Have there been improvements in Alzheimer’s disease drug discovery over the past 5 years?

Abstract

Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013-2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (<1% each). Expert opinion: Unsuccessful outcomes in AD therapeutics are attributed to pathogenic misconceptions, erratic procedures in drug development and inappropriate regulations. Recommendations for the future are as follows: (i) the reconsideration of dominant pathogenic theories, (ii) the identification of reliable biomarkers, (iii) the redefinition of diagnostic criteria, (iv) new guidelines for disease management, (v) the reorientation of drug discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.

How plausible is an Alzheimer’s disease vaccine?

“…The purpose of a vaccine is not to resuscitate dying neurons but to prevent their premature neurodegeneration. Therefore, the clinical trial design has to be adapted to this new therapeutic modality, not reproducing obsolete procedures used for the clinical testing of symptomatic drugs (with no breakthroughs during the past 20 years) [1]. In this regard, regulatory authorities (FDA, European Medicines Agency, Koseisho, and other national regulators), together with the pharmaceutical industry and the scientific community, have to design novel protocols for preventive intervention in AD.…”

“…After almost 20 years of therapeutic stagnation in Alzheimer's disease (AD), despite important investment and scientific effort [1], some reflections are opportune concerning strategies in drug development, especially immunotherapy and AD vaccination. It was a great achievement to demonstrate that AD is the result of a neurodegenerative process which commences decades before the onset of the disease, caused by multifactorial events (genomic defects, epigenetic dysregulation, cerebrovascular damage, and diverse environmental factors), in order to implement potential prophylactic/preventive strategies.…”

Perspectives of stem cells use in alzheimer’s disease treatment

“…Serious cognitive dysfunctions in AD patients result from disruptions of neural circuitry due to failure in coordinated development of neural processes provoked by pathological events at the intra-and extracellular brain levels. [1][2][3] One of the key factors playing a role in this pathology is a defect in amyloid precursor protein excretion. [1][2][3] Excessive accumulation of amyloid beta in the brain is accompanied by the formation of plaques around the nerve cells.…”

“…[1][2][3] One of the key factors playing a role in this pathology is a defect in amyloid precursor protein excretion. [1][2][3] Excessive accumulation of amyloid beta in the brain is accompanied by the formation of plaques around the nerve cells. Noticeably, pathological processes develop not only in the intracellular matrix but also inside the neurons: it was shown that the content of microtubule-associated tau protein extremely increases in AD patients causing interruption of normal neural networks activity.…”

“…Noticeably, pathological processes develop not only in the intracellular matrix but also inside the neurons: it was shown that the content of microtubule-associated tau protein extremely increases in AD patients causing interruption of normal neural networks activity. 1,2 Based on these data, scientists and physicians are trying nano-and immunotherapy, anti-inflammatory and neuroprotective drugs along with removal of amyloids and tau protein excess off the brain, but no relief in brain's activity is observed. 1,2 One possible reason of the inefficacy of the current therapies is the absence of effective diagnostics at early stages.…”