Alzheimer’s disease

About Alzheimer’s disease

Alzheimer’s disease is a chronic neurodegenerative condition that leads 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 ageing is normal, but in a disease such as Alzheimer’s, the decline begins earlier, and progresses faster. This rapid cognitive decline can have a dramatic effect on a person’s ability to function in normal daily life.

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

Alzheimer’s is a serious disease

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.

Worldwide, the aggregate estimated cost of dementia (of which 62% of sufferers are diagnosed with Alzheimer’s disease) is US$818 billion. Current conservative estimates expect the global cost to double by 2030.

ALZHEIMER’S DISEASE IS EMERGING AS THE MOST SIGNIFICANT HEALTH CHALLENGE OF OUR TIME

No cure and limited treatment options currently available

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 slow the 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 are therefore a vital hurdle to overcome before we see a significant reduction in the burden of this disease. Approximately 8% of those over the age of 65 are affected by mild cognitive impairment (MCI) due to Alzheimer’s Disease, translating to approximately 4.2 million patients in the US alone.

Association with excess cortisol underpins Xanamem as a potential treatment

While no single clear cause for the development of Alzheimer’s disease has been identified, there is strong evidence to support an association between excess cortisol – the “stress hormone”- and the development and progression of Alzheimer’s disease. Increasing age is the single biggest risk factor for developing Alzheimer’s disease, and more than half of cognitively normal 65 year-olds have been shown to have persistently raised cortisol – it appears that increasing cortisol is a consequence of normal aging. 

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

The 11β-HSD1 enzyme is highly concentrated in the hippocampus, frontal cortex and cerebellum, the areas of the brain associated with cognitive impairment in neurological diseases, including Alzheimer’s disease.

ACW Focus on Mild Cognitive Impairment due to Alzheimer’s Disease

Mild cognitive impairment (MCI) due to Alzheimer’s disease affects approximately 8% of those over 65 years of age. MCI represents a large unmet need, with a conversion rate to mild stage Alzheimer’s disease of approximately 10-15% per annum. Patients with MCI due to Alzheimer’s disease have the characteristic biomarker evidence of Alzheimer’s disease brain changes (for example, abnormal β-amyloid levels) as well as subtle problems with memory and thinking. While these changes do not have clear impacts on the day-to-day functioning of patients, they are detectable on sensitive neurophysiologic measures. 

In 2019, Actinogen completed a Phase II clinical trial for patients with mild dementia due to Alzheimer’s disease, known as XanADu and a Phase I dose escalation study in healthy elderly patients, known as XanaHES. Evidence of positive pro-cognitive effects produced by Xanamem in XanaHES have guided the development of Actinogen’s next study – targeting MCI due to Alzheimer’s Disease. This upcoming study bridges the gap between the healthy elderly and mild Alzheimer’s Disease patient populations and aligns with recent industry and regulatory shift towards clinical trials in the earliest stage of Alzheimer’s Disease process – prior to the onset of overt cognitive and functional symptoms.

Read more about Actinogen’s clinical trials here.

EXTERNAL LINKS

Dementia Australia: Help Sheets
https://www.dementia.org.au/resources/help-sheets

Alzheimer’s Association (United States): Brain Basics
https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour

Alzheimer’s Association (United States): Disease and the Brain
https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour

Alzheimer’s Society (United Kingdom)
http://www.alzheimers.org.uk/info/20033/publications_and_factsheets

Alzheimer’s Research (United Kingdom): Share The Orange
https://www.alzheimersresearchuk.org/orange/

PUBLICATIONS

Publications
Circulating cortisol and cognitive and structural brain measures

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. Neurology: 10-1212.

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

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. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

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

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. Neurobiology of Aging, 36, 601-607.

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

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. Nature Neuroscience, 1(1), 69-73.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Long-term cortisol measures predict Alzheimer disease risk

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

Hippocampal damage associated with prolonged glucocorticoid exposure in primates

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

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

Kimberley E. Stuart, Anna E. King, Carmen M. Fernandez-Martos, Mathew J. Summers & James C. Vickers 2018. Nature Scientific Reports 7: 2764.