed ARIA-E.
Gantenerumab
Gantenerumab (F. Hoffmann–La Roche AG) is the first fully human
IgG1 anti–β-amyloid mAb that binds selectively β-amyloid–
insoluble fibrils but reacts also with soluble oligomers. In the Scar-
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Review Clinical Review & Education
let Road (Study of Gantenerumab in Participants With Prodromal Alz-
heimer’s Disease) phase 3 study (ascending dosage from 105 to 225
mg subcutaneously every 4 weeks)27 including 797 patients with pro-
dromal AD, ARIA-E was observed in as many as 15% of ApoE ε4 car-
riers and 11% of ApoE ε4 noncarriers treated with the highest dose.
ARIA-E was detected most frequently from months 3 to 6 of treat-
ment, whereas incidence lowered after month 9 (Figure 2A). Re-
currence rate in those who did not discontinue the study (and con-
tinued treatment at half dose) was 13.8%. The frequency of ARIA-H
occurrence was ApoE ε4 genotype dependent and drug dosage in-
dependent. More than 80% of cases with ARIA-E were asymptom-
atic and resolved with dose halving; in the remaining cases, head-
ache was the most common related symptom.27 Participants in the
Scarlet Road and Marguerite Road (A Study of Gantenerumab in Par-
ticipants With Mild Alzheimer Disease; same study design as Scar-
let Road but involving patients with mild AD) studies who entered
the open-label extension study (154 and 225 patients,
respectively)28,29 had dose titration to 1200 mg of monthly gan-
tenerumab given subcutaneously. Overall ARIA-E incidence at ap-
proximately 2 years of study duration was 28.6% in the Scarlet Road
and 29.2% in the Marguerite Road studies (Figure 2A). Among pa-
tients with ARIA-E, 61% in the Scarlet Road and 62.5% in the Mar-
guerite Road studies also developed ARIA-H, and 84.0% and 76.5%
of cases with ARIA-E, respectively, were asymptomatic.30 In the
DIAN-TU (Dominantly Inherited Alzheimer Network–Trials Unit)
study, a phase 3 trial testing gantenerumab (1200 mg subcutane-
ously every 4 weeks)31 in asymptomatic patients with dominantly
inherited AD, cases with ARIA-E and ARIA-H were observed in 19.2%
and 42.3% of patients, respectively.
Aducanumab
Aducanumab (Biogen Inc/Eisai Co, Ltd) is a fully humanized IgG1 mAb
that selectively reacts with β-amyloid aggregates, including soluble
oligomers and insoluble fibrils. In the PRIME (Multiple Dose Study
of Aducanumab [BIIB037] Participants With Prodromal or Mild Alz-
heimer’s Disease) phase 1b study (ascending dosage from 1 to 10
mg/kg intravenously every 4 weeks)32,46 including 165 partici-
pants with prodromal-to-mild AD, ARIA-E occurred at higher levels
than in any previous anti–β-amyloid mAb study (35.9% overall), af-
fecting none of the participants in the placebo group compared with
the 40.6% of patients receiving aducanumab, 10 mg/kg (55% of
ApoE ε4 carriers) (Figure 2B and Table 2). ARIA-E was generally ob-
served early in treatment. In the phase 3 studies ENGAGE (221AD301
Phase 3 Study of Aducanumab [BIIB037] in Early Alzheimer’s
Disease) 35 and EMERGE (221AD302 Phase 3 Study of Adu-
canumab [BIIB037] in Early Alzheimer’s Disease)36 that included
3285 patients, ARIA-E occurred in 20.3% of ApoE ε4 noncarriers and
42.2% of ApoE ε4 carriers (Figure 2B). ARIA events were sympto-
matic in 19.2% of cases receiving low doses and in 24.4% of cases
receiving high doses. Reported symptoms were headache, dizzi-
ness, visual disturbances, and nausea and vomiting. Most patients
with ARIA continued investigational treatment.
Emergent ARIA-H was also relatively frequent in the PRIME
study, being observed in 17% among ApoE ε4 noncarriers and 25%
among ApoE ε4 carriers in the treatment group (independently of
aducanumab dosage) and in 8% among ApoE ε4 noncarriers and 0
ApoE ε4 carriers in the placebo group. Superficial siderosis was ob-
served in 9% of patients receiving 10 mg/kg of aducanumab. In phase
(Reprinted) JAMA Neurology Published online January 31, 2022 E9
 Clinical Review & Education Review Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies

Figure 2. Incidence Proportion of Amyloid-Related Imaging Abnormalities With Edema and Effusion (ARIA-E)
in Clinical Trials Testing Anti–β-Amyloid Agents

