The Clinical Spectrum of Alzheimer ’ s Disease – The Charge Toward

The prevalence of dementia is expected to increase exponentially worldwide. Global estimates of Alzheimer’s disease (AD) generally considered to be the most common subtype of dementia are expected to increase from the current estimated 25 million to 63 million in 2030, and by 2050, a staggering 114 million (Wimo et al., 2003). Traditional approaches in AD diagnosis (Diagnostic and Statistical ManualIV (DSM-IV) – Text Revision (American Psychiatric Association [APA], 2000) and National Institute of Neurological Disorders and StrokeAlzheimer Disease and Related Disorders (NINCDSADRDA) (McKhann et al., 1984) criteria have varying diagnostic accuracy of 65-96% and specificity of 23-88% compared to the neuropathologic gold standard (Kazee et al., 1993; Lim et al., 1999; Petrovich et al., 2001; Varma et al., 1999). Studies have shown that the hallmark histopathological changes of AD (┚-amyloid plaques and neurofibrillary tangles) precede the clinical onset of disease by as long as 20-30 years (Price & Morris, 1999). This translates clinically to functional and structural brain damage where these pathologic changes may occur prior to apparent clinical manifestations of cognitive decline by way of standard clinical assessments. This has fuelled an increasing shift of diagnostic focus to the predementia transitional state between normal aging and early AD, which represents a window of opportunity for identifying subjects at a phase when pathogenesis has already begun but clinical diagnosis of established dementia is still not achievable. This would logically be the stage most amenable to disease-modifying interventions (such as ┚and gamma-secretase inhibitors, anti-amyloid and anti-neurofibrillary tangle therapies). Diagnostic focus thus has shifted towards prodromal stages of Alzheimer’s Disease (AD), such as mild cognitive impairment (MCI) (Morris et al., 2001; Peterson, 2004). Clinical criteria alone, which by their very nature subjective and entail judgment, are thus inadequate to identify the pre-clinical stages of AD and may have contributed to the disappointing results of therapeutic trials in MCI (a heterogeneous entity) to date. This has prompted revisions in the upcoming DSM-V criteria due in 2013 (Kupfer & Regier, 2010) which include major and minor neurocognitive disorder classification, as well as the proposed revision of NINCDS-ADRDA criteria for AD to include prodromal AD and preclinical AD, which characterises earliest stage of AD that predate crossing of the dementia threshold of functional disability. In the proposed criterion by Dubois et al (Dubois et al., 2007), other than clinical criterion of episodic memory deficit,