Alzheimer's Disease

Alzheimer’s disease is a chronic neurodegenerative condition leading to rapid cognitive decline. ‘Cognition’ relates to how a person understands and acts in the world around them. Cognitive functions include memory, reasoning, awareness and decision-making, and to a large extent, influences our personality.

A gradual decline in cognitive function with age is normal, but in certain diseases, like Alzheimer’s, the decline begins earlier, and at a faster pace. The rapid cognitive decline can have a dramatic effect on a person’s ability to function in normal daily life, also affecting their family and the community around them.

Alzheimer’s disease is characterised by the presence of abnormal protein build-up in the brain, called amyloid plaques, with associated nerve cell degeneration and death, and loss of brain volume. It is not clear why these changes occur and what causes the rapid degeneration and death of the nerve cells. Unfortunately, the few drugs that are available to treat Alzheimer’s disease provide only a limited symptomatic benefit and do not slow down neurodegeneration.

As the leading cause of death in the UK, and second only to heart disease in Australia, Alzheimer’s disease is poised to become the next global public health crisis. There are almost 50 million Alzheimer’s disease sufferers world-wide and the number is set to double every 20 years. In the US alone, the cost of managing Alzheimer’s disease in 2013 was estimated at US$250bn, reaching US$1 trillion by 2050.

Alzheimer's disease is emerging as the most
significant health challenge of our time

Of the top ten fatal illnesses, Alzheimer’s disease remains the only one that cannot be prevented, treated or cured. None of the current treatment options provide much more than short-term relief of dementia symptoms, and significantly, none can slow the progression of the disease.  Alzheimer’s disease sufferers desperately need new alternative treatment options, and ideally, drugs with the potential to reverse the decline in brain function or to slow disease progression.

Alzheimer’s disease develops years before the symptoms of dementia appear. It is likely that brain pathology begins up to 15 years before the appearance of mild cognitive impairment or clinical dementia. Earlier diagnosis and treatment is therefore a vital hurdle to overcome before we see a significant reduction in the burden of this disease.

While no single clear cause for the development of Alzheimer’s disease has been reported, there is strong evidence to support an association between excess cortisol – the “stress hormone”- and the development of Alzheimer’s disease. Excess cortisol has been shown to cause cognitive decline, lead to β-amyloid plaque deposition and neurotoxicity in the brain, and loss of brain volume, all hallmarks of Alzheimer’s disease.

Actinogen Medical’s drug candidate Xanamem has been specifically designed to inhibit the production of cortisol in the brain by blocking the activity of a specific enzyme, 11β-HSD1. Blocking this enzyme prevents conversion of the inactive cortisone into the active cortisol.

PUBLICATIONS

Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease

Endocrinology, 1-12. Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. (2015).

Selection and early clinical evaluation of the brain-penetrant 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™)

British Journal of Pharmacology. Scott P Webster, AndrewMcBride, Margaret Binnie, Karen Sooy, Jonathan R Seckl, Ruth Andrew, T David Pallin, Hazel J Hunt, Trevor R Perrior, Vincent S Ruffles, J William Ketelbey, Alan Boyd and Brian R Walker (2017).

Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors

Bioorganic & medicinal chemistry letters, 17(10), 2838-2843. Webster, S. P., Ward, P., Binnie, M., Craigie, E., McConnell, K. M., Sooy, K., Vinter, A., Seckl, J.R. & Walker, B. R. (2007).

Circulating cortisol and cognitive and structural brain measures

Neurology: 10-1212. Echouffo-Tcheugui, Justin B., Sarah C. Conner, Jayandra J. Himali, Pauline Maillard, Charles S. DeCarli, Alexa S. Beiser, Ramachandran S. Vasan, and Sudha Seshadri (2018)

Environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer’s model

Scientific Reports 7: 2764, DOI:10.1038/s41598-017-03016-0. Kimberley E. Stuart, Anna E. King, Carmen M. Fernandez-Martos, Mathew J. Summers & James C. Vickers (2017)

Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. Robert H. Pietrzak, Simon M. Laws, Yen Ying Lim, Sophie J. Bender, Tenielle Porter, James Doecke, David Ames, Christopher Fowler, Colin L. Masters, Lidija Milicic, Stephanie Rainey-Smith, Victor L. Villemagne, Christopher C. Rowe, Ralph N. Martins, and Paul Maruff, for the Australian Imaging, Biomarkers and Lifestyle Research Group (2017).

