Alzheimer’s disease and its treatment–yesterday, today, and tomorrow

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 24, 2024

Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is most frequently diagnosed of dementias. a multi-factorial neurodegenerative disorder familial, life style comorbidity influences impacting global population more than 47 million projected escalation by 2050 to exceed 130 million. In USA demographic encompasses approximately six individuals, expected increase surpass 13 2050, antecedent phase AD, recognized as mild cognitive impairment (MCI), involves nearly 12 individuals. The economic outlay for management AD-related decline estimated at 355 billion USD. addition, intensifying prevalence cases countries modest intermediate income further enhances urgency therapeutically cost-effective treatments improving quality patients their families. This narrative review evaluates pathophysiological basis an initial focus on therapeutic efficacy limitations existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, N-methyl-D-aspartate receptor (NMDA) allosteric modulator, memantine. hypothesis amyloid-β (Aβ) tau are appropriate targets have potential halt progress critically analyzed particular clinical trial data anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab donanemab. challenges dogma targeting Aβ will benefit majority subjects MABs unlikely be “magic bullet”. A comparison benefits disadvantages different classes forms determining new directions research alternative drug undergoing pre-clinical assessments. we discuss stress importance treatment co-morbidities, including hypertension, diabetes, obesity depression known risk developing AD.

Language: Английский

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Conquering Alzheimer’s: a look at the therapies of the future

Nature, Journal Year: 2023, Volume and Issue: 616(7955), P. 26 - 28

Published: April 4, 2023

Language: Английский

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Alzheimer’s Disease: Models and Molecular Mechanisms Informing Disease and Treatments

Bioengineering, Journal Year: 2024, Volume and Issue: 11(1), P. 45 - 45

Published: Jan. 1, 2024

Alzheimer’s Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical hippocampal degeneration. This review captures the landscape understanding AD pathology, diagnostics, current therapies. Two major mechanisms direct pathology: (1) accumulation amyloid β (Aβ) plaque (2) tau-derived neurofibrillary tangles (NFT). The most common variants Aβ pathway APP, PSEN1, PSEN2 are largely responsible for early-onset (EOAD), while MAPT, APOE, TREM2 ABCA7 have modifying effect on late-onset (LOAD). More recent studies implicate chaperone proteins degrading AD. Several tests, such as cognitive function, brain imaging, cerebral spinal fluid (CSF) blood used diagnosis. Additionally, several biomarkers seem to unique specific combination expression could potentially be improved, less invasive diagnostics. In addition genetic perturbations, environmental influences, altered gut microbiome signatures, affect Effective treatments been challenging develop. Currently, there FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies an NMDA antagonist) that mitigate rate decline symptoms distress.

Language: Английский

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Multi-target-directed therapeutic strategies for Alzheimer’s disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

This review highlights the potential of multi-target-directed strategies that address amyloid-β aggregation, metal ion dyshomeostasis, and enzyme dysfunction, offering a comprehensive effective approach to treating Alzheimer's disease.

Language: Английский

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Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 279 - 279

Published: Jan. 23, 2025

Alzheimer’s disease (AD) is traditionally viewed through the lens of amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as main pathological culprits. However, burgeoning research points to brain’s resident immune cells, microglia, critical players in AD pathogenesis, progression, potential therapeutic interventions. This review examines dynamic roles microglia within intricate framework AD. We detail involvement these cells neuroinflammation, explaining how their activation response fluctuations may influence trajectory. further elucidate complex relationship between pathology. study highlights dual nature which contribute both aggregation clearance protein. Moreover, an in-depth analysis interplay unveils significant, yet often overlooked, impact this interaction on neurodegeneration Shifting from conventional approaches, we assess current treatments primarily targeting introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a paradigm shift management Finally, explore field precision diagnosis pursuit robust biomarkers. underline more profound comprehension biology could enrich essential areas, potentially paving way for accurate diagnostic tools tailored treatment strategies. In conclusion, expands perspective pathology treatment, drawing attention multifaceted microglia. As continue enhance our understanding microglial-focused interventions emerge promising frontier bolster arsenal fight against

Language: Английский

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Newer Therapeutic Approaches in Treating Alzheimer’s Disease: A Comprehensive Review

