Vascular Considerations for Amyloid Immunotherapy

Abstract

Purpose of Review
Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer’s disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides recommendations moving forward.

Recent Findings
In 20 years of both animal and human studies, anti-Aβ immunotherapies have been a prevalent avenue of reducing hallmark Aβ plaques. In both models and with different anti-Aβ antibody designs, amyloid-related imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning occurrence.

Summary
ARIA caused by anti-Aβ immunotherapy has been noted since the early 2000s, and the mechanisms driving it are still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aβ immunotherapy.

Full text

Current Neurology and Neuroscience Reports (2022) 22:709–719
Vol.:(0123456789)
1 3
https://doi.org/10.1007/s11910-022-01235-1
DEMENTIA (K.S. MARDER, SECTION EDITOR)
Vascular Considerations forAmyloid Immunotherapy
KateE.Foley1 · DonnaM.Wilcock1
Accepted: 18 September 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose of Review Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer’s dis-
ease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies
provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated
vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides rec-
ommendations moving forward.
Recent Findings In 20years of both animal and human studies, anti-Aβ immunotherapies have been a prevalent
avenue of reducing hallmark Aβ plaques. In both models and with different anti-Aβ antibody designs, amyloid-related
imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning
occurrence.
Summary ARIA caused by anti-Aβ immunotherapy has been noted since the early 2000s, and the mechanisms driving it are
still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aβ
immunotherapy.
Keywords Vascular· Alzheimer’s disease· Aducanumab· Amyloid· Immunotherapy· Biomarkers
Introduction
The accelerated approval of aducanumab under the FDA in
June 2021 as an anti-Aβ immunotherapy for Alzheimer’s
disease (AD) has reinvigorated the field to understand if
a reduction in amyloid burden in the brain results in cog-
nitive changes in humans and, further, what causes the
detrimental side effects known as amyloid-related imag-
ing abnormalities (ARIA). Decades of anti-Aβ immuno-
therapy research have resulted in a clear dichotomy of
researchers and clinicians that support or oppose the use
of these drugs. This review will detail both the findings
that paved the way for anti-Aβ immunotherapies in trials
today and evaluate key considerations moving forward.
Preclinical History ofAβ‑Immunotherapy
Research
Nuances andCharacterization oftheAβ Peptide
Methods to remove Aβ from the brain have been investigated
for over 20years. While amyloid plaques were identified and
described by Dr. Alois Alzheimer in 1906, it was the association
of the mutation in amyloid precursor protein, APP, which relayed
an autosomal dominant mode of AD inheritance that led to the
later “amyloid cascade hypothesis” [1–4]. Experiments starting
in the mid-1990s began to parse out the characteristics of the Aβ
peptide that led to it being the hallmark pathology in Alzheimer’s
disease. Early studies revealed that N-terminal deletions resulted
in the formation of Aβ into β-pleated sheets and showed increased
aggregation [5]. Additionally, Iwatsubo etal. identified the Aβ
peptide’s solubility as a key determinant in pathological toxicity,
highlighting that the C-terminus of Aβ is hydrophobic, and longer
C-termini (Aβ42) results in more, and earlier Aβ deposition in
the brain versus shorter isoforms [6]. Today we understand this
to be the insoluble Aβ1-42 peptide which is the primary form of
deposited plaques, while Aβ1-40 is found around the vasculature in
cerebral amyloid angiopathy (CAA) pathology [7, 8].
This article is part of the Topical Collection on Dementia
* Donna M. Wilcock
donna.wilcock@uky.edu
1 Sanders-Brown Center On Aging, Department
ofPhysiology, University ofKentucky, Lexington, KY, USA
/ Published online: 21 October 2022
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