Impact of Apolipoprotein E genotype in Mild Cognitive Impairment: Findings from the InDDEx study

Martin R. Farlow¹, Yunsheng He², Sibel Tekin³, Roger Lane³, Jane Xu⁴, Linda Mancione³, and Mihael Polymeropoulos². (1) Neurology, Indiana University School of Medicine, Indianapolis, IN, USA, (2) Clinical Pharmacogenetics, Novartis Pharmaceuticals Corporation, Gaithersburg, MD, USA, (3) Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, (4) Biostatistics, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Objective: To investigate the impact of APOE genotype on the symptom profile of mild cognitive impairment (MCI). Design: InDDEx study is a prospective randomized multicenter double-blind placebo-controlled investigation of rivastigmine on time to clinical diagnosis of dementia in subjects with MCI. Study entry criteria included clinical dementia rating (CDR) stage = 0.5, NYU paragraph recall < 9, 17-item Hamilton Depression Test (HAM-D)<13 and HAM-D item 1 score <1.

Materials and Methods:DNA extraction used Puregene DNA isolation kit (D-50K) on pharmacogenetic samples from 494 subjects. Cognitive assessments included Alzheimer Disease Assessment Scale Cognitive (ADAS-cog), Mini Mental State Examination (MMSE) and a cognitive battery for assessment of memory, attention and executive function. Behavioral assessment employed Neuropsychiatric Inventory (NPI) and Beck Depression Inventory (BDI). Activities of daily living were assessed by Alzheimer Disease Cooperative Study Activities of Daily Living Scale (ADCS-ADL). Hippocampal volumes were measured on the magnetic resonance imaging scans. Differences between the groups were tested by ANOVA for continuous demographics variables and chi’quare tests for the discrete variables. An ANCOVA model adjusting for baseline MMSE scores was used to test group differences in ADAS-cog and cognitive battery subitems and hippocampal volumes.

Results: Forty percent of the subjects were APOE4 allele carriers. At baseline, MCI subjects carrying APOE4 allele had lower MMSE (p<0.01) and higher ADAS-cog (p<0.0001) scores. ADAS-cog sub-item differences were observed in word recall, delayed word recall, word recognition, naming and orientation. APOE4 allele carrying subjects had greater deficits on NYU delayed paragraph recall and Buschke free & cued selective reminding tests, and on the ADCS-ADL scale (p<0.0003). They also had smaller hippocampal volumes (p<0.002).

Conclusion: In MCI subjects, the APOE4 allele is associated with greater cognitive and activities of daily living deficits as well as reduced hippocampal volumes.