Arbitrary associative memory: a candidate cognitive endophenotype for probable Alzheimer's disease
The genetic basis of sporadic, senile onset Alzheimer’s disease (AD) is not as well documented as familial, younger-onset AD. At present, there is no evidence to support monogenic inheritance in senile onset AD or “probable AD”. As far as genetic risk factors are concerned, the apolipoprotein E epsilon-4 allele is the only reliable genetic susceptibility factor for probable AD. The investigation of cognitive endophenotypes for probable AD, or cognitive markers of liability to the condition that are theoretically closer to its genetic mechanisms than its clinical phenotype, might assist in the identification of susceptibility genes for AD. This is especially the case if these cognitive differences reflect genetically predetermined differences in brain structure and function. The traditional view of probable AD is that cognitive dysfunction emerges many years, and possibly decades, after underlying brain neuropathological, metabolic, and structural changes have begun. According to this theory, while brain functional and structural changes might be present in middle age in people at risk of developing the disease, cognitive abnormalities emerge only when a “threshold” of neurodegeneration has been reached and unaffected brain regions can no longer compensate functionally for affected areas. An alternative viewpoint is that cognitive deficits are present in the earliest stages of probable AD, but that two issues have limited our ability to detect such changes: First, previous studies have utilised tests which are not sensitive to the earliest neurocognitive changes in the condition. Second, the heterogeneous clinical phenotype of probable AD has meant that the conventional approach of comparing mean scores on cognitive tests between low-risk and high-risk groups might be masking subsets of affected people within high-risk groups. The use of more sensitive tests, in conjunction with cognitive discrepancy analyses, which compare performances within high-risk groups on combinations of tasks (e.g., Test A versus Test B) that are related to the neuroanatomical changes in probable AD, might reveal cognitive markers of liability to the condition. The current research focused on middle-aged people with a parental history of probable AD. These people are at a greater risk of developing the condition themselves, than any other first-degree relative, and this risk might be independent of the apolipoprotein E epsilon-4 allele. People with a maternal history of probable AD might be particularly vulnerable to developing the condition themselves, with studies suggesting that this group is more likely than people with a paternal history to demonstrate patterns of brain structural and metabolic change in middle-age that are similar to those observed in probable AD. Thus, the identification of cognitive markers of liability to probable AD in offspring of probable AD patients, and in particular, those with a maternal history of the condition, has the potential to assist in the early identification of the disease and, if these markers turn out to be endophenotypic in probable AD, it might also lead to the identification of putative susceptibility genes for the condition. The research had two major aims. The first aim was to summarise the limited data on the cognitive functioning of people with and without a parental history of probable AD, and determine whether conventional between-group analyses could reveal differences in cognitive functioning between these two groups. To this end, the investigator conducted a meta-analysis of 17 relevant studies in literature, and examined the magnitude of cognitive impairment across several domains, with a particular focus on episodic memory (Study 1). As expected, effect sizes for all cognitive domains were small, and none were significantly different to zero. The largest difference between groups was found for visuospatial ability (d = 0.16), with offspring of probable AD patients outperforming controls. This was followed by verbal ability (d = -0.10) and episodic memory (d = -0.09), with offspring performing worse than controls. Effect sizes for all other cognitive domains, including global cognition (d = 0), executive function (d = 0), attention and concentration (d = 0), and perceptual speed (d = -0.04) were essentially zero. The results suggested that differences in cognitive function between high-and low-risk groups were present, but subtle, and raised the possibility that the use of more sensitive memory tasks and analytical techniques, could reveal more pronounced deficits in memory function in the offspring group. The second aim of the research was to determine whether differences in arbitrary associative memory function were detectable in middle-aged people with a parental history of probable AD, using conventional between-group analyses and novel cognitive discrepancy analyses. Arbitrary associative memory function was examined for four reasons: First, the arbitrary associative memory system is responsible for the rapid uptake of novel relationships. This function is considered crucial for all new learning and memory in humans. Second, arbitrary associative memory is heavily reliant on the medial temporal lobe – a region that is affected in the earliest stages of probable AD. Third, measures of arbitrary associative cued-recall are sensitive to the earliest changes in cognition in amnestic mild cognitive impairment and probable AD, but have not been utilised in parental AD. Finally, the arbitrary associative recognition literature suggests that the ability to recognise that two similar items belong together, or “within-domain arbitrary associative recognition”, is heavily dependent on the rhinal