5,6 The classical definition of AD, restricted to the concept of dementia, was mainly justified by the fact that the diagnosis was more difficult to make in the early, predementia phase in the last decades: and this was the reason for considering

it a stage of MCI. However, the emerging literature on MCI has emphasized an intrinsic etiological heterogeneity and a diversity of outcomes within research Inhibitors,research,lifescience,medical studies. Efforts to address these issues have not succeeded, and the limitations of MCI are apparent. Hie risk of intervening on an etiologically heterogeneous sample of MCI subjects will include running the risk of “diluting” a significant treatment effect.6 Recently, research has begun to focus on developing new tools, such as neuroimaging and cerebrospinal fluid (CSF) biomarkers, that could increase the specificity of the prodromal AD diagnosis.7 Before using such invasive or expensive tools, it is necessary to screen patients Inhibitors,research,lifescience,medical in memory clinics with neurological exams and find more neuropsychological assessment. The most prominent feature of AD is the decline in cognitive function. Memory impairment of recent events, Inhibitors,research,lifescience,medical unusual repeated omissions, and difficulty learning new information characterize the first clinical signs.8,9 This progression of cognitive deficits

is related to the progression of the underlying cerebral lesions, as established by Braak and Braak.10 In the early

stages of AD (Braak I-III), critical areas for episodic memory are already Inhibitors,research,lifescience,medical affected by neuropathological changes (neurofibrillary degeneration) in medial temporal regions (hippocampal formations, parahippocampal gyrus, and entorhinal cortex) and, consequently, episodic memory deficit Inhibitors,research,lifescience,medical is the initial and reliable neuropsychological marker of AD. As the condition progresses, deficits occur in instrumental functions (language, praxis, visuospatial capacities), which are consistent with the extension of lesions into the crotamiton neocortical associative areas (Braak V). The situation faced by clinicians is easy to summarize: i) memory disorders are the most reliable sign of prodromal AD; ii) unfortunately, memory disorders are a verycommon sign, observed in many disorders: for example in depression, anxiety, sleep disorders, brain vascular lesions, frontal lobe dysfunction, and even in normal aging. Is it possible, therefore, to identify the memory disorders of AD? Here again, the answer is yes, because the memory disorders of AD are not like other memory disorders: there are very specific because they result from a hippocampal dysfunction. This is why the neuropsychological evaluation is crucial at the prodromal stage, for establishing the nature of memory impairment.