Alzheimer Assay Deserves Qualified Embrace
A pattern of 3 markers in CSF—beta amyloid 1-42, phosphorylated tau, and total tau—appears to strongly predict Alzheimer disease in people with mild cognitive impairment (MCI), according to a newly published and highly publicized study from the US Alzheimer’s Disease Neuroimaging Initiative. But the study findings, which can be found in the Archives of Neurology (subscription required), do not necessarily mean that the CSF assay should be incorporated immediately into clinical care—despite the fact that 1) the authors are lobbying hard for the test to be included in the diagnostic criteria for AD and 2) an accompany editorial urges clinical use of the CSF assay with the wince-inducing title, “Sharpen That Needle.”
The “AD signature” of low beta amyloid 1-42 and elevated tau levels was found in 90% of AD patients (n = 102), 72% of MCI patients (n = 72), and 36% of cognitively normal subjects (n = 114). Consequently the sensitivity of the test is 90% (the rate of positivity in AD patients), and the specificity is 64% (the percentage of cognitively normal subjects who don’t show the AD CSF pattern [ie, 100% – 36%]).
Among a subset of 68 people with autopsy-confirmed AD, 64 (94%) showed the AD CSF pattern, which correlates well with the 90% sensitivity measure in clinically diagnosed AD patients (via the MMSE). In another subset of 57 patients with MCI who developed AD during 5-year follow-up, all exhibited the AD CSF pattern for a sensitivity of 100%.
Rather than view a positive CSF assay in cognitively normal people as a failing of the test (ie, it has limited use in normal subjects), the authors conclude that these people are at risk of AD. This conclusion may well be true, but it seems that further study is warranted before such a bold statement can be made. The authors did find an “enrichment” of the apolipoprotein E ε4 allele, a recognized genetic risk factor for AD, in this population, but the finding was not uniform.
At least ABCNews, unlike many other news sources, found medical commentators who advise against the whole-hearted embrace of this assay. Cliff Saper, who is one of the most level-headed neurologists I’ve ever met, said there is no reason to perform the test until there is a successful treatment for AD. “This test shows up positive in presymptomatic individuals, and Alzheimer’s disease is a common disorder,” Saper was quoted. “The main value would be to detect [Alzheimer’s disease] in atypical cases.” For what it’s worth, I agree.
The CSF assay currently appears to be most useful in the context of research—as an additional tool to reinforce the diagnosis of MCI or AD in clinical studies. Assay results may also inform the use of investigative therapies at different stages of cognitive decline. One of the most intriguing findings from the study is that there appears to be a distinctive pattern change as MCI progresses to mild AD and then to advanced disease: CSF beta amyloid levels fall while tau levels rise. Anti-beta-amyloid therapies like bapineuzumab, may provide relatively greater benefit in MCI or very early AD, while anti-tau therapies may have their place in more severe dementia.
In the meantime, Innogenetics, which employs or employed several of the authors, provides the tripartite CSF assay (Inno-Bio AlzBio 3) for “research use only.” Information on the cost of the assay, after several Google searches, remains elusive.
CSF = cerebrospinal fluid.
Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.