Normal means different things to different people. In Alzheimer’s disease research, “normal controls” are compared to people with dementia every day. Naturally. But what’s normal nowadays? The definition may be changing. In the December 22 Annals of Neurology, researchers led by Jonathan Schott at the Dementia Research Centre, University College London, U.K., report stark differences among cognitively normal people enrolled in the Alzheimer’s Disease Neuroimaging Initiative. Over the course of one year, volunteers with low levels of cerebrospinal fluid amyloid-β (Aβ) had rates of brain loss that suggest they are actually, unbeknownst to them, in the early stage of Alzheimer’s. The finding further reinforces the idea that biomarkers can identify people years before the first signs of dementia.
Schott and colleagues divided 105 cognitively normal controls based on concentration of CSF Aβ42, using the 192 pg/ml cutoff previously set by Les Shaw and colleagues at the University of Pennsylvania, Philadelphia, as having predictive value for those susceptible to dementia (see ARF related news story on Shaw et al., 2009). The London scientists found that the 40 people with CSF Aβ42 below this value lost tissue in whole brain and hippocampus faster, and their brain ventricles correspondingly enlarged more than did the other 65 volunteers. This suggests “...they may be in the earliest stages of neurodegeneration,” write the authors.
This work, together with similar findings reported earlier this year from a group in Belgium (see ARF related news story), and longstanding work from the Antecedent Biomarkers Study run by John Morris and colleagues at Washington University, St. Louis, indicates that biomarkers are useful in determining who is at risk for AD. “In general, people are getting more interested in analyzing cognitively normal elderly folks with longitudinal biomarker and cognitive testing,” suggested Anne Fagan, Washington University, in an e-mail to ARF. “This ‘appreciation’ has caused a paradigm shift in the way people are thinking about clinical trial design, as well,” she wrote. This idea has been promulgated not only among researchers (e.g., see Aisen comment at recent trials conference), but also in the larger community, as is apparent by recent coverage of AD research trends by The New York Times (see also ARF related news story).—Tom Fagan
- ADNI: GWA Nearly Complete, Biomarker Analysis Update
- Triple Confirmation: AD Footprint in CSF of Cognitively Normal People
- London: What, No Argument? Speakers Agree on Trials for Familial AD
- Alzheimer’s in Science Times
- Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ, Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009 Apr;65(4):403-13. PubMed.
- Schott JM, Bartlett JW, Fox NC, Barnes J, . Increased brain atrophy rates in cognitively normal older adults with low cerebrospinal fluid Aβ1-42. Ann Neurol. 2010 Dec;68(6):825-34. PubMed.