A Scarlet Road and Marguerite Road B PRIME, EMERGE, and ENGAGE

35 60
ApoE ε4 noncarriers ApoE ε4 noncarriers
30 50
1 ApoE ε4 carriers ApoE ε4 carriers
2 ApoE ε4 carriers Overall
25
ARIA-E incidence, %

ARIA-E incidence, %
Overall 40
20
30
15
20
10

5 10

0 0
Placebo 105 225 OLE OLE Placebo 1 3 6 10 6 10
Q4W Q4W Scarlet Road Marguerite Road Q4W Q4W Q4W Q4W Q4W Q4W
1200 Q4W 1200 Q4W
Scarlet Road placebo-controlled PRIME EMERGE and ENGAGE
Gantenerumab administered, mg Aducanumab administered, mg/kg

C Study 201 D TRAILBLAZER-ALZ

25 60
ApoE ε4 noncarriers ApoE ε4 noncarriers
ApoE ε4 carriers 50 1 ApoE ε4 carriers
20
2 ApoE ε4 carriers
ARIA-E incidence, %

ARIA-E incidence, %

40
15

30

10
20

5
10

0 0
Placebo 2.5 5 5 10 10 Placebo 1400
Q2W Q4W Q2W Q4W Q2W Q4W
Lecanemab administered, mg/kg Donanemab administered, mg

Studies include a gantenerumab phase 3 study and 2 open-label extension
(OLE) studies,27-29 an aducanumab phase 1b study and 2 phase 3 studies,32 a
lecanemab phase 2b study,33 and a donanemab phase 2 study.34 ApoE indicates
apolipoprotein E; EMERGE, 221AD302 Phase 3 Study of Aducanumab (BIIB037)
in Early Alzheimer’s Disease; ENGAGE, 221AD301 Phase 3 Study of Aducanumab
(BIIB037) in Early Alzheimer’s Disease; Marguerite Road, A Study of
Gantenerumab in Participants With Mild Alzheimer Disease; PRIME, Multiple
Dose Study of Aducanumab (BIIB037) Participants With Prodromal or Mild
Alzheimer’s Disease; Q2W, every 2 weeks; Q4W, every 4 weeks; Scarlet Road,
Study of Gantenerumab in Participants With Prodromal Alzheimer’s Disease;
and TRAILBLAZER-ALZ, A Study of LY3002813 in Participants With Early
Symptomatic Alzheimer’s Disease.

3 trials, ARIA-H was observed in 6.6% of patients receiving pla-
cebo, 16.4% of those receiving low-dose aducanumab, and 19.3%
of those receiving high-dose aducanumab (Figure 3B).
A case report45 of a patient with ARIAs with severe symptoms
(encephalopathy, hypertension, and headache) requiring admis-
sion to the intensive care unit was recently published. The patient,
a 65-year-old man with ApoE ε4/ε4 genotype, had 4 prior infu-
sions of aducanumab. Brain MRI showed confluent hyperintensi-
ties and microbleeds in left frontal and temporal regions and adja-
cent gadolinium enhancement. A clinical and radiological worsening
1 month later prompted intravenous methylprednisolone, 1000 mg
for 5 days, with subsequent rapid clinical improvement.
Lecanemab
Lecanemab (Eisai Co, Ltd/Biogen Inc) is a humanized IgG1 mAb
that binds to soluble β-amyloid aggregates (oligomers and proto-
fibrils). In the phase 2b Study 201 (ascending intravenous doses
to 10 mg/kg biweekly)33 including 854 patients, incident ARIA-E
was observed in 8.0% of patients at the highest dose in ApoE ε4
noncarriers and 14.3% at the highest dose in ApoE ε4 carriers
(Figure 2C). A protocol amendment during the study course
requested that patients who were ApoE ε4 carriers no longer
receive the 10-mg/kg biweekly dose owing to the higher risk of
developing ARIA-E. Among cases with ARIA-E, 11% were sympto-
matic (headache, visual disturbances, and confusion). ARIA-H was
seen in 13.1% of ApoE ε4 carriers and in 4.6% of ApoE ε4 noncar-
riers, without symptoms (Figure 3C).
Donanemab
Donanemab (Eli Lilly & Company) is a humanized IgG1 anti–β-
amyloid mAb that reacts with β-amyloid aggregates and shows
no off-target binding to other amyloid species.34 In the phase 2

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 Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies Review Clinical Review & Education

Figure 3. Incidence Proportion of Amyloid-Related Imaging Abnormalities With Hemosiderin (ARIA-H) in Clinical Trials Testing Anti–β-Amyloid Agents

