Early diagnosis of Alzheimer’s disease

This was published in the BMJ as a letter on the 18 October 2011:

A ‘Position Paper’ by Dubois and colleagues suggests that certain biomarkers are now reliable enough to be employed clinically in the earliest possible diagnosis of Alzheimer’s disease[1]; however a follow-up Swedish study concluded the opposite[2] and a review in the Lancet considered the proposed ‘Dubois criteria’ as follows: “but they proceed as if such biomarkers are already available. Moreover, the presence of biomarkers must not be confused with the disease itself. Thus, this new framework for Alzheimer’s disease might represent a tower of Babel rather than a coherent lexicon.”[3]

At the same time as neuroscience is focussing research on the development of biomarkers for the “pre-clinical” detection of Alzheimer’s disease, there has been a general impetus, originating from UK health departments and voluntary organisations to encourage the early diagnosis of Alzheimer’s dementia. This was identified as an area for action given consistent evidence over the delayed diagnosis of dementia. It is perhaps understandable given that the nomenclature (“AD”) is often used inter-changeably for ‘Alzheimer’s disease’ and ‘Alzheimer’s dementia’ that these two imperatives risk becoming confused.

The National Institute on Ageing Preclinical Alzheimer’s disease Workgroup has classified “preclinical “Alzheimer’s disease based upon microscopic pathology. In this study, out of 126 cognitively intact patients with mean age 83.7 years at death, post-mortem found that 53/126 or 43% had pathology consistent with preclinical Alzheimer’s disease[4]. Worldwide epidemiological follow-up studies have found that the rates of transition between mild cognitive impairment (MCI) and Alzheimer’s dementia is about one-third to one-half over three years when looking at the type of MCI considered most likely to be ‘pre-Alzheimer’s.’[5] The InDDEx study, covering 4 years follow up found 5% per year of those with MCI progressed to dementia[6], whilst the Pala study, covering 2 – 6 years follow-up, found that 4.1% progressed to Alzheimer’s dementia[7]. Taken together, these findings suggest a large potential for false-positive diagnoses of Alzheimer’s disease, if diagnostic criteria are stretched to include identification of ‘pre-clinical’ states. It is vital that the clinical community heeds the warning of the research community that at this point our recommendations are strictly for research purposes only.”[8]

A correct early diagnosis of Alzheimer’s disease may be clarifying and appreciated by patients even without disease-modifying treatment, and a diagnosis could be valuable since it allows informed planning for the future[9]. However the consequences in falsely diagnosed cases could be grave. Conferring a diagnostic label is far from a neutral act and is most potent when it is provided by those, such as doctors, deemed to have authority and dependability. Physicians should be aware that explaining to a patient that they have a chronic disease which will likely drastically reduce their quality of life over time, means altering the course of that patient’s life and that of his or her family whether or not they go on to develop dementia.

We must consider whether the earliest possible diagnosis of Alzheimer’s disease might result in an increased suicide risk and possible requests for doctor-assisted suicide[10]. Preserved awareness and the ability to perform planned actions, provide a potentially deadly combination.

It seems somewhat reckless to advocate for greater recognition of ‘early Alzheimer’s disease’ when knowledge is virtually non-existent on how patients would react to such a diagnosis[11], long before dementia may (or, indeed, may not) develop, and whilst research seems to point to large numbers of people with MCI not going on to develop dementia. Our evolving understanding of the pathologic changes that predate Alzheimer’s disease may one day revolutionize management. Better ways of identifying persons at risk of Alzheimer’s dementia will clearly be necessary for finding strategies to prevent clinical manifestation.8 But as we learn to identify risk, we need to do so in a way that is more likely to benefit patients than harm them.[12]

[1] Dubois B, Feldman H, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurology 2007; 6:734-46.

[2] Oksengard AR, Cavallin L, Axelsson R, Andersson C, Nägga K, Winblad B, Eriksdotter-Jönhagen M, Wahlund LO Lack of accuracy for the proposed ‘Dubois criteria’ in Alzheimer’s disease: a validation study from the Swedish brain power initiative. Dement Geriatr Cogn Disord. 2010;30(4):374-80.

[3] Giorgio Giaccone , Thomas Arzberger, Irina Alafuzoff, Safa Al-Sarraj, Herbert Budka, Charles Duyckaerts, on behalf of the BrainNet Europe consortium New lexicon and criteria for the diagnosis of Alzheimer’s disease The Lancet Neurology, Volume 10, Issue 4, Pages 298 – 299, April 2011

[4] Gregory A. Jichaa, Erin L. Abnerb, Frederick A. Schmitt Preclinical AD Workgroup staging: pathological correlates and potential challenges. Neurobiology of ageing 2011. Article in press

[5] Palmer, K., Backman, L., Winblad, B., Fratiglioni, L., 2008. Mild cognitive impairment in the general population: occurrence and progression to Alzheimer disease. Am. J. Geriatr. Psychiatry 16, 603–611.

[6] Alistair Burns et al, Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment:  the InDDEx study Lancet Neurol 2007; 6: 501–12

[7] Marcia L. Chaves, Claudia C. Godinho, Diego Onyszko, Ana L. Camozzato. Mild cognitive impairment conversion rate to dementia in a community sample in Southern Brazil: the Pala study Alzheimer’s and Dementia, Volume 6, Issue 4

[8] Reisa 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 Alzheimer’s & Dementia 7 (2011) 280–292.

[9] Nuffield Council on Bioethics, Dementia: ethical issues28 Bedford Square, LondonWC1B   3JS. 2008

[10] Brian Draper, Carmelle Peisah, John Snowdon, Henry Brodat Early dementia diagnosis and the risk of suicide and euthanasia Alzheimer’s & Dementia 6 (2010) 75–82. New South Wales, Australia

[11] Corinna Porteri, Samantha Galluzzi, Cristina Geroldi, Giovanni B. Frisoni  Diagnosis Disclosure of Prodromal Alzheimer Disease-Ethical Analysis of 2 Cases.  Can. J. Neurol. Sci. 2010; 37: 67-75

[12] Niklas Mattsson, David Brax, and Henrik Zetterberg. To Know or Not to Know: Ethical Issues Related to Early Diagnosis of Alzheimer’s Disease. International Journal of Alzheimer’s Disease Volume 2010 (2010), Article ID 841941,

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