cortex. The rhinal cortex, in turn, is the site of the earliest neuropathological change in AD. The ability to recognise that two dissimilar items belong together, or “between-domain arbitrary associative recognition”, is more dependent on the hippocampus. The hippocampus is affected at a later stage in AD. The investigator reasoned that within-domain and between-domain arbitrary associative recognition function could be differentially affected in the parental AD group and conducted two studies to investigate this hypothesis. Based on the staging of neuropathological and structural change in probable AD, it was hypothesised that a subset of people with a parental history of the condition would perform more poorly on within-domain arbitrary associative recognition tasks, than on between-domain recognition tasks. In Study 2, 25 cognitively and neurologically normal people, aged between 45 and 55 years, completed four novel arbitrary associative recognition tasks, developed by the investigator in a series of pilot studies. They had no first-degree family history of any dementia. Two within-domain arbitrary associative recognition tasks (i.e., word-word, face-face), and two between-domain arbitrary associative recognition tasks (i.e., word-face, pattern-word) were developed. The purpose of the study was to examine the difficulty of the recognition tasks. The results demonstrated that the tasks did not suffer from floor or ceiling effects. Discrimination scores for the word-word (d’ = 1.81 ± 0.62) and pattern-word tasks (d’ = 1.58 ± 0.56) were not significantly different, but both were significantly higher than scores for the face-face (d’ = 0.64 ± 0.39) and word-face (d’ = 0.82 ± 0.41) tasks. Discrimination scores for the latter two tasks were also not significantly different. The results of Study 2 meant that discrepancies in within-domain and between-domain arbitrary associative recognition could be examined at “easy” and “hard” difficulty levels in people with a parental history of probable AD in Study 3. The word-word and pattern-word tasks comprised the “easy” cognitive discrepancy, while the face-face and word-face tasks comprised the “hard” cognitive discrepancy. Twenty three people with only a parental history of probable AD, and 30 people without a first-degree family history of any dementia, completed a range of clinical memory tests (e.g., California Verbal Learning Test-II), as well as arbitrary associative cued-recall (e.g., Paired Associate Learning Test of the Cambridge Neuropsychological Test Automated Battery) and arbitrary associative recognition tasks (e.g., novel word-word face-face, word-face, and pattern-word tasks). As predicted, mean scores on the clinical memory tasks were compared between groups, and no significant differences were found; however, contrary to predictions, offspring did not perform worse than controls on measures of arbitrary associative cued-recall and recognition. The hypothesis that group membership (offspring, control) and apolipoprotein epsilon 4 status (positive, negative) would not interact to affect memory test scores was partially supported, with significant interactions found only for average discrimination scores on the Face-Face and Word-Face tasks. No between-group differences were found on memory test scores when the parental AD group was broken down into maternal AD and paternal AD subgroups. Cognitive discrepancy analyses were conducted on z-scores for the arbitrary associative recognition tasks. It was hypothesised that, when z-scores on each within-domain and between-domain task were compared within groups (e.g., word-word minus pattern-word; face-face minus word-face), greater-than-expected percentages of offspring would perform more poorly on the within-domain tasks, than on the between-domain tasks – i.e., display negative cognitive discrepancy scores or negative cognitive profiles. Controls were expected to perform similarly on the within-domain and between-domain arbitrary associative recognition tasks – i.e., display neutral discrepancy scores. The hypotheses were partially supported: while associations between group (offspring and control) and profile type were not statistically significant, the percentages of offspring who displayed negative cognitive profiles were greater than expected by chance alone. This pattern was found for most indices of within-domain and between-domain arbitrary associative recognition function. Moreover, as predicted, the results were largely driven by the maternal AD group, with greater-than-expected percentages of these people displaying negative discrepancy scores. When task difficulty was ignored and z-scores for composite within-domain (e.g., word-word, face-face) and between-domain (e.g., pattern-word, word-face) variables were compared, the association between parental history type (maternal AD, paternal AD, control) and profile type (negative, positive) was statistically significant. By contrast, controls were consistently more likely to display neutral or positive discrepancy scores. The current research challenges the notion that differences in cognitive function are not detectable in middle-aged people at risk of probable AD and raises the possibility that deficits in arbitrary associative memory are endophenotypic in the condition. It is hoped that the knowledge gained from the present research will add to the growing body of literature attempting to assist in the early detection of probable AD and will encourage other researchers to search for cognitive endophenotypes for the condition, as it might provide some clues about its underlying neurobiological and genetic mechanisms.
arbitrary associative memory, Alzheimer's disease, cognition, parental history, endophenotype
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