With the promising development of effective treatment, significant improvement in the very early diagnosis of Alzheimer's disease (AD) is required. There is vast agreement that a decline in memory, especially in verbal episodic memory, is the earliest and perhaps the most sensitive sign of incipient AD at the preclinical stage. However, this review offers evidence that impairment in episodic memory can be observed in normal elderly people as well as in aged subjects with mild cognitive impairment (MCI), a large proportion of whom will, however, not convert to dementia. Quantitative measurement of atrophy and brain activation in the hippocampal-parahippocampal formation by using structural and functional magnetic resonance imaging may help to distinguish the MCI decliners from the nondecliners. Cerebrospinal fluid levels of tau protein and Abet1-42 peptide, together with the presence of an apolipoprotein (apo)E epsilon4 allele may also increase our confidence in the early positive diagnosis of AD. This review concludes, however, that while adequate for constituting groups of patients in a research perspective, the extensive diagnostic procedure based on specific cognitive testing, neuroimaging and biological investigations is still out of reach for the practitioner.