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Appendix 2: More information about the changing definition of AD

2016: Ethical issues linked to the changing definitions/use of terms related to Alzheimer’s disease

Historical description

In 1906, Dr Alois Alzheimer first described the symptoms and the amyloid plaques and neurobrillary tangles in the brain, which have come to be considered as the hallmarks of Alzheimer’s disease (AD). More than a hundred years later, the causes of this neurodegenerative disease are still unknown and no cure is currently available, but it is important not to lose sight of how far we have come since then.

For a long time, dementia has been related to old age but the first patient described by Alois Alzheimer was actually quite young. For many years, AD dementia was also called “presenile dementia” and was used as a diagnosis for people aged between 45 and 65. It was only in the 1970s that a link was made between dementia in the young and old populations and the term AD dementia extended to old age.

In 1984, the NINCDS-ADRDA Alzheimer's criteria (McKhann 1984) were proposed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association). The NINCDS-ADRDA criteria were based on a “clinico-pathological dual diagnosis”. This involves first determining clinically the presence of dementia and trying to rule out other possible diagnoses, which may account for the clinical presentation, and then, for a definite diagnosis, confirming AD brain pathology at post mortem. A direct consequence of such an approach is therefore the long period of uncertainty about the diagnosis. The clinical diagnosis can only be ‘probable’ until the person dies and theplaques and tangles mentioned earlier can be detected in his/her brain. This “probable” diagnosis can only be made when the disease is sufficiently advanced to reach the threshold of dementia. Consequently, according to these criteria, a diagnosis of AD is synonymous with a diagnosis of AD dementia, even if the latter term is sometimes used.

Research has shown that these criteria have low accuracy as they do not take into account certain features of the disease such as biomarkers or hippocampal lesions (NIA and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease 1997; Beach et al. 2012) and as only 70% of diagnoses are accurate, the others being false positive or false negative cases.

The lack of precision in the diagnostic criteria and the discovery of AD pathology biomarkers made it necessary to reach a new consensus on diagnosis and evaluation. Since 2007, starting with the first International Working Group proposal (Dubois et al. 2007, 2010) and followed by other groups’ definitions such as the NIA-AA (McKhann et al. 2011) and IWG2 (Dubois et al. 2014), new conceptual approaches to the disease have been developed. All consider AD as a clinical-biological entity based on the presence of biomarkers. These new approaches could, if used in clinical practice, increase diagnostic accuracy and allow for an earlier diagnosis. In addition, when used in research settings, these new criteria could enable the development of standards that are critical for drug development (Cumming 2011). 

The new approach: AD pathology as a continuum

The last decade of research has been a testimony to the change in the conceptual approach to AD. As described above, 2 main groups have developed criteria aimed at improving AD diagnosis and its related research. First, in 2007, an International Working Group (IWG) published its criteria (Dubois et al. 2007), followed by an update in 2014 (Dubois et al. 2014). In 2011 in the US, other criteria were published by 3 working groups in the National Institute on Aging and the Alzheimer’s Association (NIA-AA) (Jack et al. 2011; McKhann et al. 2011; Albert et al. 2011; Sperling et al. 2011). Each set of criteria has a few differences, but all agree on the need to consider AD pathology as a continuum where biomarkers play an essential role. Both groups define AD as a clinical-biological entity that, through the identification of biomarkers, can be diagnosed during the lifetime of the patient. AD is also defined as a clinico-biological continuum, ranging from normal cognition to severe dementia, including 3 phases:  

  1. preclinical AD: asymptomatic at risk or presymptomatic AD (abnormal pathophysiological biomarkers and no cognitive impairment),
  2. mild cognitive impairment due to AD (NIA-AA) or prodromal AD (IWG) (abnormal pathophysiological biomarkers and mild cognitive impairment),
  3. AD dementia (abnormal pathophysiological biomarkers and dementia).

The image below (from Molinuevo et al. 2013) shows the gradual changes in the brain along the AD pathological continuum.

