Ten years ago, when considering Alzheimer's prevention research, it was predominately limited to healthy lifestyle interventions, vitamins and supplements. This has recently changed, with clinical trials of experimental treatments being tested or planning to be tested in high-risk populations. These populations include, but are not limited to, autosomal dominant Alzheimer's disease mutation carriers, apolipoprotein E (APOE) 4 carriers and older adults with significant fibrillar amyloid deposits. There are many reasons why some researchers, pharmaceutical companies and regulatory agencies are beginning to embrace this approach.
Biological Changes Occur Before Impairment
Perhaps one of the greatest catalysts is the growing evidence from natural history, epidemiological and biomarker studies of individuals at risk for developing Alzheimer's because of age, genetics, family history or other factors. This evidence has led to a greater understanding of disease progression and a recognition that the pathogenic cascade of Alzheimer's disease begins at least one to two decades before cognitive impairment.
Efforts from the Dominantly Inherited Alzheimer's Network (DIAN) and the Alzheimer's Prevention Initiative that were published in 2012 in the New England Journal of Medicine (367; doi:10.10S6/ NEJMcl2U767) and Lancet Neurology (11; doi:10.1016/S1474-4422(12)70228-4), reported that in autosomal dominant Alzheimer's disease mutation carriers, a cascade of biological changes occurs. Fibrillar amyloid plaque deposition- a cardinal neuropathological feature of Alzheimer's-begins approximately 17 years before mild cognitive impairment, rises steeply over the next decade and may plateau prior to the onset of cognitive impairment.
Other biomarkers, such as magnetic resonance imaging (MRI) measures of brain tissue and volume and cerebrospinal fluid (CSF), may show even earlier evidence of abnormalities among mutation carriers. These results generally support the hypothetical dynamic biomarkers of the Alzheimer's disease biological cascade proposed by Dr. Clifford Jack and published in Lancet Neurology in 2010 (9; doi:10.1016/S1474-4422(09)70299-6) and slightly revised in 2013 (12; doi:10. 1016/S1474-4422(12)70291-0).
For some scientists, this "silent" period between when pathological evidence of the disease is present but there are no clinical symptoms may be the ideal period to intervene and test if a treatment to delay cognitive impairment is effective. These studies have also been important in identifying biomarker measurements best able to detect and track changes associated with Alzheimer's- MRI measures of brain tissue, fluorodeoxyglucose positron emission tomography (PET) measures of brain glucose metabolism, PET measures of fibrillar amyloid in the brain and CSF measures of amyloid and tau pathology.
The detailed neuropsychological data collected as part of longitudinal studies have allowed researchers to determine the optimal combination of tests to detect and track presymptomatic cognitive change- creating a test score that can be used in preventive treatment trials. The recent lack of positive results from trials of anti-amyloid therapies in cognitively impaired patients has been used to dismiss amyloidbased treatments. This includes trials of the passive immunotherapies bapineuzumab and solanezumab and the gamma (?) secretase inhibitor semagacestat. Alternatively, these treatments may have been too weak, off target or need to be started earlier, in the silent or preclinical phase of Alzheimer's. …