Past and Future of Drug Treatments for Alzheimer's Disease

Seong Yoon Kim

doi:10.4306/jknpa.2018.57.1.30

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Kim: Past and Future of Drug Treatments for Alzheimer's Disease

Special Article

J Korean Neuropsychiatr Assoc 2018;57(1):30-42.

Published online: 17 January 2018

DOI: https://doi.org/10.4306/jknpa.2018.57.1.30

Past and Future of Drug Treatments for Alzheimer's Disease

Seong Yoon Kim, MD, PhD

Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Seong Yoon Kim, MD, PhD Department of Psychiatry, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel +82-2-3010-3417 Fax +82-2-485-8381 E-mail sykim@amc.seoul.kr

Revised 19 February 201819 February 2018 Accepted 21 February 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This study reviews evidence for the use of acetyl-choline esterase inhibitors (AChEIs) in treating Alzheimer's patients for the past decades. Even though large number of clinical trials have been conducted to prove the efficacy of these drugs in various clinical situations, questions remain to be answered due to the use of heterogeneous subject population, trial designs, and measurement tools in these studies. Many drugs with unproven clinical benefits, including vitamins, ginko biloba extracts, anti-inflammatory agents, estrogen hormone, and statins, are commonly prescribed in real-world settings for dementia patients. Despite the lack of clinical benefits statistically proven by clinical trials or metaanalyses, anecdotal dramatic improvements in some patients may foster such practices. A further look into why some patients benefit from these medications, while other don't, may shed light on future individually tailored medicine for dementia patients. This study provides a brief review of currently existing immuno-therapeutics in the hope that we can learn from the failures of the amyloid-based active and passive immunization. Issues that we need to address for the successful development of new anti-AD drugs include : 1) the brain pathology precedes clinical symptoms by several decades, 2) we need biological markers that reliably reflect cognitive or functional impairment of AD patients, and 3) we need more detailed and plausible explanations for our brain immune responses and neurodegenerative changes.

Keywords: Alzheimer's disease, Drug, Amyloid, Tau, Acetyl-choline esterase inhibitors

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Fig. 1.

Production of amyloid beta and the formation of amyloid beta oligomers. Modified from Cummings et al. Alzheimers Dement 2017;3:367-384.⁸¹⁾

Fig. 2.

Influence of amyloid beta oligomers with the mitochondrial oxidation, neuroinflammation, neuronal death and neurotransmitter de-⁸¹⁾

Fig. 3.

Agents in clinical trials for the treatment of Alzheimer's disease. Modified from Cummings et al. Alzheimers Dement 2017;3:367-384. ⁸¹⁾ ATP : Adenosine triphosphate, BNC : Bisnorcymserine, GM-CSF : Granulocyte-macrophage colony-stimulating factor, OAA : Ox-aloacetate, IVIG : Intravenous immunoglobulin, SLAT : Simvastatin 1 L-arginine 1 tetrahydrobiopterin.

Table 1.

Therapeutic strategies in Alzheimer's disease

Therapeutic strategies in Alzheimer's disease
1.	Modulating neurotransmission
	Cholinesterase inhibitors
	N-methyl D-aspartate receptor antagonism
	GABAergic modulation
	Serotonin receptor modulation
	Histaminergic modulation
	Adenosine receptor modulation
2.	Tau based therapies
	Tau phosphorylation inhibition
	Microtubule stabilization
	Blocking Tau oligomerization
	Enhancing Tau degradation
	Tau based immunotherapy
3.	Amyloid based strategies
	Secretase enzymes modulation
	Amyloid transport
	Preventing amyloid aggregation
	Promoting amyloid clearance
	Amyloid based immunotherapy
4.	Modulating intracellular signaling cascades
5.	Oxidative stress reduction
	Exogenous antioxidant supplementation
	Augmenting endogenous defense
6.	Mitochondrial targeted therapy
7.	Modulation of cellular calcium homeostasis
8.	Anti-inflammatory therapy
9.	Others
	Gonadotropin supplementation
	Lipid modifiers - Statins
	Growth factor supplementation
	Metal chelation
	Epigenetic modifiers
	Caspase inhibitors
	Nitric oxide synthase modulation
	Nucleic acid drugs
	Multi-target directed ligands

Modified from Anand et al. Neuropharmacology 2014;76 Pt A:27-50, with permission of Anand R.

⁷⁸⁾

Table 2.

Clinical trials of amyloid or tau based immuno-therapeutics

Agent	Sponsor	Target	Phase	Population
AADvac1	Axon Neuroscience	Anti-tau mAb	1, 2	Mild/mod AD
ABBV-8E12	AbbVie	Anti-tau mAb	2	Early AD
Aducanumab	Biogen	mAb targeting multiple forms of Aβ	1	HC-mild AD
Aducanumab	Biogen	mAb targeting multiple forms of Aβ	3	Early AD
Albumin and immunoglobulin	Grifols	Polyclonal antibody targeting multiple forms of Aβ	3	Mild/mod AD
BAN2401	Eisai	mAb targeting N terminal protofibrils	2	Early AD
CAD106	Novartis, NIA	Aβ1-6, active vaccine	2	AD, at risk
Crenezumab	Genentech	mAb targeting soluble oligomer and fibrillar Aβ	1, 2, 3	Mild/mod AD-ADAD
Gantenerumab	Roche, Lilly, AA	mAb targeting aggregated Aβ	2, 3	Prodromal-mild AD
Solanezumab	Lilly, Roche, AA	mAb targeting monomeric Aβ	2, 3	AD, at risk
KH6640	Kyowa Hakko Kirin	mAb targeting aggregated Aβ	1	AD
Lu AF20513	Lundbeck		1	Mild AD
NewGam 10% IVIG	Sutter Health	Polyclonal antibody targeting multiple forms of Aβ	2	Amnestic MCI
LY2599666 & solanezumab	Lilly	Combination of BACE inhibitor and MAb targeting monomeric Aβ	1	MCI due to AD
LY3303560	Lilly		1	MCI-mild AD
LY30032813	Lilly		1	MCI-mod AD
RO7105705	Genentech	Anti-tau mAb	1	Mild/mod AD
Solanezumab	Lilly	mAb targeting monomeric Aβ	3	Prodromal-mild AD
UB-311	United Neuroscience	mAb targeting N terminal Aβ1–14	2	Mild AD

Modified from Cummings et al. Alzheimers Dement 2017;3:367-384.

⁸¹⁾ AD : Alzheimer's disease, ADAD : Autosomal dominant Alzheimer's disease, mAb : Monoclonal antibody, MCI : Mild cognitive impairment, IVIG : Intravenous immunoglobulin, NIA : National Institute on Aging, BACE : β-site amyloid precursor protein cleaving enzyme

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