Challenges in the treatment of Alzheimer’s disease: recent progress and treatment strategies of pharmaceuticals targeting notable pathological factors

ABSTRACT

Introduction: Alzheimer’s disease (AD), a commonly encountered neurodegenerative disorder, causes cognitive decline and has a devastating effect on the quality of life. AD occurs mainly through abnormal amyloid β peptide (Aβ) and tau protein (tau) activity around/in neurons. Aβ-based therapeutic techniques have been struggled to treat AD over the past few decades. In addition, the complexity in treating AD is due to diverse factors regulating its pathology.

Areas covered: This review emphasizes recent advances regarding various pathological approaches and provides an overview of the most recent medications for AD. The authors focus on the regulatory factors, which mediate AD pathology, and discuss a variety of newly developed drugs and compounds used to inhibit β-secretase and γ-secretase activity, remove oligomeric Aβ and aggregated Aβ that is given responsibility in the amyloid cascade hypothesis, prevent tau hyperphosphorylation, restrain phosphorylated tau (p-tau) aggregation, remove aggregated p-tau that is proposed in tauopathy, and other related pathways.

Expert opinion: The approaches to the treatment of AD towards Aβ and tau have failed in most clinical attempts due to insufficient disease models arising from complex AD biology. It is the time to look for other approaches and pathological factors to cure AD.

KEYWORDS:

• Alzheimer’s disease
• pathology
• amyloid cascade hypothesis
• tauopathy
• regulatory factor
• inhibitor

Article highlights

• Drugs targeting Aβ resulted generally in failure in clinical trials, and removal of amyloid from AD brain did not cure AD.

• Immense threat from Aβ appeared by causing tau phosphorylation, α-synuclein aggregation, type II diabetes, and cardiovascular diseases.

• Drugs developed to target tauopathy can be promising in treating AD and in finding cure for AD.

• Targeting HSV1, GLP-1 receptors, DPP4 and neurotrophins can be effective approaches to suppress AD syndrome.

• Since iPSCs are derived from gene-reprogramming biotechnology, iPSC-based disease model can be of potential for analyzing familial AD.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work is funded by the Ministry of Science and Technology of the Republic of China under the grant numbers [MOST 103–2221–E–194–043–MY3, MOST 105–2811–E–194–005– and MOST 106–2811–E–194–002].