Sažetak sa skupa
https://doi.org/10.21857/ypn4oc4189
New possible treatments for dementia
Nenad Bogdanović
; Karolinska University Hospital
*
* Dopisni autor.
Sažetak
Dementias are complex neurodegenerative and cerebrovascular disorders that necessitate distinct pharmacological
strategies due to their diverse pathological mechanisms. Among the most prevalent forms
are Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia.
While no curative treatment currently exists to halt disease progression, recent advancements in Alzheimer’s
research have introduced therapeutic approaches aimed at slowing neurodegeneration.
A dominant framework in Alzheimer’s disease pathophysiology is the amyloid cascade hypothesis,
which posits that the accumulation of β-amyloid (Aβ) in the brain initiates a sequence of neurodegenerative
events, ultimately leading to widespread neuronal degeneration and cognitive impairment. Aβ
is a ubiquitous protein with several essential functions, including synaptic regulation, injury recovery,
microangiogenesis, cell growth inhibition, antimicrobial activity, and maintenance of the blood-brain
barrier. In individuals with Alzheimer’s disease, Aβ accumulation begins 15 to 20 years before the onset
of clinical symptoms. The etiology of this accumulation differs between early-onset and late-onset
Alzheimer’s; in early-onset cases, overproduction of Aβ drives its pathological aggregation, whereas
in late-onset cases, impaired clearance mechanisms are primarily responsible. Current symptomatic
therapies do not facilitate Aβ clearance; however, experimental and clinical studies involving monoclonal
antibodies have demonstrated promising efficacy in reducing amyloid burden and slowing disease
progression.
Recent FDA-approved monoclonal antibodies, such as lecanemab and donanemab, have garnered
significant attention for their ability to target Aβ fibers, remove Aβ plaques, and mitigate cognitive
decline. Clinical trials indicate that these therapies can slow cognitive decline by approximately 30
percent over 18 months. Lecanemab preferentially binds to Aβ protofibrils, preventing the formation
of mature plaques, whereas donanemab binds to existing amyloid plaques, facilitating their rapid
clearance via immune-mediated mechanisms. Both therapies, however, are associated with amyloidrelated
imaging abnormalities (ARIA), including cerebral oedema and microhemorrhages. Notably, the
incidence of ARIA is lower with lecanemab compared to donanemab.
To address the limitations of first-generation monoclonal antibodies, trontinemab, a novel therapeutic
currently in late-stage development, employs a brain shuttle mechanism that enhances blood-brain
barrier penetration. Unlike lecanemab and donanemab, trontinemab incorporates a transferrin receptor
binding domain, allowing superior brain penetration at lower doses, thereby improving efficacy
while reducing systemic exposure and side effects.
Despite the therapeutic promise of monoclonal antibodies, their clinical application necessitates stringent
patient selection. These treatments are indicated exclusively for early-stage Alzheimer’s disease,
specifically in individuals with mild cognitive impairment or mild dementia, representing only 10
to 20 percent of patients. They do not provide significant benefit in moderate or severe Alzheimer’s
disease, where extensive neurodegeneration has already occurred.
Prior to initiating treatment, confirmation of Aβ pathology via PET imaging or cerebrospinal fluid
biomarkers is mandatory. Additionally, APOE genotype testing is strongly recommended due to its significant influence on treatment safety. Carriers of the APOE ε4 allele, particularly homozygous ε4/
ε4 individuals, exhibit the highest ARIA risk, with approximately 30 to 40 percent developing complications.
Heterozygous ε3/ε4 carriers face a moderate risk, while non-carriers (ε3/ε3 or ε2/ε3) are
at lower risk. Given these risks, APOE ε4 carriers require enhanced MRI surveillance throughout the
course of treatment.
The efficacy and safety of monoclonal antibody therapy are also influenced by patient comorbidities.
Individuals with a history of stroke, cerebral microbleeds, or severe cardiovascular disease are at an
increased risk of ARIA and may not be suitable candidates. Furthermore, patients on anticoagulant
therapy, such as warfarin or direct oral anticoagulants, face an elevated risk of intracranial hemorrhage.
Those with severe hepatic or renal impairment may also have altered drug metabolism and clearance,
necessitating careful assessment prior to treatment initiation.
Beyond clinical considerations, logistical challenges further limit widespread implementation. The
administration of monoclonal antibodies requires specialized infusion centers, highly trained medical
personnel, and frequent MRI monitoring, significantly increasing healthcare burdens. MRI scans are
required at baseline and at regular intervals, such as at one, three, and six months’ post-initiation, to
monitor ARIA. Additionally, the high cost of treatment remains a major barrier, restricting access to
only a subset of eligible patients.
In conclusion, monoclonal antibody therapy represents a significant milestone in the treatment of
Alzheimer’s disease, offering moderate yet meaningful cognitive benefits in select patient populations.
However, stringent patient selection criteria, the risk of ARIA, the necessity for continuous MRI surveillance,
and cost constraints pose substantial challenges to widespread clinical adoption. While these
therapies mark a critical advancement in Alzheimer’s disease management, their long-term clinical
impact and cost-effectiveness remain areas of ongoing investigation.
Ključne riječi
Alzheimer, amyloid, antibodies, lecanemab, donanemab
Hrčak ID:
333472
URI
Datum izdavanja:
25.6.2025.
Posjeta: 401 *