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type

Neurobiology of Aging, 36, 601-607. Popp, J., Wolfsgruber, S., Heuser, I., Peters, O., Hull, M., Schroder, J., Moller, H. J., Lewczuk, P., Schneider, A., Jahn, H., Luckhaus, C., Perneczky, R., Frolich, L., Wagner, M., Maier, W., Wiltfang, J., Kornhuber, J., & Jessen, F. (2015).

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

Nature Neuroscience, 1(1), 69-73. Lupien, S. J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N. P. V., Thakur, M., McEwen, B. S., Hauger, L., & Meaney, M. J. (1998).

Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia

American Journal of Psychiatry, 163, 2164-2169. Csernansky, J. G., Dong, H., Fagan, A. M., Wang, L., Xiong, C., Holtzman, D. M., & Morris, J. C. (2006).

Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia

Neurology, 85(11), 976-983. Geerlings, M. I., Sigurdsson, S., Eiriksdottir, G., Garcia, M. E., Harris, T. B., Gudnason, V., & Launer, L. J. (2015).

Plasma cortisol levels, brain volumes and cognition in healthy elderly men

Psychoneuroendocrinology, 30(5), 505-515. MacLullich, A. M., Deary, I. J., Starr, J. M., Ferguson, K. J., Wardlaw, J. M., & Seckl, J. R. (2005).

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Nature reviews neuroscience10(6), 434-445. Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009).

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease

Biological psychiatry, 46(12), 1595-1602. Starkman, M. N., Giordani, B., Gebarski, S. S., Berent, S., Schork, M. A., & Schteingart, D. E. (1999).

Translational Research in Stress Neuroendocrinology: 11β‐Hydroxysteroid Dehydrogenase 1 (11β‐HSD1), A Case Study

Neuroendocrinology of Stress, 327-350. Reynolds, R. M., & Webster, S. P. (2015).

Glucocorticoids increase amyloid beta and tau pathology in a mouse model of Alzheimer’s disease

J. Neurosci. 26: 9047–56 Green K.N., Billings L.M., Roozendaal B. et al. (2006).

Combined plasma and cerebrospinal fluid signature for the prediction of midterm progression from mild cognitive impairment to Alzheimer disease

JAMA neurology, 73(2), 203-212. Lehallier, B., Essioux, L., Gayan, J., Alexandridis, R., Nikolcheva, T., Wyss-Coray, T., & Britschgi, M. (2016).

Long-term cortisol measures predict Alzheimer disease risk

Neurology, 88(4), 371-378. Ennis, G. E., An, Y., Resnick, S. M., Ferrucci, L., O’brien, R. J., & Moffat, S. D. (2017).

Hippocampal damage associated with prolonged glucocorticoid exposure in primates

J Neurosci. 10: 2897–2902. Sapolsky RM, Uno H, Rebert CS et al. (1990).

11β-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

PNAS, 101(17), 6734-6739. Sandeep, T. C., Yau, J. L. W., MacLullich, A. M. J., Noble, J., Deary, I. J., Walker, B. R., & Seckl, J. R. (2004).

Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease

Endocrinology, 1-12. Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. (2015).

Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning

Neuropharmacology, 81, 231-6. Sarabdjitsingh, R. A., Zhou, M., Yau, J. L., Webster, S. P., Walker, B.R., Seckl, J. R., Joëls, M., & Krugers, H. J. (2014).

11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline

Journal of Neurobiological Aging, 33(1), 5406-13. MacLullich, A. M. 1., Ferguson, K. J., Reid, L. M., Deary, I. J., Starr, J. M., Wardlaw, J. M., Walker, B. R., Andrew, R., & Seckl, J. R. (2012).

Acute inhibition of 11beta-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition

Journal of Neuroscience, 31(4), 5406-13. Mohler, E. G., Browman, K. E., Roderwald, V. A., Cronin, E. A., Markosyan, S., Scott Bitner, R., Strakhova, M. I., Drescher, K. U., Hornberger, W., Rohde, J. J., Brune, M. E., Jacobson, P. B., & Rueter, L. E. (2011).

11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments

Journal of Neuroscience, 30(20), 6916-20. Holmes, M. C., Carter, R. N., Noble, J., Chitnis, S., Dutia, A., Paterson, J. M., Mullins, J. J., Seckl, J. R., Yau, J.L. (2010).

Partial deficiency or short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice

Journal of Neuroscience, 30(41), 13867-13872. Sooy, K., Webster, S. P., Noble, J., Binnie, M., Walker, B. R., Seckl, J. R., & Yau, J. L. W. (2010).