Dysexecutive and amnesic AD subtypes defined by single indicator and modern psychometric approaches: relationships with SNPs in ADNI.

Previous investigators have suggested the existence of distinct cognitive phenotypes of Alzheimer's disease (AD): a dysexecutive subgroup with executive functioning worse than memory and an amnesic subgroup with memory worse than executive functioning. We evaluated data from the AD Neuroimaging Initiative. We assigned people with AD to dysexecutive and amnesic subgroups using single indicators, and analogously using the ADNI-Mem and ADNI-EF composite scores developed using modern psychometric approaches. We evaluated associations between subgroup membership, APOE genotype, and single nucleotide polymorphisms (SNPs) are associated with AD, and brain vascular disease defined as white matter hyperintensities (WMH) and MRI-identified infarcts. We hypothesized that APOE ε4 and alleles associated with higher risk for AD would predict amnesic subgroup membership; alleles associated with higher WMH or infarct burden would predict dysexecutive subgroup membership. Classification agreement between the two approaches was only fair (kappa = 0.23). There was no relationship between APOE alleles and the dysexecutive or amnesic phenotypes defined by either categorization approach. There were 58 AD-related and 25 WMH- or infarct-related SNPs for which odds ratios were > 1.5 or < 0.67 for dysexecutive vs. amnesic subgroup defined by either categorization approach. Higher proportions of SNPs had odds ratios in the hypothesized direction for the subgroups defined by the modern psychometric approach for AD-related (58 % vs. 38 %, p-value < 0.001) and brain vascular disease-related SNPs (48 vs. 32 %, p-value = 0.01). Genetic variation may underlie differential performance in memory and executive functioning among people with AD. Modern psychometric composite scores produced group assignments with more SNP associations in the hypothesized direction.