A Scarlet Road and Marguerite Road B PRIME, EMERGE, and ENGAGE

45 25

40 ApoE ε4 noncarriers ApoE ε4 noncarriers

1 ApoE ε4 carriers ApoE ε4 carriers
35 20
2 ApoE ε4 carriers Overall
ARIA-H incidence, %

ARIA-H incidence, %
30 Overall
15
25

20
10
15

10 5
5

0 0
Placebo 105 225 OLE OLE Placebo 1 3 6 10 6 10
Q4W Q4W Scarlet Road Marguerite Road Q4W Q4W Q4W Q4W Q4W Q4W
1200 Q4W 1200 Q4W
Scarlet Road placebo-controlled PRIME EMERGE and ENGAGE
Gantenerumab administered, mg Aducanumab administered, mg/kg

C Study 201 D TRAILBLAZER-ALZ

40 40

35 35

30 30
ARIA-H incidence, %

ARIA-H incidence, %

25 25

20 20

15 15

10 10

5 5

0 0
Placebo 2.5 5 5 10 10 Placebo 1400
Q2W Q4W Q2W Q4W Q2W Q4W
Lecanemab administered, mg/kg Donanemab administered, mg

Studies include a gantenerumab phase 3 study and 2 open-label extension
(OLE) studies,27-29 an aducanumab phase 1b study32 and 2 phase 3 studies,35,36
a lecanemab phase 2b study,33 and a donanemab phase 2 study.34 ApoE
indicates apolipoprotein E; EMERGE, 221AD302 Phase 3 Study of Aducanumab
(BIIB037) in Early Alzheimer’s Disease; ENGAGE, 221AD301 Phase 3 Study of
Aducanumab (BIIB037) in Early Alzheimer’s Disease; Marguerite Road, A Study
of Gantenerumab in Participants With Mild Alzheimer Disease; PRIME, Multiple
Dose Study of Aducanumab (BIIB037) Participants With Prodromal or Mild
Alzheimer’s Disease; Q2W, every 2 weeks; Q4W, every 4 weeks; Scarlet Road,
Study of Gantenerumab in Participants With Prodromal Alzheimer’s Disease;
and TRAILBLAZER-ALZ, A Study of LY3002813 in Participants With Early
Symptomatic Alzheimer’s Disease.

TRAILBLAZER-ALZ (A Study of LY3002813 in Participants With

Early Symptomatic Alzheimer’s Disease) study (ascending intra-
venous dose from 700 to 1400 mg every 4 weeks) including 257
patients with prodromal-to-mild AD, incident ARIA-E was
observed in 28.8% of treated individuals. More specifically,
ARIA-E occurred in 11.4% of ApoE ε4 noncarriers and in 44.0% of
homozygous carriers (Figure 2D). Most cases appeared at or by
week 12 from randomization. Symptomatic ARIA-E was found in
6.1% of all participants in the donanemab group, whereas serious
symptomatic ARIA-E occurred in 2 patients (confusion and
aphasia).
Detection of new microhemorrhages occurred in 20% of the
treatment and 5% of the placebo groups. Superficial siderosis was
observed instead in 18% of the treatment and 2.5% of the placebo
groups (Figure 3D). No macrohemorrhages were detected in either
group.
Discussion
The Alzheimer Association Research Roundtable Workgroup6 in 2011
concluded that there was too limited information regarding ARIAs
in the natural setting from clinical trials to make conclusive recom-
mendations for clinical trial policies. Different from previous US Food
and Drug Administration guidance to exclude all patients with any
evidence of ARIA-H at baseline, the workgroup suggested a cutoff
value of 5 microhemorrhages for patient enrollment and the even-
tual discontinuation from study treatment of individuals whose MRI
abnormalities were associated with significant clinical symptoms. De-
spite the large amount of data collected since 2011, there is still a para-
mount need for information about whether specific components of
ARIAs have an impact on clinical course and response to treat-
ment. Safety assessments and protocols still show heterogeneity

