The main finding of this study is that APOE e4 affects age-related memory performance even in the absence of MCI and dementia, and does so in a gene-dose pattern that mirrors AD risk. Further, APOE e4 HMZ, whose symptomatic onset of AD is typically during their 60s (15
), also experience declining MMSE scores and visuospatial skills during the same age-range despite their normal clinical status. By using a genetically enriched cohort and mixed model for cross-sectional and longitudinal data we were able to analyze adequate numbers of individuals in each of three APOE subgroups to demonstrate, for the first time, the profile and trajectory of cognitive aging in the absence of clinical impairment across the adult lifespan.
We expect AD to be more prevalent in APOE e4 carriers than noncarriers. The preferential effect of e4 carrier status on age-related memory decline, the subsequent decline in visuospatial function in e4/4 HMZ, and the similarity of our model-predicted memory decline with the original predictions of Corder et al for the age of onset of AD in each of these three genetic subgroups (12
) raises the possibility that accelerated memory decline in e4 carriers is caused by subclinical AD. Other lines of evidence support this explanation. We have previously found that e4/4 HMZ in their early 60s develop accelerated neuropsychological decline in a cognitive-domain specific pattern (pre-MCI) that anticipates the onset of clinically symptomatic memory loss by several years (19
). FDG-PET studies of individuals manifesting this pre-MCI pattern of memory decline have reduced cerebral metabolic rate for glucose (CMRgl) patterns in cortical regions that overlap those known to be affected by AD (20
). More recently, we have shown that PIB-PET studies of asymptomatic APOE e4/4 HMZ at this age reveal early amyloid deposition in AD salient regions (32
). Finally, AD-like neuropathology in thirty and forty year olds (33
) and in nondemented elderly (35
) is more prevalent and severe in APOE e4 carriers than NC.
Not all previous studies have supported this interpretation, however (38
). Driscoll and colleagues compared the cognitive trajectories of 27 clinically normal elders lacking AD pathology after death to 21 clinically normal elders with mild AD pathology and found that not one of 12 neuropsychological measures (including three specific for memory) showed any steeper decline in those with AD pathology (39
). Our data nonetheless show that healthy appearing APOE e4 carriers cognitively decline at a faster rate than NC, and that the decline has a cognitive profile that resembles AD. If we also accept that e4 carriers are likely to have a higher AD pathology burden at autopsy (40
), the discrepancy appears difficult to reconcile. Possibly the memory decline we observed is mediated by a non-amyloid mechanism (42
), analogous to the increased rate of ischemic heart disease (43
), cerebral infarction (44
) and mortality (45
), observed in e4 carriers. We suspect, however, that the resolution lies in the different methodologies including the longer duration of prospective observation of larger numbers of genetically defined participants in our study that facilitated the elucidation of this relatively subtle difference in cognitive trajectories between the different APOE groups.
APOE e4 may be a genetic cause of dementia prior to age 60 (47
), but the literature is divided on the potential effect of APOE e4 on cognitive functioning in healthy younger adults. Snowdon and colleagues reported psycholinguistic differences in twenty year old women that correlated with AD and neuropathological disease burden 60 years later (48
). Whalley et al. found that school age performances on psychometric tests were predictive of dementia in old age (49
), although subsequently it was shown this was explained by increased vascular dementia rather than AD (50
). In contrast, we found no correlation between APOE genotype and intellectual achievement as measured by educational and occupational outcomes (51
), although we have found middle age e4 HMZ to be more sensitive to the effects of fatigue (52
) and anxiety (53
) than noncarriers. Our current data show that age-related cognitive decline prior to age 50 is essentially identical in e4 carriers and noncarriers as a group, and any childhood or young adult differences are likely to be lifelong and superimposed on this APOE-age interaction.
A potential limitation of our study is that it is not population based, but instead genetically enriched for APOE e4. APOE e4 HMZ represent the single largest source of individuals whose risk for AD is nearly that of autosomal dominant mutation carriers. This small but important subgroup provides an opportunity to study the changes that may occur before the clinical onset of MCI and AD, and compiling such a cohort is not practical in a community based sample as current U.S. epidemiologic cohorts have demonstrated. In the absence of random community based sampling, however, we risk recruiting individuals concerned about their own cognitive health perhaps due in some to early stage AD. To address this we eliminated anyone who developed clinically symptomatic MCI or dementia at any point. While this might theoretically raise the possibility of survivor bias in our study, the number of clinical converters was small, and if anything would have reduced our sensitivity to the differential APOE e4 effect that we found. Also, the mean age of our cohort is quite young and 74% had at least two epochs of testing (85% for e4 HMZ) with mean followup duration of 5 years further reducing the likelihood that individuals with incipient symptoms were enrolled. Therefore, selection bias is unlikely to explain our findings.
Another potential limitation is the unbalanced distribution of age and APOE e4 carriers (especially HMZ) in this study. There were a greater number of participants over than under age 50 years, and a slightly older NC group (probably reflecting the predicted higher rates of symptomatic conversion in aging e4 carriers). Possibly APOE e4 effects at an even earlier age might be detected in a larger cohort of younger individuals and employing a memory measure with potentially greater sensitivity than the AVLT. The more participants, the greater the power to detect a change so the pattern of age imbalance (more older NC and fewer younger participants), if anything reduced the strength of our study making our findings all the more remarkable. Finally, the HMZ had slightly longer mean followup than NC. We elected not to limit the duration of followup data to achieve greater balance because the difference, though statistically significant, was small. We felt it was better strategically to err on the side of more than less data inclusion, and do not believe this had any impact on our results.
In summary, APOE e4 affects age-related memory trajectories with accelerating declines beginning prior to age 60 even in the absence of MCI and dementia, and does so in a gene-dose pattern that mirrors AD risk.