Cognitive phenotypes in Alzheimer's disease and genetic risk

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Variation in the clinical characteristics of patients with Alzheimer's disease (AD) is increasingly recognised, although the factors underlying variation are not fully understood. The study examined the cognitive characteristics of 523 AD patients at the time of their presentation to a neurological dementia clinic and explored the relationship to family history and apolipoprotein E (APOE) genotype. Distinct profiles were identified, which were mirrored by topographical differences on neuroimaging. Clinical distinctions were maintained over time. Two-thirds of patients showed a constellation of deficits at presentation which included memory, language, visuospatial and constructional difficulties. However, a quarter had circumscribed presentations of amnesia, aphasia, perceptuospatial disorder or apraxia. The rare presence of frontal lobe characteristics was associated with a younger age of onset, an increased incidence of myoclonus at presentation, a positive family history but not with possession of APOE F-4 allele. An amnestic presentation (severe, yet circumscribed amnesia) was strongly associated with an older age of onset, a positive family history and the presence of APOE F-4 allele. Posterior cortical presentations showed a female bias, were typically sporadic, and showed no association with APOE F-4. The findings support the notion of phenotypic variation in AD, and show that genetic risk factors can influence clinical presentation. The findings draw attention to the specific association between APOE P-4 allele and memory but challenge the commonly held notion that the presence of the ε4 allele inevitably reduces onset age. The findings indicate that risk factors other than APOE ε4 allele underlie the non-familial, early onset posterior hemisphere presentations of AD.




Snowden, J. S., Stopford, C. L., Julien, C. L., Thompson, J. C., Davidson, Y., Gibbons, L., … Mann, D. M. A. (2007). Cognitive phenotypes in Alzheimer’s disease and genetic risk. Cortex, 43(7), 835–845.

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