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 Clinical Review & Education Review
among clinical trials, and updated common guidelines are
lacking.40,41
In this framework, we performed a systematic review of
21 RCTs (evidence level 1B), 11 secondary analyses of RCT data
(level 2B), and 1 clinical case report (level 4), including a total of
15 508 adult patients. Evidence strongly outlined ApoE ε4
genotype as the main risk factor for both ARIA-E and ARIA-H
development.5,12,28,29,32,34,37,39-41 ApoE ε4 carriers have a higher
parenchymal and vascular β-amyloid load.47 When treated with
anti–β-amyloid mAbs, these patients are expected to develop a
larger β-amyloid clearance through perivascular and vascular
spaces due to therapeutic effect, leading to increased transient
cerebral amyloid angiopathy and to a greater vascular permeabil-
ity, resulting in an easier extravasation of both proteinaceous fluid
(ARIA-E) and erythrocytes (ARIA-H). 37 Likely due to a similar
mechanism (ie, greater mobilization of β-amyloid), the rate of
ARIA-E was further associated with treatment dose, emerging as
a frequent finding in patient groups treated with high-dose
b a p i n e u z u m a b ( 2 6.7 % o f p a t i e n t s ) , 5 g a n t e n e r u m a b
(28.6%-29.2%),28,29 aducanumab (35.9% overall and 55% of
ApoE ε4 carriers),32 and donanemab (28.8%).34 Both ARIA types
manifested early during the study course, and symptomatic cases
accounted for the 6.1% to 39.3% of ARIA-E cases at higher treat-
ment doses, whereas ARIA-H cases were generally asymptomatic.
Regarding differences in ARIA incidence among mAbs, a pivotal
role has been attributed to their mechanisms of action; indeed, a
good safety profile has been linked to the selective targeting of
β-amyloid–soluble conformations (ie, not binding to plaques) of
some mAbs (eg, solanezumab, lecanemab) and to the
anti-inflammatory capabilities of others (eg, crenezumab,
ponezumab).46,48
Some studies37,38,40,41 have further investigated ARIA risk fac-
tors and/or longitudinal changes of patients experiencing ARIA, sug-
gesting that ARIA-E might be a marker for better treatment re-
sponse. However, these studies analyzed only data from
bapineuzumab RCTs and therefore are not directly applicable to
other mAbs, for which longitudinal evidence with regard to pa-
tients with ARIAs is still lacking.
Evidence also suggests that the most relevant indications from
the original Alzheimer’s Association Research Roundtable Work-
group report6 are still valid, including specific MRI protocol mini-
mum standards (field strength of at least 1.5 T, acquisition of gradi-
ent echo and/or T2-weighted and fluid-attenuated inversion recovery
sequences, section thickness of ⱕ5 mm, and echo time of ⱖ20 mil-
liseconds), indications on frequency of scanning protocols within
clinical developments of new drugs, and procedures for reading and
reporting (in particular, highlighting the importance of detailed re-
porting forms, as standardized as possible, covering the whole spec-
trum of findings).6 If monitoring for ARIAs remains the responsibil-
ity of local neuroradiologists, however, education about MRI features
of ARIA and correct use of rating scales is fundamental. Because
ARIAs are clinically undetectable in many cases, indeed, robust and
validated radiological scoring systems are critical monitoring tools
for the detection of these events (Table 1 and Figure 1 provide the
main neuroradiological features of ARIA). The Barkhof MRI sever-
ity scale7 is an established 60-point scoring system for ARIA-E, used
in clinical trials testing gantenerumab and crenezumab and in the
bapineuzumab safety read and final read project. The score is ob-
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Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
tained by summing the individual extension scores of 12 brain
regions7,11 and has demonstrated a high interrater agreement (in-
traclass correlation coefficient, 0.78 [95% CI, 0.36-0.94]) be-
tween trained neuroradiologists, with sulcal hyperintensity being the
single most recognizable and common MRI feature of ARIA-E.11 More
recently, a simplified 3-point scale (and its 5-point variant) has been
widely used in RCTs (eg, aducanumab), showing an even higher in-
terrater agreement (intraclass correlation coefficients, 0.95 [95%
CI, 0.92-0.97] and 0.94 [95% CI, 0.92-0.97], respectively) and a
good correlation with the Barkhof MRI severity scale (eTable 2 in the
Supplement).8,9 Regarding ARIA-H, the Microbleed Anatomical Rat-
ing Scale has been proposed as a reliable tool to enumerate micro-
bleeds within prespecified brain anatomical regions with a good
intrarater and interrater reliability,10,38 and it has been applied in a
study reviewing ARIA-H cases in 2 phase 2 clinical trials with
bapineuzumab.38
Given the high impact of ARIA during the course of RCTs, in re-
sponse to the US Food and Drug Administration conditional ap-
proval of aducanumab, an expert panel has been recently as-