ACS Omega, Journal Year: 2025, Volume and Issue: 10(6), P. 5148 - 5171

Published: Feb. 3, 2025

Alzheimer's disease (AD) is an aging-related irreversible neurodegenerative affecting mostly the elderly population. The main pathological features of AD are extracellular Aβ plaques generated by APP cleavage through amyloidogenic pathway, intracellular neurofibrillary tangles (NFT) resulting from hyperphosphorylated tau proteins, and cholinergic neurodegeneration. However, actual causes unknown, but several studies suggest hereditary mutations in PSEN1 -2, APOE4, APP, TAU genes major perpetrators. In order to understand etiology pathogenesis AD, various hypotheses proposed. These include following hypotheses: amyloid accumulation, tauopathy, inflammation, oxidative stress, mitochondrial dysfunction, glutamate/excitotoxicity, deficiency, gut dysbiosis. Currently approved therapeutic interventions donepezil, galantamine, rivastigmine, which cholinesterase inhibitors (ChEIs), memantine, N-methyl-d-aspartate (NMDA) antagonist. treatment strategies focus on only symptomatic management attenuating symptoms not regeneration neurons or clearance Tau. This review focuses pathophysiology, novel targets, disease-altering treatments such as α-secretase modulators, active immunotherapy, passive natural antioxidant products, nanomaterials, antiamyloid therapy, aggregation inhibitors, transplantation fecal microbiota stem cells, microtubule stabilizers that clinical trials still under investigation.

Language: Английский

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The Roles of the Amyloid Beta Monomers in Physiological and Pathological Conditions

Biomedicines, Journal Year: 2023, Volume and Issue: 11(5), P. 1411 - 1411

Published: May 10, 2023

Amyloid beta peptide is an important biomarker in Alzheimer’s disease, with the amyloidogenic hypothesis as one of central hypotheses trying to explain this type dementia. Despite numerous studies, etiology disease remains incompletely known, pathological accumulation amyloid aggregates cannot fully complex clinical picture disease. Or, for development effective therapies, it mandatory understand roles at brain level, from its initial monomeric stage prior aggregation form senile plaques. In sense, review aims bring new, clinically relevant data on a subject intensely debated literature last years. first part, cascade reviewed and possible subtypes are differentiated. second played by monomers physiological (neurodegenerative) conditions illustrated based most recent studies published topic. Finally, considering importance pathophysiology new research directions diagnostic therapeutic impacts suggested.

Language: Английский

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Navigating the Maze of Alzheimer’s disease by exploring BACE1: Discovery, current scenario, and future prospects

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 98, P. 102342 - 102342

Published: May 16, 2024

Language: Английский

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Approaches for Increasing Cerebral Efflux of Amyloid-β in Experimental Systems

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 100(2), P. 379 - 411

Published: June 14, 2024

Amyloid protein-β (Aβ) concentrations are increased in the brain both early onset and late Alzheimer's disease (AD). In AD, cerebral Aβ production is its clearance decreased, while burden AD due to impaired clearance. has been focus of therapeutics since development amyloid hypothesis, but efforts slow progression by lowering failed until phase 3 trials with monoclonal antibodies lecanemab donanemab. addition promoting phagocytic Aβ, lower efflux Aβ-antibody complexes across capillary endothelia, dissolving aggregates, a "peripheral sink" mechanism. Although blood-brain barrier main route which soluble leaves (facilitated low-density lipoprotein receptor-related protein-1 ATP-binding cassette sub-family B member 1), can also be removed via blood-cerebrospinal fluid barrier, glymphatic drainage, intramural periarterial drainage. This review discusses experimental approaches increase these mechanisms, clinical applications approaches, findings patients or mild cognitive impairment. Based on negative previous targeting monomeric increasing unlikely if used as monotherapy. But an adjunct treatment donanemab, this approach might allow greater slowing than either antibody alone.

Language: Английский

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BACE1 inhibitor drugs for the treatment of Alzheimer's disease: Lessons learned, challenges to overcome, and future prospects^†

Global Health & Medicine, Journal Year: 2024, Volume and Issue: 6(3), P. 164 - 169

Published: June 5, 2024

Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around globe. Currently, there is no cure or effective treatment. The majority drug development efforts to date have targeted reduction amyloid-β peptide (Aβ). Drug through inhibition beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed live up expectations later phase trials, due toxicity and efficacy issues. This commentary aims provide brief review two decades challenges for treatment AD prospects future BACE1-based drugs.

Language: Английский

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