The strategy of Alzheimer's therapy is moving from targeting cholinergic structures and function, to modifying pathogenesis. We can visualize this passage as a gradual one going through several phases. Discoveries based on genetic analysis of human mutations, cellular biology and use of transgenic models of beta-amyloidosis, indicate as a most urgent question the validity of the hypothesis that A-beta is intimately, if not causatively, associated with AD. If this is the case, prevention of accumulation or reduction of beta-amyloid should not only ameliorate clinical manifestations, but slow down the progression of the disease. Following this strategy, subsequent phases of AD therapy will be developed and tested in clinical trials.
A Prevention Phase is to be established during the asymptomatic stage of the disease. This phase may include one or several of the following pharmacological approaches: anti-inflammatories, estrogens, anti-oxidants or cholesterol lowering drugs. These therapies need to span over a period of several years in order to be preventive, therefore, the choice is based not only on efficacy but also on side effects (see estrogens as an example).
A First Treatment Phase may be applied during the prodromic stage of the disease to individuals diagnosed with minimal cognitive or behavioral impairment being at risk to convert to AD. The treatment may consist of A-beta reducing interventions (secretase inhibitors, anti-aggregants or anti-folding drugs) or immunization. For the latter, there may be several methodologies available for immunization such as active immunization with immunoconjugates, passive immunization with selective monoclonal antibodies having A-beta targeted epitopes or combination with anti-inflammatories (to reduce microglial toxic reactions) alone or in combination with symptomatic cholinesterase inhibitors (ChEI) in order to potentiate cognitive effects. In addition, a new generation of non-symptomatic, bifunctional ChEI with potent anti-beta-amyloid and ChE inhibitory properties can be be tested.
A Second Treatment Phase may be necessary to reinforce immunization treatment and prolong its effect. The importance of controlling neurofibrillary degeneration should not be neglected in a therapeutic protocol of this kind, however, a direct intervention in this area of pathology is not presently available.
The possible outcome of these combined therapy phases may be a long term stabilization with a delay of the symptoms in the order of 3-5 years. This intervention could result in a reduction of the prevalence of the disease and have a significant impact on length of care and costs of the disease.
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