Dementia in 2010: Paving the way for Alzheimer disease drug development

Abstract

2010 will be viewed as an important year in alzheimer disease (aD) research. reports from clinical trials of anti-amyloid-β (aβ) drug candidates were disappointing; however, many studies published this year provide information that might aid the development of novel drug therapies for aD or enable the early diagnosis of individuals at risk of developing this condition. this ‘Year in review’ article provides a summary of four of these studies. in march 2010, Fukumoto et al. reported the development of a new assay that can detect aβ oligomers in the cerebro spinal fluid (CsF; Figure 1).1 the ability to measure these proteins could provide a means of assessing their contribution to the pathogenesis of aD. synaptic loss shows a better correlation with cognitive disturbances associ ated with aD than do plaque and tangle counts. aβ oligomers have been shown to impair long-term potentiation (ltP), decrease dendritic spine density in hippocampal brain slices in vitro, and impair memory in vivo;2 however, little evidence exists to link aβ oligomers with synaptic degeneration and memory loss in patients with aD. this lack of evidence might reflect the fact that low levels of aβ oligo mers are present within the CsF, which makes their measurement notoriously difficult. Fukumoto et al. developed a novel enzyme-linked immunosorbent assay (elisa) for CsF aβ oligomers.1 the assay used the same antibody for both capture and detection of aβ oligomers, thereby preventing reacti vity with aβ monomers but allowing measurement of aβ dimers and larger oligomer species. indeed, the assay was shown to react specifically with highmolecular-weight aβ oligomers (10–20mers of aβ). through use of this novel elisa, the researchers demon strated a significant increase in CsF aβ oligomers in patients with aD and in prodromal aD cases compared with controls, suggesting that measurement of levels of aβ oligomers in the CsF has diagnostic potential. interestingly, an inverse correlation was shown to exist between the levels of aβ oligomers and cognitive function in the patient group. longitudinal clinical studies that directly assess the relationship between aβ oligomers and cognition in humans will, hopefully, clarify the effects of aβ oligo mers on memory and aD progression. moreover, this type of biomarker may provide a means of monitoring the effects of anti-aβ disease-modifying therapies. in the september 2010 issue of Nature, He and colleagues demonstrated that inhibi tion of γ-secretase activating protein (GsaP) can selectively reduce aβ production.3 inhibition of γ-secretase, an enzyme involved in aβ generation, has been a major

DOI: 10.1038/nrneurol.2010.214

Cite this paper

@article{Blennow2011DementiaI2, title={Dementia in 2010: Paving the way for Alzheimer disease drug development}, author={Kaj Blennow}, journal={Nature Reviews Neurology}, year={2011}, volume={7}, pages={65-66} }