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Alzheimer’s is the most frequent neurodegenerative disease. Currently about 60,000-70,000 Austrians are affected, it is estimated that there are about 25 million Alzheimer’s patients worldwide. The main risk factor is the increasing age. Given the demographic development experts expect a duplication of the Alzheimer’s prevalence within the next 20 to 25 years.
Alois Alzheimer, a German neurologist, first described the neuropathological features of AD back in 1906. He noticed extracellular amyloid plaques, intraneuronal neurofibrillay tangles and realized that the number of neurons was reduced in the brain of his patient. Nowadays, we not only know the main constituents of both the amyloid plaques and the neurofibrillary tangles, namely Aβ /its variants and Tau (hyperphosphorylated) but also have an understanding of the processes that culminate in the demise of neurons. Cerebral accumulation of Aβ is generally regarded as the upstream event. Aß exists in different forms and aggregation states. N-terminally truncated and pyroglutamate-modified forms of Aß have entered the focus of AD recent in the last couple of years. They are increasingly recognized to function as seed for Aβ aggregation. Aß (and in particular its pyroglutamated versions) is not only toxic by itself but was found to trigger tau pathology. Effects of both molecules end up in the demise of neurons with tau pathology being more directly involved in the death process. Based on this scenario it is postulated that therapeutic measures which decrease cerebral Aß-load can modify disease progression.
Leading symptom of the disease is the cognitive decline, initially the episodic memory is affected in particular. Besides memory, further higher brain functions are being affected by the disease. These include functional (activities of daily living) and behavioral domains. Following an insidious onset, the patient’s condition worsens progressively, and ultimately results in premature death. The duration of the disease from diagnosis to death is 8 years on average.
Nowadays, diagnosis is done by exclusion. It requires profound dementia and a 2-step procedure. As a first step, dementia needs to be registered. This requires progression to a stage where dementia significantly alters everyday’s life. In a second step, potential dementia causes other than AD are excluded. New diagnostic algorithms, as the one postulated by the group of Dubois, rely on specific memory deficits and combine them with emerging biomarkers of the disease. As a result, a diagnosis can be done earlier.
Currently approved AD drugs are of symptomatic benefit only and fall into two classes: acetylcholinesterase-inhibitors (AChE-I), which are represented by the three substances donezepil, rivastigmine and galantamine (all approved for mild to moderate AD ) and the non-competitive NMDA-receptor-antagonist memantine, which is approved for the treatment of moderate to severe AD since 2002. These drugs were found to improve cognitive symptoms of AD patients. Combination therapy (AChE-I and memantine) may be beneficial for moderate to severe AD. In particular memantine has been reported to improve behavioral symptoms associated with the disease.
Table: Drugs approved for AD therapy
AChE-I = Acetycholinesterase-Inhibitor, BuChE-I = Butyrylcholinesterase-Inhibitor; ACh = Acetylcholin; NMDA = N-Methyl-D-Aspartat (Glutamatreceptor)
