Breaking Ground in Alzheimer’s with 10 Cutting-Edge Treatments Paving the Way in 2024

Alzheimer’s disease (AD) is a common and severe neurodegenerative disease, profoundly impacting the lives of millions globally. In recent years, with ongoing research into this disease, many new therapeutic approaches and diagnostic tools have been developed and applied. Among them, Leqembi (lecanemab), HT-ALZ, Simufilam, AR1001, Rexulti (Brexpiprazole), Buntanetap, pTau217 blood biomarker test, and amyloid beta blood test have shown promising results in AD treatment and diagnosis research and trials. This article will detail these studies and advancements.

Leqembi (Lecanemab)

Leqembi (Lecanemab) is a monoclonal antibody targeting beta-amyloid (Aβ) plaques, approved by the U.S. Food and Drug Administration (FDA) for AD treatment. This drug aims to reduce Aβ plaques in the brain, slowing cognitive decline in mild cognitive impairment or mild dementia patients.

Clinical trials have shown Leqembi significantly slows cognitive and functional decline, albeit less effective in females and APOE4 gene carriers [1]. Furthermore, Leqembi’s clinical application requires careful patient selection and safety monitoring, especially for patients on anticoagulants due to potential increased bleeding risk [2].

HT-ALZ

HT-ALZ affects the Substance P/neurokinin-1 receptor signaling pathway, presenting a new therapy against AD-related neuroinflammation and cognitive deficits [3]. Substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play crucial roles in various physiological and pathological processes, including pain transmission, inflammation, and cancer cell proliferation. The SP/NK1R complex further participates in neuroinflammation associated with infectious and neurodegenerative diseases.

By mitigating SP’s harmful effects, NK1R antagonists emerge as potential therapeutic approaches [4]. Through specific NK1 receptor antagonism, HT-ALZ not only lowers soluble Aβ levels in the brain interstitial fluid but also significantly reduces anxiety behaviors and enhances cognitive function in preclinical animal models.

Simufilam

Simufilam is a novel oral candidate drug under investigation for AD treatment potential. Targeting and reversing filamin A protein mutations, this drug improves cognitive function, reduces neuroinflammation, and decreases Tau protein hyperphosphorylation. Clinical trials show Simufilam significantly improves various AD-related physiological indicators and demonstrates safety and tolerability in long-term studies [5]. Additionally, Simufilam restores mTOR sensitivity to insulin, normalizing overactive mTOR activity in lymphocytes of AD patients [6].

AR1001

AR1001 is a highly selective and potent phosphodiesterase-5 (PDE5) inhibitor studied for AD treatment. Preclinical studies indicate AR1001 markedly improves AD pathology and symptoms, including promoting neuronal cell survival, inhibiting Aβ accumulation, and enhancing learning and memory functions. AR1001’s ability to selectively degrade cGMP is crucial for the nitric oxide/cGMP/CREB signaling pathway involved in learning and memory processes.

Rexulti (Brexpiprazole)

Brexpiprazole is a novel antipsychotic used to treat AD-related agitation symptoms. Two 12-week, randomized, double-blind, placebo-controlled trials showed Brexpiprazole 2 mg/day significantly improved Cohen-Mansfield Agitation Inventory (CMAI) scores, compared to placebo, in managing agitation symptoms. These trial results led to the FDA’s approval of Brexpiprazole for treating AD-related agitation symptoms.

Compared to existing second-generation antipsychotics, Brexpiprazole demonstrates lower metabolic abnormalities and stroke risk, with higher tolerability. Common side effects include headache and somnolence, mostly mild to moderate. Brexpiprazole is believed to act by partially agonizing 5-HT1A receptors and D2 receptors while antagonizing 5-HT2A and α1B/α2C adrenergic receptors, exhibiting antipsychotic and pro-cognitive effects in animal models.

Buntanetap

Buntanetap (also known as Posiphen or ANVS401) is a novel translational inhibitor suppressing the generation of various neurotoxic proteins, showing safety and potential in AD and Parkinson’s disease (PD) patients. In double-blind, placebo-controlled, multicenter studies of early AD and PD patients, Buntanetap demonstrated good safety and tolerability. Biomarker data indicates Buntanetap reduces neurotoxic protein and inflammation factor concentrations, improving axonal integrity and synaptic function.

By inhibiting neurotoxic aggregate proteins (such as Aβ, Tau protein, and α-synuclein) translation, Buntanetap restores axonal transport, reduces inflammation, and protects neurons from death. These effects are validated in animal models and clinical trials. In a phase II clinical trial, Buntanetap showed efficacy in AD and PD patients, supporting its progression to phase III clinical trials.

pTau217 Blood Biomarker Test

pTau217 (phosphorylated tau protein at position 217) is a novel AD biomarker critical for early detection and diagnosis. Studies show using pTau217 immunoassay technology for plasma testing accurately identifies AD pathology changes, with comparable accuracy to cerebrospinal fluid (CSF) biomarkers. pTau217 excels in early detecting AD pathology and cognitive decline, highly correlating with brain PET markers (such as Aβ and tau proteins), capable of detecting the disease before clinical symptoms appear.

In AD mouse models, increased pTau217 levels closely correlate with increased brain tau protein deposition, reflected in CSF pTau217 concentrations. Comparing different pTau sites’ biomarker performance, pTau217 outperforms pTau181 in predicting AD pathology relevance and distinguishing AD dementia from other neurodegenerative diseases. As AD progresses, plasma pTau217 concentration increases over time, closely associated with cognitive decline, indicating pTau217 as an effective marker for monitoring disease progression.

Aβ Blood Test

Aβ blood testing is an emerging method for early AD detection and diagnosis. Studies show using magnetic bead-based flow cytometry can simultaneously detect Aβ1-40, Aβ1-42, and Aβ oligomers in human plasma, exhibiting 70% sensitivity and 81% specificity in AD patients and controls. Platelets are identified as the primary source of Aβ in human blood, accounting for nearly 90% of total Aβ immunoreactivity. Utilizing immunoprecipitation combined with mass spectrometry for plasma Aβ biomarker measurement shows good detection performance, with approximately 90% accuracy in predicting brain Aβ content.

Additionally, the Aβ42/40 ratio in plasma correlates significantly with brain Aβ deposition, indicating plasma Aβ as a potential biomarker for predicting brain Aβ deposition. Measuring the Aβ42 and Aβ40 ratio in plasma using fully automated immunoassay accurately predicts AD-related brain Aβ status, further improving diagnostic accuracy when combined with APOE genotype analysis. Overall, detecting plasma Aβ concentrations and oligomerization status provides a non-invasive and highly sensitive diagnostic tool.

Recent Advances in Alzheimer’s Disease Treatment and Diagnosis Outline Promising Paths Forward

In summary, there have been significant advancements in AD treatment and diagnosis research in recent years. From new drugs like Leqembi (lecanemab), HT-ALZ, Simufilam, AR1001, and Buntanetap to new diagnostic tools like pTau217 blood biomarker test and Aβ blood test, these studies and findings bring new hope for AD patients. However, clinical application of these treatment methods and diagnostic tools still faces many challenges, requiring careful consideration in patient selection, monitoring side effects, and resource allocation. Through ongoing research and collaboration, it is hoped that more effective treatment methods will be developed in the future to improve the quality of life for AD patients.

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Author

Bernice Lottering