Jan 112012
 

As 2012 begins, I would like to review some of the highlights of the Alzheimer’s Disease world this past year, and the new directions that we will likely be heading toward in 2012.

  • This year we saw the publication of new diagnostic guidelines for Alzheimer’ s disease formulated by committees sponsored by the National Institute on Aging and the Alzheimer’s Association. The National Institute on Aging and the Alzheimer’s Association also published guidelines for diagnosis of mild cognitive impairment due to Alzheimer’s disease and for preclinical Alzheimer’s disease. These guidelines will be important tools for clinicians to diagnose Alzheimer’s in its earliest stages, and represent the first revision in 25 years.
  • An FDA advisory committee gave preliminary approval of the PET amyloid imaging ligand AV-45, citing work to be done to ensure consistency in reading PET scans. Full approval is expected sometime in 2012, if a uniform training program is implemented for radiologists interpreting the scans.
  • The European Medicines Agency announced the likely approval of hippocampal atrophy as a marker of early Alzheimer’s disease for the purpose of clinical trials. Much work has gone into linking hippocampal atrophy visualized by MRI  as an early and specific biomarker of neurodegeneration seen in Alzheimer’s disease.
  • IGAP—the International Genomics of Alzheimer’s Project, a transatlantic collaboration to create the most detailed map of genetic variants that link to Alzheimer’s disease was also launched in 2011. Meta analysis of genome-wide association studies (GWAS) revealed four new genetic risk variants for Alzheimer’s disease.
  • In terms of clinical trials, Gantenerumab, an antibody against beta-amyloid, was shown to clear plaques when given intravenously, according to results from a Phase 1 trial. The drug seems to be one of the most potent developed thus far in reducing plaques. A Phase 2 gene therapy trial for Parkinson’s disease was deemed a success. A similar Phase II gene therapy trial for Alzheimer’s disease, called the Nerve Growth Factor Study, is currently ongoing and recruiting. Multiple clinical trials, including the ADCS Phase III Resveratrol and Roche Phase II Gantenerumab trial are launching in 2012.
  • A very important paper by the Holtzman group at Washington University further established the relationship between ApoE4 genotype and decreased clearance of beta-amyloid from brain, both in humans and animal models. The idea that ApoE4 is less effective in removing beta-amyloid from the brain is not necessarily novel, per se, and had been previously shown. However, it had never been proven so convincingly and in such a complete manner in humans and animal models of Alzheimer’s disease. Together, the data suggest that ApoE variants contribute to a person’s risk for Alzheimer’s by affecting the clearance of beta-amyloid from the brain long before amyloid plaque deposition begins. Later in the year, the same group reported that, in mice, lowering the levels of ApoE4 results in fewer amyloid plaques. The results imply that ApoE-lowering treatments have a place among proposed Alzheimer’s therapies, including immunotherapy, gene therapy, and beta- and gamma- secretase inhibitors.
  • Results published in the Journal of the American Medical Association showed that women with sleep-disordered breathing (SDB)— pauses in breathing or reduced ventilation quality during sleep — are more likely to develop cognitive impairment five years later. The biology behind this finding may include hypoxia, or decreased oxygen delivery to certain parts of the brain, including the hippocampus which is critical in memory function. In addition, sleep fragmentation, which can interfere with memory consolidation, which occurs during certain stages of sleep, may also lead to cognitive problems. This study has really brought much needed attention to the evaluation of sleep as part of the work-up in individuals with Mild Cognitive Impairment.

We anticipate further progress in understanding the progression of the earliest stages of Mild Cognitive Impairment and Alzheimer’s disease with the Alzheimer’s Disease Neuroimaging Initiative (ADNI2), The Dominantly Inherited Alzheimers Network (DIAN) study and the Alzheimer’s Prevention Initiative (API) during 2012.

By Michael Rafii, M.D., Ph.D.
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California, San Diego

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