Changing the Course of Alzheimer’s Disease: Anti-Amyloid Disease-Modifying Treatments on the Horizon

Objectives: To review the amyloid hypothesis as the predominant mechanistic theory of Alzheimer’s disease and update the status of new disease-modifying, anti-amyloid treatments in clinical development.

Data Sources: Governmental Web sites and those of professional Alzheimer’s disease associations and drug manufacturers were searched for new drugs in development. An English-language search of PubMed (January 2003-January 2006) was conducted using the search terms Alzheimer’s disease and amyloid hypothesis and each of the drugs and immunotherapies from the 4 identified classes of anti-amyloid, disease-modifying therapies.

Study Selection and Data Extraction: Studies and reports were selected on the basis of recent publication, adequate methodology, and completeness of data.

Data Synthesis: Immunotherapy, gamma-secretase inhibitors, selective neurotoxic aggregated 42-amino acid peptide subspecies of amyloid beta (Abeta₄₂)-lowering agents (tarenflurbil), inhibitors of amyloid aggregation (tramiprosate), and statins show promise in clinical trials. Safety remains an important factor. Disease-modifying drugs that specifically target the amyloid cascade and do not interact with essential biological pathways are expected to possess a lower rate of unintended adverse events.

Agents that selectively target Abeta₄₂ production (e.g., tarenflurbil), block Abeta aggregation (e.g., tramiprosate), or enhance alpha-secretase activity (statins) offer hope for disease modification and prevention and do not appear to interfere with other biological pathways.

Conclusions: Discovery of safe and effective disease-modifying therapies will usher in a new age of Alzheimer’s disease treatment.