Kwasi G. Mawuenyega, Wendy Sigurdson, Vitaliy Ovod, Ling Munsell, Tom Kasten, John C. Morris, Kevin E. Yarasheski and Randall J. Bateman. Decreased Clearance of CNS ?-Amyloid in Alzheimer’s Disease. Science DOI: 10.1126/science.1197623 Published Online 9 December 2010
http://www.sciencemag.org/content/early/2010/12/08/science.1197623
The reporting of this on the BBC News health website was for me inadequate by academic professional standards.
http://www.bbc.co.uk/news/health-11962174
“Plaques” of a protein called amyloid build up in the brains of patients in Alzheimer’s disease (AD). Actually, Alzheimer’s disease is characterized by increased amounts of soluble and insoluble b(=beta) amyloid (Ab) – this predominantly is in the form of Ab42 in amyloid plaques and Ab40 in amyloid angiopathy (amyloid build-up in the blood vessels inter alia).
The amyloid hypothesis proposes that AD is caused by an imbalance between Ab amyloid production and clearance, resulting in increased amounts of Ab amyloid in various forms in the Central Nervous System. High levels of this type of amyloid then initiate a powerful chain-reaction of events culminating in damage and death to brain cells, manifesting sadly as progressive clinical dementia of the Alzheimer type. In rare cases of AD, straightforward inherited alterations increase the production of Ab. However, Ab dysregulation in the far-more common late-onset non-family history types of AD is less well understood. Impaired clearance of Ab may also cause late onset AD and this is what this paper from the prestigious journal Science is about. Limitations of this study stated in the paper include the relatively small numbers of participants (twelve in each group) and the inability to prove causality of impaired Ab clearance for AD, and these seem entirely reasonable.
Research participants were enrolled from the “Washington University Alzheimer ’s Disease Research Center”. The inclusion criteria were age >60 years, cognitively normal (Clinical Dementia Rating or CDR 0), very mild AD (CDR 0.5) or mild AD (CDR 1). The study included the typical exclusion criteria. 25 participants were clinically evaluated and rated as either very mild to mild dementia of the Alzheimer type (n=12, average age 77), or as cognitively normal (n=12 average age 71). After baseline blood and spinal fluid samples were collected, a shot of radioactively-labelled material was infused at 2 mg/kg over 10 minutes, followed by 2 mg/kg/hr for the remaining 8 hours and 50 minutes. During and after infusion, spinal fluid and blood samples were collected for a total of 36 hours and frozen at -70°C.
The first major criticism of this study must be that an approximate screening test for Alzheimer’s Disease was administered (the Clinical Dementia Rating scale); of course, there is no definitive diagnosis of patients until death, but with such small numbers taking part in this study, this is a concern, as some of the patients with a proposed diagnosis of Alzheimer’s disease could turn out to have a totally different type of dementia, such as dementia with Lewy Bodies or frontotemporal dementia, or not even dementia at all (such as geriatric depression).
To determine the balance of Ab production to clearance rates in AD versus controls, they measured the ratios of production to clearance (fig. S2). The ratio of Ab42 production to clearance rates were balanced for cognitively normal participants (0.95), however, due to decreased clearance in the AD participants, there was an imbalance in the A42 production to clearance ratio (1.35). Similarly, they observed an imbalance in AD Ab 40 production to clearance ratio (1.37), compared with cognitively normal participants (0.99). They found that late onset AD was associated with a 30% impairment in the clearance of both Ab 42 and Ab40, indicating that Ab clearance mechanisms may be critically important in the development of AD.
This is the most significant problem with this study, because it does matter whether these differences were statistically significant. I would find it hard to convince myself that they are using ‘parametric tests’ (assuming that all samples were as equally widespread in variation, in other words) simply eyeballing the data. It is, of course, a moot point whether these biomarkers in the spinal fluid reflect very accurately what is happening in the brain at all, but I have written about the possible usefulness of these ‘biomarkers’ elsewhere on this blog, and there is much excitement over their use currently in the research community.
The data supplied in their ‘supporting materials’ are as follows.
Dr Shibley Rahman is an international academic expert in frontotemporal dementia