The IWG (Dubois 2007) was the first to introduce the idea of a continuum. AD is defined as a clinico-biological entity based on a major clinical criterion, namely the deficit in episodic memory (i.e. long-term memory of specific events and experience, technically known as “amnestic syndrome of the ‘hippocampal type’), either on its own or associated with other cognitive or behavioural changes. The criteria also requires 1 or more AD pathology biomarkers. These include atrophy of the medial temporal lobe observed by MRI (shrinkage of a certain part of the brain as shown on a scan), changes in cerebrospinal fluid (CSF) biomarkers and alterations in PET scans. In 2007, all these biomarkers were treated equally. This was revised in 2014 by the IWG2. In this second diagnostic criteria consensus, the IWG considered weighting of clinical significance and specificities for biomarkers (i.e. certain characteristics, levels and combinations of biomarkers were given greater or lesser importance as diagnostic criteria).

The NIA-AA criteria focus on “syndromes” within the AD continuum. According to the NIA-AA, clinical diagnosis is based first on syndromic criteria (i.e. information about the syndromes), followed by the likelihood (high, intermediate or likely) of what is observed being due to AD, as assessed by use of biomarkers (if available). The continuum is divided into syndromes, which have been described in different papers: AD (Mac Khann et al. 2011), mild cognitive impairment (MCI) due to AD (Albert et al. 2011) and the preclinical phase (Sperling et al. 2011).

A new lexicon

In order to reach a consensus on the diagnostic criteria and harmonisation of standards for research, a new consensus lexicon was needed to unify all definitions, stages and processes (Dubois et al. 2010). The lexicon developed by Dubois et al. (2010) was intended for researchers in the context of research protocols and clinical trials and to provide clinicians with a clear view of an evolving field. The new definitions are also described in the context of new diagnostic framework/criteria (Dubois et al. 2010 & 2016) which is still undergoing modifications. The definitions below are presented as described in Dubois et al. (2010 and 2016). However, readers should bear in mind that there may be further changes in the upcoming years.

ALZHEIMER’S DISEASE is defined as a clinical entity that encompasses the full spectrum of the disease including both pre-dementia (prodromal) and dementia phases. Its diagnosis can be establishedin vivobased on a dual clinico-biological entity.

AD PATHOLOGY refers to the neurophysiopathological changes underlying AD. This terminology can be applied irrespective of the clinical manifestation.

PRECLINICAL STATE is the long asymptomatic stage between the earliest AD pathogenic and the first specific cognitive changes. It includes two different populations:

        i.           ASYMPTOMATIC AT RISK: population that includes individuals experiencing pathological changes in their brain specific to AD but without clinical changes;

       ii.           PRESYMPTOMATIC: mutation carriers of the dominant genetic variants of AD.

PRODROMAL AD (also called MCI due to AD by the NIA-AA) corresponds to the early symptomatic pre-dementia phase of AD. During this phase clinical symptoms are present but not severe enough to affect activities of daily life and are associated with specific biomarker changes.

MCI is applied when patients do not fulfill the criteria for the clinico-biological phenotype of prodromal AD (memory symptoms not characteristic of AD or biomarker negative).

AD DEMENTIA consists of the stage of the disease in which the cognitive symptoms are severe enough to affect not only memory but also daily life activities.

A concept in constant evolution

There is currently agreement in the field of biomedical research on AD being a continuum, both from a biological and a clinical perspective, and current research criteria, whilst constantly in evolution, reflect this. Research and discussions are focusing on improving current research criteria through defining which biomarkers can, with sufficient accuracy, define the physiopathology of AD and its stages. Furthermore, even if today in 2016, we still do not know the causes of AD and how to treat it, research carried out worldwide has resulted in in-depth knowledge about the molecular and pathological changes occurring in the brain during the disease.

We are currently at the dawn of a new era of discoveries concerning the development of technologies for brain physiopathology research (neuroimaging, cerebrospinal fluid analysis and blood biomarkers identification and new biomarker research). This research will permit a better knowledge of the changes involved along the AD continuum. This valuable information is needed to better understand the different processes taking place during the course of the disease.

Nevertheless, it is essential to take into consideration that every day new results are obtained that provide new insights into the disease process and lead to more precise knowledge about AD. For this reason, we are facing a field in constant evolution where new criteria may emerge in the near future.



Last Updated: Thursday 20 April 2017


  • Acknowledgements

    The discussion paper on ethical issues linked to the changing definitions/use of terms related to Alzheimer’s disease received funding under an operating grant from the European Union’s Health Programme (2014-2020). The content of this publication represents the views of the author only and is his/her sole responsibility. It cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.
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