Disease-Modifying Therapies in Alzheimer’s Disease
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Currently, there are no disease-modifying therapies available for Alzheimer’s disease (AD). Acetylcholinesterase inhibitors and memantine are licensed for AD and have moderate symptomatic benefits. Epidemiological studies have suggested that NSAIDs, estrogen, HMG-CoA reductase inhibitors (statins) or tocopherol (vitamin E) can prevent AD. However, prospective, randomised studies have not convincingly been able to demonstrate clinical efficacy. Major progress in molecular medicine suggests further drug targets.
The metabolism of the amyloid-precursor protein and the aggregation of its Aβ fragment are the focus of current studies. Aβ peptides are produced by the enzymes β- and γ-secretase. Inhibition of γ-secretase has been shown to reduce Aβ production. However, γ-secretase activity is also involved in other vital physiological pathways. Involvement of γ-secretase in cell differentiation may preclude complete blockade of γ-secretase for prolonged times in vivo. Inhibition of β-secretase seems to be devoid of serious adverse effects according to studies with knockout animals. However, targeting β-secretase is hampered by the lack of suitable inhibitors to date. Other approaches focus on enzymes that cut inside the Aβ sequence such as α-secretase and neprilysin. Stimulation of the expression or activity of α-secretase or neprilysin has been shown to enhance Aβ degradation. Furthermore, inhibitors of Aβ aggregation have been described and clinical trials have been initiated. Peroxisome proliferator activated receptor-γ agonists and selected NSAIDs may be suitable to modulate both Aβ production and inflammatory activation. On the basis of autopsy reports, active immunisation against Aβ in humans seems to have proven its ability to clear amyloid deposits from the brain. However, a first clinical trial with active vaccination against the full length Aβ peptide has been halted because of adverse effects. Further trials with vaccination or passive transfer of antibodies are planned.