Alpha Lipoic Acid for Alzheimer’s

Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70. Epub 2008 Jul 4.

Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease.

Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G.

Department of Pharmacology, School of Medicine, University of Western Sydney, Australia.


Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment – particularly for the early stages of disease – remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need.


A naturally occurring cofactor for the mitochondrial enzymes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, LA has been shown to have a variety of properties which can interfere with the pathogenesis or progression of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. In addition, LA down-regulates the expression of redox-sensitive pro-inflammatory proteins including TNF and inducible nitric oxide synthase. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein.


In human plasma, LA exists in an equilibrium of free and plasma protein bound form. Up to 150 muM, it is bound completely, most likely binding to high affinity fatty acid sites on human serum albumin, suggesting that one large dose rather than continuous low doses (as provided by “slow release” LA) will be beneficial for delivery of LA to the brain. Evidence for a clinical benefit for LA in dementia is yet limited. There are only two published studies, in which 600 mg LA was given daily to 43 patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of up to 48 months. Whereas the improvement in patients with moderate dementia was not significant, the disease progressed extremely slowly (change in ADAScog: 1.2 points=year, MMSE: -0.6 points=year) in patients with mild dementia (ADAScog<15). Data from cell culture and animal models suggest that LA could be combined with nutraceuticals such as curcumin, (-)-epigallocatechin gallate (from green tea) and docosahexaenoic acid (from fish oil) to synergistically decrease oxidative stress, inflammation, Abeta levels and Abeta plaque load and thus provide a combined benefit in the treatment of AD.



Alzheimer’s disease: the pros and cons of pharmaceutical, nutritional, botanical, and stimulatory therapies, with a discussion of treatment strategies from the perspective of patients and practitioners.

Wollen KA. Altern Med Rev. 2010 Sep;15(3):223-44. Review.


Ibuprofen and lipoic acid diamide as co-drug with neuroprotective activity: pharmacological properties and effects in beta-amyloid (1-40) infused Alzheimer’s disease rat model.

Di Stefano A, Sozio P, Cerasa LS, Iannitelli A, Cataldi A, Zara S, Giorgioni G, Nasuti C.

Int J Immunopathol Pharmacol. 2010 Apr-Jun;23(2):589-99.


Ibuprofen and lipoic acid diamides as potential codrugs with neuroprotective activity.

Sozio P, D’Aurizio E, Iannitelli A, Cataldi A, Zara S, Cantalamessa F, Nasuti C, Di Stefano A.

Arch Pharm (Weinheim). 2010 Mar;343(3):133-42.


The combination of exercise training and alpha-lipoic acid treatment has therapeutic effects on the pathogenic phenotypes of Alzheimer’s disease in NSE/APPsw-transgenic mice.

Cho JY, Um HS, Kang EB, Cho IH, Kim CH, Cho JS, Hwang DY.

Int J Mol Med. 2010 Mar;25(3):337-46.


Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks.

Bolognesi ML, Cavalli A, Bergamini C, Fato R, Lenaz G, Rosini M, Bartolini M, Andrisano V, Melchiorre C.

J Med Chem. 2009 Dec 10;52(23):7883-6.


[Progress in the research on multi-target-directed drugs against Alzheimer’s disease].

Liu RT, Lü QJ.

Yao Xue Xue Bao. 2009 Mar;44(3):258-63. Review. Chinese.


The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer’s disease.

Shenk JC, Liu J, Fischbach K, Xu K, Puchowicz M, Obrenovich ME, Gasimov E, Alvarez LM, Ames BN, Lamanna JC, Aliev G.

J Neurol Sci. 2009 Aug 15;283(1-2):199-206. Epub 2009 Apr 1.


MTDL design strategy in the context of Alzheimer’s disease: from lipocrine to memoquin and beyond.

Bolognesi ML, Rosini M, Andrisano V, Bartolini M, Minarini A, Tumiatti V, Melchiorre C.

Curr Pharm Des. 2009;15(6):601-13. Review.


Dietary supplementation with a combination of alpha-lipoic acid, acetyl-L-carnitine, glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to murine brain and improves cognitive performance.

Suchy J, Chan A, Shea TB.

Nutr Res. 2009 Jan;29(1):70-4.


Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer’s disease.

Siedlak SL, Casadesus G, Webber KM, Pappolla MA, Atwood CS, Smith MA, Perry G.

Free Radic Res. 2009 Feb;43(2):156-64.


Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease.

Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G.

Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70. Epub 2008 Jul 4. Review.


Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS.

Salinthone S, Yadav V, Bourdette DN, Carr DW.

Endocr Metab Immune Disord Drug Targets. 2008 Jun;8(2):132-42. Review.


Alpha-lipoic acid as a new treatment option for Alzheimer’s disease–a 48 months follow-up analysis.

Hager K, Kenklies M, McAfoose J, Engel J, Münch G.

J Neural Transm Suppl. 2007;(72):189-93.


Lipoic acid and N-acetyl cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts.

Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA, Perry G.

J Alzheimers Dis. 2007 Sep;12(2):195-206. Review.


Autophagocytosis of mitochondria is prominent in Alzheimer disease.

Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M, Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X, Perry G.

J Neuropathol Exp Neurol. 2007 Jun;66(6):525-32. Erratum in: J Neuropathol Exp Neurol. 2007 Jul;66(7):674.


Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease.

Abdul HM, Butterfield DA.

Free Radic Biol Med. 2007 Feb 1;42(3):371-84. Epub 2006 Nov 10.


Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias.

Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Münch G.

Pharmacol Ther. 2007 Jan;113(1):154-64. Epub 2006 Sep 20. Review.


Managing psychiatric disorders with antidiabetic agents: translational research and treatment opportunities.

McIntyre RS, Soczynska JK, Lewis GF, MacQueen GM, Konarski JZ, Kennedy SH.

Expert Opin Pharmacother. 2006 Jul;7(10):1305-21.


Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid.

Cui X, Zuo P, Zhang Q, Li X, Hu Y, Long J, Packer L, Liu J.

J Neurosci Res. 2006 Aug 15;84(3):647-54.


Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice.

Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE, Stackman RW Jr.

Neurobiol Aging. 2007 Feb;28(2):213-25. Epub 2006 Jan 31.

Leave a Comment

Your email address will not be published. Required fields are marked *