Longitudinal modeling of frontal cognition in APOE epsilon 4 homozygotes, heterozygotes, and noncarriers

Background: Fibrillar amyloid deposition preferentially affects the frontal lobes, temporal pole/neocortex, and posterior cingulate by age 65 years in APOE epsilon 4 carriers prior to the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), but is it impairing frontally mediated neuropsychological performance? Methods: A total of 71 epsilon 4 homozygotes (HMZ), 194 epsilon 4 heterozygotes (HTZ), and 356 epsilon 4 noncarriers (NC) who did not differ significantly in mean age (56.6 years), years of education (15.6), gender (70% women), or follow-up duration (6.3 years) had neuropsychological testing every 2 years including the Auditory Verbal Learning Test (AVLT) and frontal/executive tasks sensitive to psychomotor speed, working memory, problem solving, and activity. A subset also received the Iowa Gambling Task (IGT). Findings were then tested in a clinical sample of 27 patients with incident MCI and AD. Results: APOE epsilon A carriers had greater acceleration of decline (quadratic effect) than NC on the AVLT (p = 0.04) but not on any frontal test. APOE epsilon 4 HMZ had greater velocity of decline (linear effects) than NC on all mental arithmetic tests: paced auditory serial attention task (PASAT) 3 second (p = 0.01) and 2 second (p = 0.004) versions; and Wechsler Adult Intelligence Scale-Revised arithmetic (p = 0.048). IGT performance did not differ between 12 epsilon 4 HMZ, 27 epsilon A HTZ, and 44 NC. Among 27 patients with incident MCI and AD, the PASAT showed progressive decline preceding diagnosis in 50%. Conclusions: No frontal cognitive effects were as robust as memory decline. APOE epsilon 4 HMZ declined more quickly than NC on mental arithmetic tests related to frontal lobe-mediated working memory ability.