sembled to provide guidelines for ARIA monitoring during treatment
with this specific molecule in a real-world setting.49 According to
these guidelines, MRI scans, including at least fluid-attenuated in-
version recovery, T2-weighted gradient echo (or susceptibility-
weighted imaging), and diffusion-weighted imaging sequences, are
recommended within 1 year before treatment initiation and before
the 5th, 7th, and 12th infusions during dose titration. Alongside these
scheduled MRIs, additional scans should also be obtained when-
ever patients show any symptoms suggestive of ARIAs. If patients
with ARIAs have symptoms, treatment should be discontinued, and
monthly MRIs should be obtained to evaluate reinitiation until reso-
lution of ARIA-E or stability of ARIA-H. Otherwise, in the absence of
symptoms, treatment suspension is recommended only in the case
of radiologically severe or moderate ARIAs (eTable 2 in the Supple-
ment). Given the association of ApoE ε4 genotype with the risk of
ARIA development, clinicians might discuss with the patient, be-
fore treatment initiation, the opportunity to perform genetic test-
ing. To date, no recommendations about potential pharmacologi-
cal treatments for ARIAs are available in the literature; anecdotal case
reports suggest that the use of corticosteroids might be necessary
to facilitate resolution of ARIAs (and related symptoms).5,6,45
Limitations
This study has some limitations, including the frequent paucity of
detailed ARIA-related safety reports in RCTs (especially about clini-
cal and treatment aspects) and the subsequent need to include stud-
ies performing secondary analyses of RCT data. Moreover, despite
the robustness of most of the included RCTs, the generalization of
findings into a real-world setting is mainly limited by the strict in-
clusion criteria applied to RCT patients and by their relatively short
time of exposure to mAbs.
Conclusions
In line with conclusions of the 2011 Alzheimer’s Association Re-
search Roundtable Workgroup report, current evidence highlights
the significant impact of ARIAs on anti–β-amyloid treatment regi-
mens. Evidence from RCTs supports the notion that treatments can
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 Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies
be continued with careful monitoring and possible dose adjust-
ment after the occurrence of ARIAs but still underlines the para-
ARTICLE INFORMATION
Accepted for Publication: October 22, 2021.
Published Online: January 31, 2022.
doi:10.1001/jamaneurol.2021.5205
Author Affiliations: Neurology Unit, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS)
Ospedale San Raffaele, Milan, Italy (Filippi,
Cecchetti, Spinelli, Agosta); Neurorehabilitation
Unit, IRCCS Ospedale San Raffaele, Milan, Italy
(Filippi); Neurophysiology Service, IRCCS Ospedale
San Raffaele, Milan, Italy (Filippi, Cecchetti);
Neuroimaging Research Unit, Division of
Neuroscience, IRCCS Ospedale San Raffaele, Milan,
Italy (Filippi, Cecchetti, Spinelli, Agosta); Vita-Salute
San Raffaele University, Milan, Italy (Filippi,
Cecchetti, Spinelli, Falini, Agosta); Neuroradiology
Unit and CERMAC (Centro Eccellenza Risonanza
Magnetica ad Alto Campo), Division of
Neuroscience, IRCCS Ospedale San Raffaele, Milan,
Italy (Vezzulli, Falini).
Author Contributions: Drs Cecchetti and Spinelli
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Filippi, Cecchetti, Vezzulli,
Falini, Agosta.
Acquisition, analysis, or interpretation of data:
Cecchetti, Spinelli, Agosta.
Drafting of the manuscript: Filippi, Cecchetti,
Spinelli, Vezzulli.
Critical revision of the manuscript for important
intellectual content: Filippi, Cecchetti, Spinelli,
Falini, Agosta.
Statistical analysis: Spinelli.
Administrative, technical, or material support:
Spinelli.
Supervision: Filippi, Spinelli, Falini.
Other: Vezzulli.
Other (literature review, figure creation): Cecchetti.
Conflict of Interest Disclosures: Dr Filippi
reported receiving personal fees from Alexion
Pharmaceuticals, Almirall SA, Bayer AG, Biogen Inc,
Celgene Corporation, Eli Lilly & Company,
Genzyme, Merck Serono, Novartis International AG,
La Roche AG, Sanofi SA, Takeda Pharmaceutical
Company Limited, and Teva Pharmaceutical
Industries Ltd; receiving institutional grants from
Biogen Idec, Merck Serono, Novartis International
AG, La Roche AG, and Teva Pharmaceutical
Industries Ltd outside the submitted work; and
serving as editor-in-chief of the Journal of
Neurology, associate editor of Human Brain
Mapping, associate editor of Radiology, and
associate editor of Neurological Sciences. Dr Agosta
reported receiving personal fees for consulting
services and/or speaking activities from F.
Hoffmann-La Roche AG, Biogen Inc, and Philips
outside the submitted work; serving as the
associate editor of NeuroImage: Clinical; and
receiving research support from Italian Ministry of
Health, AriSLA (Fondazione Italiana di Ricerca per la
SLA), and the European Research Council. No other
disclosures were reported.
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