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Madera's Approach to Alzheimer’s Therapeutics: Beta Amyloid and the Inflammatory Response

Recently, the search for a treatment for Alzheimer's disease (AD) has reached a turning point.  New clinical tools to identify subjects that have Alzheimer’s disease, and methods to more accurately follow the progression of the disease, have significantly enabled clinical development of new therapies.  Biogen has presented clinical data showing for the first time therapeutic intervention changing the natural course of the disease (1).  In addition, reported studies in JAMA of 9500 subjects support the critical role of amyloid-beta (Aβ) early in the disease process (2). These studies provide further and substantial evidence for Aβ’s central role in the pathobiology of Alzheimer’s disease and support therapeutic intervention limiting undesirable Aβ-driven effects as a cornerstone of the management of AD, and perhaps the prevention of dementia.  

The Alzheimer's disease process may begin as early as two decades before clinical symptoms.  Therefore, early therapeutic intervention targeting the biological dysregulations, such as apolipoprotein E (ApoE) dysfunction and and tau accumulation that set the stage for the complex late-stage disease process, is required.  A polypharmacological approach, tailored to an individual’s unique disease state, may be optimal.

Most small molecule clinical agents, designed to limit undesirable Aβ in the brain, have thus far focused on the inhibition of Aβ production.  This approach was based on the hypothesis that AD patients have increased production of Aβ. However, a recent study has shown that Aβ accumulation in AD patient’s brains is due to a decreased ability of the patients to clear pathogenic Aβ peptide from their brains and not from an overproduction of Aβ (3). 

Approaches for early therapeutic intervention in the Alzheimer’s disease process - to prevent the progression to dementia - in many ways mirrors the successful strategies employed to prevent myocardial infarction and stroke by reducing lipid accumulation in blood vessels and by controlling hypertension.  However, in AD, the therapeutic intervention with biologics to remove rather than with small molecule therapeutics, over a long period of time and involving such a large patient population, will lead to significant pharmacoeconomic challenges.  An alternative to biologics for AD is Merck’s small molecule BACE inhibitor, MK-8931, currently under evaluation in a Phase 3 trial evaluating its effects on subjects with prodromal Alzheimer’s disease (4).  This may provide a cost-effective therapeutic.  However, safety concerns have stopped the progress of other experimental Alzheimer’s therapeutics that limit the production of Aβ, and ideally a Alzheimer’s drug given to patients over many years would have a similar safety profile as mainstream cardiovascular agents.


Development of an Beta Amyloid-Mediated Chronic Inflammatory State


Neuroinflammation plays a central role in Alzheimer’s disease pathology.  The interrelationship between Aβ and the inflammatory response in the brain continues to be elucidated.  Recent genetic studies have shown genes for immune receptors TREM2 and CD33 are associated with Alzheimer’s disease.   Furthermore, a rare mutation in TREM2 increases the risk of Alzheimer’s disease to a similar extent as ApoE4 (5). TREM2 is highly expressed in microglia and mediates phagocytic clearance of Aβ and neuronal debris. A feedback-back loop may develop for Aβ whereby the immune system’s response to Aβ, damaged cells, pathogens, and proinflammatory cytokines impairs microglial clearance of Aβ and increases APP processing (6). As shown above, Aβ and proinflammatory mediators favor an activation state for microglia that leads to the expression of proinflammatory cytokines and an impaired phagocytic capacity, hence a diminution of Aβ clearance.  In addition to the modulation of inflammation though the changes in Aβ, ApoE has been shown to suppress both LPS and oligomerized Aβ-induced TNFalpha secretion (7).


References:

(1) Biogen news release: http://media.biogen.com/press-release/corporate/biogen-idec-presents-positive-interim-results-phase-1b-study-investigational

(2) a) Jansen, W. J. et al, JAMA 2015; 313(19): 1924-1938.  b) Ossenkoppele, R. JAMA 2015; 313(19): 1939-1949.

(3) Mawuenyega, K. G. et al, Science 2010; 330: 1774.

(4) Merck news release: http://www.mercknewsroom.com/news-release/prescription-medicine-news/merck-advances-development-program-investigational-alzheimer

(5) Guerreiro, R. et al, N Engl J Med 2013; 368: 117-127.

(6) a) Heneka, M. T. et al, Lancet Neurol 2015; 14: 388-405.  b) Heneka, M. T. et al, Nat. Immun. 2015; 16(3): 229-236.

(7) Tai, L. M. et al, J. Neurochem. 2015; 133: 465-488.