ALZHEIMER'S DISEASE (AD)

The preceding text provides a basis for understanding diagnostic and therapeutic strategies under current experimental and clinical scrutiny.

In the near future, physicians will be able to initiate amyloid-oriented screening maneuvers to assess their patients' risk of developing Alzheimer's disease. Conceivably, tests will include screening for genetic risk factors (ApoE4, others), plasma amyloid levels, volumetric brain scan, brain imaging to visualize amyloid deposits and explore the function of specific brain regions (temporal and limbic lobes), and, depending upon noninvasive findings, possibly cerebrospinal fluid examinations (e.g., amyloid and tau protein levels, requires lumbar puncture). Screening is crucially important because currently considered therapies may be expected to be predominantly prophylactic rather that curative (no compensation for nerve cell loss). Unfortunately, such screening can be anticipated to be very costly.

Prevention of the formation of toxic amyloid fragments

Perhaps the most obvious therapy is to develop inhibitors of the beta and gamma secretases that cut amyloid precursor protein (APP) into toxic fragments (Aβ42). Numerous gamma secretase inhibitors have been developed and shown to reduce Aβ deposition in mouse models, but only one drug has advanced to clinical trial. The development of beta secretase inhibitors has lagged behind, but may be theoretically more promising. Experiments in mice with genetically suppressed beta secretase (knock out models) are encouraging.

Very recently, FDA-approved anti-inflammatory agents (ibuprofen [Vicoprofen ®], sulindac [Clinoril ®], and indomethacin [Indocin ®] ) have been shown to lower levels of injurious amyloids (Aβ42) independently of the anti-rheumatic (anti-cyclo-oxygenase) target of the drugs (Nature 2001; vol.414, pages 212-216). The drugs appear to act by altering APP degradation to less injurious fragments (Aβ38), a finding suggesting an action through gamma secretase modulation.

Stimulation of clearance of amyloid fragments

As mentioned above, clearance of injurious amyloid fragments partly depends on cholesterol metabolism, and Aβ deposition may be reduced by interventions lowering blood cholesterol (LDL or bad cholesterol) such as low cholesterol diet or statin drugs. Mechanisms of action are complex and may involve effects on amyloid clearance as well as beneficial effects on brain vessels.

Prevention of amyloid aggregation

Agents that tightly bind certain metal ions (chelators) may help to prevent Aβ aggregation and hence plaque formation. One agent under clinical trial is clioquinol.

Immunological neutralization of toxic amyloid fragments

The mechanism by which immunization against beta amyloid might exert salutary effects is rather controversial. Aβ42 immunization (stimulation of generation of antibodies targeting toxic amyloids) was initially thought to be well tolerated by humans, but a phase II trial was discontinued because of inflammatory responses involving tissue around (meningitis) and within the brain (encephalitis). Amyloid-antibody complexes may enhance amyloid clearance by stimulating a cell-mediated uptake (phagocytosis by microglia cells) and disposal of the complexes.

Gene therapy

In the more distant future, genetic interventions to either suppress abnormal gene expression (RNA message suppression) and/or substitute lacking normal genes by introducing DNA into the brain (transfection) is theoretically possible. Another possibility is to introduce into the brain new cells (neural stem cells) that might for instance express neuro-protective (anti-cell-death or anti-apoptotic) or neuro-regenerative factors.