Novel Treatments Could Turn the Tide for Alzheimer Disease

Alzheimer disease (AD) is an age-related neurodegenerative condition that is multifaceted, intricate, irreversible and advances over time. In individuals older than 60 years, the incidence of AD doubles every 10 years.¹ Progressive memory loss and functional impairment are typical features of AD. Patients with AD experience behavioral and psychological dementia symptoms, such as delusions, misinterpretations, mood swings, and behavioral abnormalities.²

The most common cause of dementia, AD, is identified by the co-occurrence of tau and amyloid.³ β-amyloid (Aβ) and tau are 2 misfolded proteins that are considered the pathological hallmarks of AD. Tau accumulation is linked with Aβ deposition,⁴ whereas neurodegeneration, brain atrophy, and glucose hypometabolism are linked with tau accumulation.^5,6

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Current therapies are unable to stop the progression of AD or produce adequate therapeutic results, despite the significant and long-lasting symptoms. Acetylcholinesterase inhibitors (AChEIs) and NMDA-receptor antagonists (NMDAR) are part of the existing approved therapy, but their combination only offers momentary symptom relief. The FDA-approved medications to treat AD are galantamine (Razadyne; Janssen), donepezil (Aricept; Eisai Inc. and Pfizer), rivastigmine (Exelon; Novartis), and memantine (Namenda; AbbVie). AChEIs comprise the first 4 medications, whereas NMDAR antagonists make up the final medication.

AChEIs are recommended as the first-line medication for mild to moderate AD in American and European guidelines. AChEIs, however, only exhibit non-significant efficacy on functional ability and only modest effects on cognitive deficits in mild to moderate AD.⁷ Without any functional improvement, memantine's effectiveness in treating cognitive symptoms is quite limited.⁸ According to the amyloid hypothesis, one of the main causes of AD pathogenesis is Aβ formation and one of AD's current therapy goals is to reduce the buildup of Aβ. Immunotherapy directed against amyloids is a therapeutic strategy examined by the relevant authorities to combat AD.⁹

Aducanumab (Aduhelm; Biogen), an anti-amyloid immunotherapy for AD, was controversially given fast track FDA approval in June 2021 after showing a decrease in Aβ; still, it is unknown if it will stop cognitive deterioration in patients with early AD, and adverse effects are frequent.^10,11 As a result of aducanumab's ambiguous clinical benefits, the US Centers for Medicare and Medicaid Services declared that any future anti-amyloid antibodies that the FDA approved would need to undergo more research and said the agency would only pay for aducanumab treatment for patients enrolled in clinical trials.¹²

Research on numerous novel anti-amyloid treatments is still ongoing.¹³ According to data from a recent 18-month clinical trial, lecanemab (Leqembi; Eisai) demonstrated less cognitive and functional deterioration when compared to a placebo.¹⁴ Lecanemab was recently given full approval by the FDA15 and is thought to target the most toxic pathologic amyloid species. It exhibited high selectivity for soluble aggregated species of Aβ when compared with monomeric amyloid and moderate selectivity for fibrillar amyloid.^16-20 The mean amyloid level of 22.99 centiloids in the lecanemab group, following 18 months of treatment in the amyloid sub-study, was below the threshold for amyloid positivity of about 30 centiloids, above which participants are considered to have elevated brain amyloid levels.²¹ Except for neurofilament light chain, which is less sensitive to neurodegeneration than the other markers and changes more slowly than the others, lecanemab significantly decreased markers of amyloid, tau, neurodegeneration, and neuroinflammation in the cerebrospinal fluid sub-study, and plasma analyses involving the entire population. According to van Dyck et al., infusion-related responses accounted for the majority of adverse events (affecting over 10% of participants) in the lecanemab group (26.4% with lecanemab and 7.4% with placebo).¹⁴

The need for novel AD treatments has reached a critical point. Researchers from all around the world are working hard to find new targets and create innovative therapeutic molecules to treat AD. Anti-amyloid antibody administration decreased plaque volume in clinical trials of patients with early AD, indicating that passive immunotherapies could be a promising treatment for the disease.

References

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