Research Fronts: Population Effects of Revising Diagnostic Guidelines for Alzheimer’s Disease

October 2013
An elderly woman is escorted by an aide in London, March 22, 2010. REUTERS/Suzanne Plunkett

When ScienceWatch last looked at Alzheimer’s disease (AD) three years ago, the focus was on a protein known as beta-amyloid and on animal models for this most cruel of illnesses, one for which there is as yet no cure and no means of prevention. It was around that time that working groups convened by the US Alzheimer’s Association and the National Institute on Aging were revising, after a gap of around a quarter of a century, diagnostic guidelines for AD outlined by their predecessors. The results of these deliberations appeared in papers in Alzheimer’s & Dementia (the journal of the US Alzheimer’s Association) in May, 2011 (see table), with a further publication on pathological aspects in the following year (B.T. Hyman, et al.  Alzheimers Dement., 8[1]: 1-13, 2012). Revision was needed for several reasons, including clarification of “mild cognitive impairment” (MCI) and the weight to be given to biomarkers for AD such as measurements on cerebrospinal fluid and specialized imaging techniques.

This aspect of Alzheimer’s research surfaces in a Thomson Reuters Research Front, focusing on the pathology of “preclinical” and “incipient” AD. Research Fronts consist of a foundational “core” of papers that are frequently cited together by later papers, forming a distinct area of investigation that directly reflects the cognitive links made by scientists themselves.

The accompanying table presents a selection of the 46 core papers from the Front on preclinical AD (the largest such core of any of the 35 Research Fronts devoted to AD that are currently found in InCites/Essential Science Indicators, a subset of the Web of Science).

 

Selected Core Papers in the Thomson Reuters Research Front on Preclinical and Incipient Alzheimer’s Disease

(Listed by citations)

Rank

Paper

Citations
1 G.M. McKhann, et al., “The diagnosis of dementia due to Alzheimere’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimers Dement., 7(3): 263-9, 2011. [13 institutions worldwide] 392
2 R.A. Sperling, et al., “Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimers Dement., 7(3): 280-92, 2011. [16 institutions worldwide] 378
3 M.S. Albert, et al., “The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimers Dement., 7(3): 270-9, 2011. [14 institutions worldwide] 356
4 B. Dubois, et al., “Revising the definition of Alzheimer’s disease: A new lexicon,” Lancet Neurol., 9(11): 1118-27, 2010. [24 institutions worldwide] 304
5 C.R. Jack, et al., “Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” Alzheimers Dement., 7(3): 257-62, 2011. [5 US institutions] 100
SOURCE: Thomson Reuters Web of Science

 

Profound Implications

Along with the US groups mentioned above, an International Working Group had also been looking at the matter of diagnostic guidelines, publishing a year earlier (see table) and with a greater emphasis on biomarkers. The group sensibly labelled its recommendations on preclinical dementia as being for research purposes. An excellent summary of the issues written by one of its members, Dr. Jeffrey Cummings (Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada), notes key societal questions raised by the revisions. “These new criteria have profound implications,” Cummings writes, “including greatly increasing the number of people identified as suffering from AD and increasing the time that patients will spend with the knowledge of the presence of the disease” (J. Cummings, Alzheimers Res. Ther., 4[5]: 35, 2012).

Estimates of future costs of caring for people with AD are already staggering enough. For example, the US Alzheimer’s Association puts the Medicare bill for this disease at $627 billion by the year 2050; with adjustment for population size, the financial burden in the UK looks much the same. However, a lot of Thomson Reuters Research Fronts pass by before we get to anything to do with dementia. This is not to say that no research is being done, of course. The four widely licensed drugs offer, at best, some slowing of disease progression, but several trials of other treatments are in progress. There are many candidate non-invasive tests in the living patient, such as positron emission tomographic scans for beta-amyloid. Nonetheless, the diagnosis currently remains dependent on psychological tests and clinical judgment, and even in specialist centers there is a significant error rate, and as far as I am aware, help from the laboratory and imaging department lacks the high degree of sensitivity and specificity that is required. Incidentally, although AD may sometimes seem to run in families, simple genetic causation via defective amyloid precursor protein or presenilin genes accounts for fewer than 1% of cases.

 

THE QUESTION OF MCI

Since not all MCI proceeds to AD, the distinction is an important one but it has to be made on judgments of whether any cognitive impairment in a patients is affecting his or her ability to function independently—and, inevitably, that is going to be rather subjective. Indeed, much of the controversy that has followed the 2011 and 2013 revisions (the latter from the DSM-5, the fifth edition of the American Psychological Association’s Diagnostic and Statistical Manual of Mental Disorders) stems from the application of the MCI label. The debate has not been restricted to the professional press (see Paula Span’s article in the New York Times, January 25, 2013). A review of more than 17,000 people with normal cognition, MCI, or probable AD (a definitive diagnosis remains a post-mortem one) suggested that the revised criteria for MCI might compromise the diagnosis of AD (J.C. Morris, Arch. Neurol., 69[6]: 700-8, 2012).  And there will always be hidden cases, coming to light late or not at all. A telephone survey in 2011 of people aged 60 or more in 21 US states found that one in eight reported increasing confusion or memory loss over the preceding 12 months, and among those roughly a third mentioned functional difficulties but by no means had all sought professional help (M.L. Adams, et al., MMWR 62[18]: 347-50, 2013).

It is too soon perhaps to even estimate the effect of the 2010 and 2011 diagnostic revisions (followed by changes in both the DSM-5 that appeared in May of 2013 and in the International Classification of Diseases) on the statistics for Alzheimer’s disease, or to assess what earlier and/or more reliable diagnoses will mean for the morale of patients and their families, but the warnings expressed by Cummings should surely be heeded.

[Note: see also the compendium of highly cited research and interviews with key scientists in the 2011 ScienceWatch Special Topic on Alzheimer’s.]


Mr. David W. Sharp, M.A. (Cambridge), formerly deputy editor of The Lancet, is a freelance writer in Minchinhampton, UK.

The data and citation records included in this report are from Thomson Reuters Web of ScienceTM. Web of ScienceTM is a registered trademark of Thomson Reuters. All rights reserved.