The primary finding of this investigation is the identification of subtle but significant differences in serial position recall among asymptomatic persons at risk for AD compared to healthy controls, despite comparable overall memory performance (total words recalled). The nature and pattern of the differences indicate greater reliance on immediate memory at the expense of episodic memory in the at-risk subjects, a pattern that has been shown to be associated with hippocampal dysfunction and repeatedly observed among patients in early stages of AD, but exhibited here in a milder form.
It is possible that the findings of this study represent the first cognitive changes of preclinical AD, and that differences in serial position profiles for AD children and controls will increase as the population ages. The relative prominence of recency in memory among AD children is consistent with the hypothesis that early declines in function in the hippocampus and entorhinal cortex in preclinical AD [16
] may be masked for a time by reliance on compensatory strategies or recruitment of other brain regions to maintain memory performance [30
]. If this is the case, we would expect to see progression of the serial position effects in subsequent waves of testing, without changes in total words recalled; as underlying disease progresses, however, overall recall performance would eventually be expected to decline. At present, as might be expected in a middle-aged asymptomatic cohort, the effect sizes of the serial position findings are small and not clinically meaningful. Follow-up is planned to determine what significance, if any, serial position patterns may have for preclinical detection of AD.
A strength of this investigation is that it utilized a rarely studied cohort of middle-aged persons who have one or both parents diagnosed with AD. This study was undertaken because little is known about how and when first symptoms of dementia are expressed in this important at-risk group, or about the genetic or environmental factors that underlie the presumed increased risk. The few prospective studies that have been conducted on AD relatives have involved mixed samples of siblings and children and small sample sizes [32
] or lack comparison groups of individuals without a family history of AD [22
]. Also, the focus of the most recent of these studies [22
] has been on documenting associations between cognitive performance and APOE, rather than examining family history as a potential predictor of preclinical cognitive patterns.
Our results suggest a specific effect of family history on preclinical memory performance which is independent of APOE. Two recent functional neuroimaging studies, one based on data from a subsample of WRAP participants [4
] and the other on an independent family history cohort [34
], have reported hippocampal activation patterns that are unique for family history, and like our cognitive findings, are independent of APOE genotype. These neuroimaging results provide a possible neurobiological basis for the subtle differences we observed in serial position patterns for AD children, since the hippocampus is crucial for the episodic memory processes necessary for normal primacy effects. Taken together, these findings suggest that an unknown family history factor may be an important confounder in most studies of preclinical AD.
The absence of APOE effects on memory performance was somewhat surprising, since several previous studies of cognitively intact samples [35
] have found small, statistically significant, APOE effects. However, other recent investigations, including the largest prospective study of young and middle-aged adults reported to date [36
] have found no effect of APOE on cognition.
We noted the possibility that mild memory deficits observed at midlife could be a prodrome of AD, that is, a pattern of cognitive performance reflecting very early symptoms of underlying AD pathology. An alternative possibility is that mild memory problems at midlife reflect a distinctive cognitive phenotype, that is, a set of neurocognitive characteristics that may or may not be progressive and may not necessarily be predictive of AD. Greenwood and colleagues [23
] have suggested that the attentional deficits that they have observed in middle-aged persons in relation to APOE genotype may be more consistent with a cognitive phenotype than an AD prodrome. Unlike the findings of Greenwood and colleagues, the serial position changes reported in this study are characteristic of AD and are less likely to represent a non-AD phenotype. Clearly, however, longitudinal data will be needed to establish a static or progressive pattern for the serial position findings and the relationship of this pattern to AD risk.
Whether alterations in serial position recall, a known correlate of AD, have promise as a marker of preclinical AD remains to be determined. The WRAP project and other studies of AD children which are now underway (e.g., the Washington University Adult Children Study [37
] and as yet unpublished findings from the Framingham Offspring Study) will provide the data to address this question. It is unlikely that any single cognitive predictor will prove sufficiently discriminating at preclinical stages to identify individuals at risk of developing AD; however, combining early cognitive indicators with neuroimaging results or other biological markers such as the amyloid-binding ligand, Pittsburgh Compound-B [38
] may allow for the identification of groups of individuals who are at risk for the disease. This risk profiling would allow for prevention trials directed at slowing change in cognitive or biological markers of AD in asymptomatic persons.
This study has several limitations. Because autopsy confirmation of AD in a parent was available for only 10% of participants in the AD children group, there is a possibility of error in parental diagnoses of AD. We attempted to minimize any diagnostic misclassification by reviewing parental medical records to confirm the diagnosis of AD using NINCDS-ADRDA criteria. Another limitation concerns the relatively young ages of dementia-free survival that we required of control subjects’ parents. We were concerned that requiring both parents to survive without signs of dementia to age 85, for example, would severely limit the number of eligible controls. As additional autopsy information is obtained on AD children’s parents, and as control subjects’ parents continue to age, the accuracy of group membership can be clarified to some extent. As is the case with any prospective study of preclinical AD, we cannot be certain which children of AD parents will one day develop this condition and which will remain free of AD as they age. Longitudinal follow-up is planned.