Most of what we know about the pathological process of Alzheimer's disease (AD) results from research on the amyloid cascade hypothesis. This hypothesis in turn is derived largely from the characterization of rare disease-causing mutations in three genes, which code for the amyloid precursor protein (APP), presenilin 1 (PS-1) and presenilin 2 (PS-2) and account for most cases of early-onset autosomal dominant familial AD. These genetic findings also suggested that better understanding of the genetic components of AD, even in the late-onset sporadic forms of the disease, might help to identify central pathways of the AD process and lead to the rapid development of active molecules. Twin studies have reinforced the rationale of this approach, for they indicate that more than 50% of the late-onset AD risk may be attributable to genetic factors. The 1993 discovery that the apolipoprotein E4 (ApoE4) allele is genetically associated with increased risk in both sporadic and familial late-onset Alzheimer's disease strongly supports the validity of this genetic approach. Further progress based on this major finding has nonetheless been disappointing and raises questions about it. First, despite intensive researches, the exact role of APOE in the pathophysiological process still remains unknown. Second, the APOE gene is the only gene so far recognized as a consistent genetic determinant of sporadic forms of AD, even though numerous studies have looked for such genes; these disappointing results suggest persistent methodological limitations. However, recent methodologies allowing new strategies may allow important breakthrough.