A longitudinal study of asymptomatic individuals at risk of autosomal dominant familial Alzheimer's disease was performed to assess the earliest clinical and neuropsychological features of the disease. Over a 6-year period, 63 subjects underwent serial assessments. During the study, 10 subjects developed symptoms of episodic memory loss and subsequently progressed to fulfil criteria for possible or probable Alzheimer's disease. The mean time (+/-SD) from first assessment to the appearance of symptoms was 2.6+/-1.4 years. The subjects who remained well were similar to those who became clinically affected in terms of age, family history and initial Mini-Mental State Examination. Individuals who later became clinically affected already had significantly lower verbal memory (P=0.003) and performance IQ (P=0.030) scores at their first assessment, when they were ostensibly unaffected. Subsequent assessments showed progressive decline in multiple cognitive domains. Blinded assessment of serial imaging revealed the appearance of diffuse cerebral and medial temporal lobe atrophy in subjects only once they were clinically affected. These findings imply that in familial Alzheimer's disease cognitive decline predates symptoms by several years and that verbal memory deficits precede more widespread deterioration. This may have implications for the detection and treatment of Alzheimer's disease at an early stage.