Emerging Therapies for Alzheimer’s Disease
Emerging Therapies for Alzheimer’s Disease
There is consensus among researchers that the biological basis of Alzheimer’s disease (AD) lies in the abnormal accumulation of toxic amyloid protein in the brain.1,2 In brief, the amyloid hypothesis of AD states that the amyloid precursor protein (APP), encoded on chromosome 21 and ubiquitously expressed as a glycosylated transmembrane protein, is abnormally cleaved into many products, including the toxic amyloid-β42 (Aβ42). This occurs when APP is processed via an amyloidogenic pathway via sequential cleavage by β-secretase and γ-secretase, leading to the production of Aβ. Aggregated Aβ42 then forms insoluble plaque, which is laid down in the brain. These plaques and/or the upstream events in their formation are believed to underlie the neuronal loss and cognitive decline of AD.3,4 As a result, future therapies hoping to modify the disease itself must focus on this process. Whether addressing the actual accumulation and deposition of amyloid protein or the downstream oxidative damage induced by amyloid protein, researchers are basing emerging drug therapies on this model of the disease.
As a result, disease-modifying therapies can be designed to intervene at several different points along the disease pathway. These approaches include: the inhibition of secretase enzymes to prevent the formation of Aβ42; specifically modifying the γ-secretase enzyme, which is likely to be instrumental in the production of toxic Aβ42, and shunting production away from this toxic product; preventing the aggregation of Aβ42, which is believed to be a central step in plaque deposition; and increasing the body’s clearance of toxic Aβ42.5 Currently, therapies available for AD can treat only symptomatic manifestations of the disease. These include drugs that increase intrasynaptic acetylcholine levels and modulate glutamatergic transmission in the brain. However, no currently approved treatments intervene to halt or reverse the disease process itself, which makes the approaches described above exciting lines of enquiry. The current status of many of these emerging therapies will be described in the following sections.
Inhibiting Aβ42 Production
The blockade of either β-secretase or γ-secretase would ultimately prevent production of Aβ42. As such, these enzymes have been widely studied targets for therapy. However, blocking these enzymes has proved to be quite difficult.5 As the β-secretase active site is quite large, passage of similarly large inhibitor molecules through the blood–brain barrier has been difficult.6On the other hand, γ-secretase inhibitors have run into problems in development due to intolerable side effects.7,8 Despite these challenges, trials examining both types of inhibitor are ongoing. In fact, LY450139 (Lilly), a γ-secretase inhibitor, is currently the subject of phase III trials.7,8 Phase II trials were a collaborative effort of the Alzheimer’s Disease Cooperative Study Group and the sponsor company. This was a multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial focused largely on safety and tolerability. Biomarker analysis of the treatment group showed that plasma Aβ40 decreased by 58.2% in the 100mg/day group and by 64.6% in the 140mg/day group. However, the decrease in cerebrospinal fluid (CSF) Aβ40 was smaller and not statistically significant. In addition, plasma Aβ response to the drug was biphasic, suggesting that a period of reduced Aβ is transient and followed by a period of elevated Aβ.7,8
- Cummings JL, N Engl J Med, 2004;351(1):56–67.
- Archer HA, et al., Ann Neurol, 2006;60(1):145–7.
- Hardy J, Selkoe DJ, Science, 2002;297(5580):353–6.
- Näslund J, et al., JAMA, 2000;283(12):1571–7.
- Christensen DD, CNS Spectr, 2008;13(2 Suppl. 2):10–14.
- Hussain I, IDrugs, 2004;7(7):653–8.
- Siemers ER, et al., Neurology, 2006;66(4):602–4.
- Siemers ER, et al., Clin Neuropharmacol, 2007;30(6):317–25.
- www.athenagen.com/index.php?/athenagen/press_releases/48
- Pangalos MN, et al., Biochem Soc Trans, 2005;33(Pt 4):553–8.
- Cordy JM, et al., Mol Membr Biol, 2006;23(1):111–22.
- Pappolla MA, et al., Neurology, 2003;61(2):199–205.
- Arvanitakis Z, et al., Neurology, 2008;70(19 Pt 2):1795–1802.
- Kukar T, et al., BMC Neurosci, 2007;8:54.
- Christensen DD, Prim Care Companion J Clin Psychiatry, 2007;9(1):32–41.
- Vardy ER, et al., Expert Rev Neurother, 2006;6(5):695–704.
- Aisen PS, et al., Curr Alzheimer Res, 2007;4(4):473–8.
- European trial of Alzhemed ends, marketing morphs to supplement: Alzheimer’s Research Forum, drug news, 2007. Available at: www.alzforum.org/new/detail.asp?id=1691 (last accessed October 15, 2008).
- www.transitiontherapeutics.com/technology/alzheimers.php
- Schenk D, et al., Nature, 1999;400(6740):173–7.
- Hock C, et al., Neuron, 2003;38(4):547–54.
- Nicoll JA, et al., Nat Med, 2003;9(4):448–52.
- www.elan.com/News/full.asp?ID=1166655
- Karuppagounder SS, et al., Neurobiol Aging, 2008; in press.
- Bachurin SO, et al., Ann N Y Acad Sci, 2003;993:334–44.
- Doody RS, et al., Lancet, 2008;372(9634):207–15.
- Eriksson PS, et al., Nat Med, 1998;4(11):1313–17.
- Tuszynsik M, et al., Neurology, 2004;62(Suppl. 5):A174–75.
