Currently used criteria for the diagnosis of probable Alzheimer’s disease requires the presence of cognitive deficit in addition to loss of episodic memory. The recent developments in drug treatments for Alzheimer’s disease have highlighted the importance of early diagnosis and the need to characterise the cognitive profile of the earliest stages of the disease. We set out to examine the pattern of decline in terms of individual cognitive domains in non-demented subjects with clinically isolated progressive amnesia which we have termed questionable Alzheimer’s disease. Twelve subjects who fulfill criteria for a clinical diagnosis of possible Alzheimer’s disease by NINCDS-ADRDA criteria were compared to 20 age-matched controls in a longitudinal study. All subjects had MMSE scores of 24 or greater at entry to study. Individual profiles were measured by impairment in the cognitive domains of episodic memory, attention, semantic memory, visuospatial function and auditory verbal short-term (working) memory. Even after subjects were given this intensive neuropsychological battery, 8 of 12 subjects had episodic memory deficits only. Within 12 months just 3 patients were only amnesic and the other patients with pure amnesia at year 1 developed either semantic or attentional deficits. Impairment in both these cognitive domains preceded impairment in visuospatial function and auditory-verbal short-term memory. Our findings are consistent with the pattern of cognitive impairment in Alzheimer’s disease increasing in accordance with neuropathological correlates of cognitive function with amnesia linked to the initial medial temporal pathology before the pattern of spread affects critical neural substrates for attention and semantic memory. Tests of selective attention and semantic memory appear to be the most sensitive markers of decline beyond the amnestic phase of early Alzheimer’s disease.