Alzheimer’s disease (AD) pathology begins decades before the onset of clinical symptoms. It is recognized as a clinicobiological entity, being detectable in vivo independently of the clinical stage by means of pathophysiological biomarkers. Accordingly, neuropathological studies that were carried out on healthy elderly subjects, with or without subjective experience of cognitive decline, reported evidence of AD pathology in a high proportion of cases. At present, mild cognitive impairment (MCI) represents the only clinically diagnosed pre-dementia stage. Several attempts have been carried out to detect AD as early as possible, when subtle cognitive alterations, still not fulfilling MCI criteria, appear. Importantly, pre-MCI individuals showing the positivity of pathophysiological AD biomarkers show a risk of progression similar to MCI patients. In view of successful treatment with disease modifying agents, in a clinical setting, a timely diagnosis is mandatory. In clinical routine, biomarkers assessment should be taken into consideration whenever a subject with subtle cognitive deficits (pre-MCI), who is aware of his/her decline, requests to know the cause of such disturbances. In this review, we report the available neuropsychological and biomarkers data that characterize the pre-MCI patients, thus proposing pre-MCI as the first clinical manifestation of AD.
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