The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: findings from a nationally representative study.

We report a longitudinal extension of prior research on whether the e4 allele of the apolipoprotein E (APOE) genotype is a genetic marker of mild cognitive impairment (MCI). Epsilon 4 has long been accepted as a genetic marker of Alzheimer’s dementia (AD), of course (Corder et al., 1993; Strittmatter et al., 1993), with roughly half of individuals with probable AD diagnoses being carriers of at least one copy of this allele (e.g., Caselli et al., 2009). In contrast, previous research has produced inconsistent findings with respect to whether e4 is also a genetic marker of MCI (Small, Rosnick, Fratiglioni, & Backman, 2004). That result is puzzling because clinical evidence points to MCI as the AD prodrome (Petersen, 2011; Petersen et al., 2001; Serra et al., 2010; Smith, 2002). If MCI is prodromal to AD, it is natural to suppose that e4 would be a risk factor for both conditions. In a review of the methodologies of prior studies (Brainerd et al., 2011), we concluded that salient sources of both Type I error (i.e., uncontrolled variables that could produce spurious e4–MCI associations) and Type II error (i.e., uncontrolled variables that could mask e4–MCI associations) were present in the designs of these studies. On the Type I error side, no study implemented diagnostic criteria that excluded participants from MCI groups who had other diseases for which e4 is a risk factor. Thus, associations between e4 and MCI could be due to e4’s correlation with other diseases (e.g., see Hayden et al., 2009, for a study of undetected latent dementia that may be responsible for variation in associations between e4 and MCI). A source of Type II error is that MCI samples were usually small, so that failures to observe reliable e4-MCI associations could simply be due to low statistical power. Another source of Type II error is that designs failed to ensure that MCI samples consisted predominantly of individuals with significant impairments in episodic memory (amnestic MCI). MCI is normally divided into amnestic MCI (a-MCI) and nonamnestic MCI (n-MCI; Anderson & Schmitter-Edgecombe, 2010; Bhalla et al., 2009; Bizzozero, Lucchelli, Saetti, & Spinnler, 2009; Johnson, Schmitz, Asthana, Gluck, & Myers, 2008; Schmitter-Edgecombe & Sanders, 2009; Schmitter-Edgecombe, Woo, & Greeley, 2009; Seidenberg et al., 2009; Woodard et al., 2009). Only a-MCI is assumed to be prodromal to AD (Petersen, 2011; Petersen et al., 2001; Serra et al., 2010). Brainerd et al. (2011) reexamined the e4–MCI relation in a data set that minimized the sources of Type I and Type II error in prior studies, the Aging, Demographics, and Memory Study (ADAMS; Health and Retirement Study, 2011). For example, the ADAMS diagnostic procedures excluded participants from MCI diagnoses who had other diseases that seemed to explain cognitive impairment without dementia (CIND; see Plassman et al., 2008), and those procedures produced MCI groups that satisfy the key clinical criterion for a-MCI (see Petersen, 2004), which is episodic memory performance ≥ 1.5 SDs below that of healthy age mates. The ADAMS has the additional advantage that it is the only nationally representative study of cognitive impairment and dementia in older adults in the United States. Brainerd et al. (2011) used data from the initial wave of ADAMS testing (Wave A), which provided large samples of healthy control (HC), CIND, and demented (D) participants. On an age-adjusted basis, the e4 allele was found to be a risk factor for MCI (i.e., it was elevated in that diagnostic group, relative to the HC group) but not for other forms of CIND. The e4 allele was also found to be a risk factor for probable AD (it was elevated in that diagnostic group, relative to all other diagnostic groups), and to be a weaker risk factor for possible AD (it was elevated in that diagnostic group, relative to CIND groups other than MCI and to the HC group).