Diagnostic criteria for AD

The first AD case was diagnosed in 1906, but it was not until 1984 when the first diagnostic criteria for AD were devised by the National Institute of Neurological and Communicative Disorders and the Alzheimer’s disease and Related Disorders Association (NINCS-ADRDA) workgroup; these have now been used successfully for over 27 years. According to the NINCS-ADRDA criteria, AD could only have an amnestic presentation; it was considered to be a clinical and pathological entity, whose diagnosis was only probable during the subject’s lifetime; a definite diagnosis could be ascertained only after combining amnestic presentation during the patient’s life with AD-related neuropathology at autopsy.

No intermediate stage of memory loss was defined and information on biomarkers was lacking at that time as well as nothing being known about genetic forms. Furthermore non-amnestic presentations of AD were not acknowledged to any significant extent (McKhann et al., 1984).

Dementia research has recently viewed new horizons, i.e. AD pathology has been observed in the absence of clinical symptoms (Price and Morris 1999) along with non-amnestic clinical presentation of AD with prominent language and visuospatial abnormalities (Tang-Wai et al., 2004, Rabinovici et al., 2008, Alladi et al., 2007). The presence of AD pathology before the onset of clinical symptoms led to the assumption that there must be a long asymptomatic stage between the first brain lesion and the first clinical symptom, thus raising the importance of identifying this intermediate stage (Dubois et al., 2007, Dubois et al., 2010).

Based on recent developments, National Institute of Aging and Alzheimer’s Association (NIA-AA) sponsored a revision of the NINCS-ADRDA criteria (Jack et al., 2011, Sperling et al., 2011, Albert et al., 2011, McKhann G et al., 1984, McKhann et al., 2011). Moreover, an International Working Group (IWG) revised NINCS-ADRDA criteria separately and produced their recommendations for AD diagnosis [Dubois et al., 2014; Dubois et al., 2007;

Dubois et al., 2010].

The concept of dementia has been changed from a clinical-pathological entity (NINCS-ADRDA) to a dual clinical-biological entity in the IWG criteria and to a pathophysiological and clinical entity by AA. AD is now characterized as a spectrum of disease by NIA-AA, which has different stages inherent in its pathology; pre-clinical AD, mild cognitive impairment (MCI), and AD-dementia. Pre-clinical AD defined by NIA-AA is only intended for research purposes at the moment. Biomarker positivity is required for diagnosis, with evidence of AD related pathological changes not meeting the clinical criteria for MCI or dementia. Pre-clinical AD was further categorized into 3 stages mainly based on biomarker positivity. The reason for attempting to identify this stage is that it may provide a window of opportunity for drug trials which might be effective at this early disease stage (Sperling et al., 2011). MCI was defined by NIA-AA on the basis of both core clinical criteria (for clinicians) and research criteria (for clinical trials, including biomarker evidence). The MCI stage differs from the dementia stage mainly in its preservation of independence in activities of daily living (Albert et al., 2011). The core clinical criteria were sufficient to diagnose dementia due to AD in the NIA-AA guidelines. According to these criteria, dementia was defined as a progressive cognitive decline, diagnosed through history taking and which could not be explained due to other reasons. Moreover, the cognitive decline should be

sufficient to interfere significantly with activities of daily living, such as performing complex tasks at work, at home, acquiring and retaining new information, and deteriorations in language functions etc. Probable AD dementia as defined by NIA-AA was the same as that defined by NINCS-ADRDA but could have an amnestic or a non-amnestic presentation and with increased certainty among those carrying genetic mutations (amyloid precursor proteins (APP), presenilin 1 and 2). Possible AD dementia was defined among those having atypical AD or mixed dementia (McKhann et al., 2011).

The IWG initial guidelines identified various stages of AD including prodromal AD, typical AD, atypical AD, AD dementia, mixed AD and the pre-clinical state of AD. These guidelines emphasized the presence of biomarkers to diagnose different states of AD (Dubois et al., 2010). However, in their revised criteria, IWG emphasized the core clinical criteria in the diagnosis AD, so that their criteria could be used effectively in both clinical and research settings. In the revised guideline’s core clinical criteria, typical AD was defined as an amnestic syndrome of the hippocampal type. This syndrome can be identified in clinical settings by a decline in tests that assess effective registration of an item to be remembered and probe response to cueing as a measure of the storage abilities and associative function of the hippocampus. Biomarkers are a part of revised guidelines but now their purpose is to support the diagnosis rather being compulsory as in the previous IWG guidelines. The revised criteria also identified mixed AD, pre-clinical AD and atypical AD (Dubois et al., 2014).

2.3.2 Biomarkers of AD

Biomarkers are biological indicators that help to diagnose a disease with certainty. AD biomarkers were not available in 1984, when the first AD diagnostic criteria were formulated. The recently developed AD biomarkers have helped to increase the specificity of AD diagnosis and are included in both the IWG and NIA-AA criteria. A correlation between AD clinical symptoms and biomarkers has been demonstrated (Jack et al., 2010, Mormino et al., 2009, Perrin et al., 2009).

AD biomarkers are divided into two main categories: (1) biomarkers for amyloid deposition [CSF Aβ42, Positron emission tomography amyloid imaging], (2) biomarkers of neuronal injury [CSF total tau, phosphorylated tau, fluorodeoxyglucose positron emission tomography imaging, single photon emission tomography perfusion imaging, functional magnetic resonance imaging, hippocampal volume or medial temporal lobe atrophy by volumetric measures or visual rating].

Diagnostic guidelines of IWG and NIA-AA differ with respect to the use of biomarkers to diagnose pre-clinical AD (Sperling et al., 2011, Albert et al., 2011). In NIA-AA guidelines, a biomarker abnormality supported the AD diagnosis, but was not essentially required or sufficient; while IWG listed certain biomarkers as being required for AD diagnosis (Dubois et al., 2010, McKhann et al., 2011).

NIA-AA devotes equal importance to markers of Aβ deposition and neuronal injury in all stages of AD, while in the IWG-2 criteria, the presence of both markers i.e. decreased Aβ^1-42 together with high total or phosphorylated tau in CSF, is essential for the diagnosis of typical AD (Dubois et al., 2014). Recently, the state and stage of AD have emerged as two different

concepts where state denotes a pathophysiological process (such as asymptomatic but at risk of AD) and stage refers to the progression of disease in a certain state (Dubois et al., 2016). AD has both a preclinical and a clinical stage; furthermore the clinical stage of AD comprises the prodromal and the dementia stages. The clinical phenotype of AD can be either typical or atypical. (Dubois et al., 2016).

Despite the major developments in biomarker identification, there is no consensus on whether they should be required for AD diagnosis (Herrup 2010, Pimplikar et al., 2010).

Moreover, the biomarker evaluation of AD pathology needs to undergo validation and standardization in terms of CSF collection, processing, performing quantitative assays, and accessibility and costs (Morris et al., 2014).

According to Diagnostic and Statistical Manual of Diseases 5^th edition, AD is now classified as a major neurocognitive disorder and MCI as minor neurocognitive disorder based on the fact that it involves both neurological functions and interference with activities of daily living. It is true that diagnosing and labeling an individual with dementia without a definite diagnosis can raise serious ethical issues, on the other hand, it can help undiagnosed dementia cases who suffer from this disorder without proper care and support. Thus, their needs may be acknowledged and appropriate care can be planned after their diagnosis.