Two different studies that attack the problem from the standpoint of both cognitive abilities and genetics appear in the April issue of Neuropsychology, published by the American Psychological Association (APA).
In the first study, researchers at the Veterans Affairs San Diego Healthcare System, and the University of California, San Diego, began with two bits of knowledge: First, subtle cognitive changes can precede disease onset by as many as seven to 10 years; second, brain images of many AD patients reveal asymmetrical -- uneven -- changes to the brain.
With those changes in mind, the research team scrutinized neuropsychological test data from 40 people, averaging about 75 years old, enrolled in a long-term study at the university's Alzheimer's Disease Research Center. Mark Jacobson, Ph.D., of the VA San Diego Healthcare System, and his co-researchers compared the cognitive performance of two groups within that sample. People in the first group of 20, the "pre-clinical" group, were diagnosed with possible Alzheimer's Disease within a year or two of testing. The other 20 people, who remained symptom-free for several years after testing, became a matched control group.
The researchers looked for whether either group had been markedly stronger on some neuropsychological tests than others, even when free of overt signs and symptoms -- possibly reflecting how Alzheimer's creeps up on the brain, damaging differing parts unevenly. The most revealing data emerged from tests in which people had to name common items from pictures, and to use actual 3-D blocks to copy printed block designs (visuoconstruction). These skills tests, which are sensitive to brain asymmetries, have been useful in following Alzheimer's Disease. They also tap into different brain regions that are among the earliest to deteriorate.
The data supported the team's hypotheses: The pre-clinical AD group had significantly greater discrepancies between naming ability and visuoconstruction ability, compared with the control group. The pre-clinical group also had a significantly higher than expected proportion of these asymmetric profiles compared with a larger normative group. In short, the verbal-versus-visuoconstruction gaps in the pre-clinical Alzheimer's group were bigger and more frequent.
Thus, the authors suggest that this kind of non-invasive, paper-and-pencil testing could be of particular value in populations known to be at risk, such as people carrying a certain gene or with a strong family history of AD. The key, says Jacobson, is to track not only the absolute levels of abilities, but also how they change over time -- especially from a healthy state -- in relation to one another.
"Our analyses," he continues, "show that although AD is typically marked by a global cognitive decline, some individuals in a pre-clinical stage may show a subtle change in one area of cognition prior to this global decline. As a result, in addition to looking at cognitive deficits, we might also look for large differences in one cognitive domain relative to another -- especially if this difference represents a change from earlier patterns of functioning."
Jacobson and his colleagues are now studying elderly people on a longitudinal basis, to see whether relative differences in cognition between pre-clinical AD and non-AD groups are always there, or represent actual changes from cognition before the disease. They also hope that research will better define cognitive asymmetry and raise the predictive power of cognitive profiling in AD to minimize false positives.
Jacobson et al. comment that genotype (carrying a certain allele, or type of gene, associated with AD) is consistently a more accurate predictor than asymmetry. However, genotype may be superior for evaluating disease incidence (rate at which AD occurs across a population) rather than onset in a given individual. In other words, genetic testing may indicate a higher probability of developing the disease, but neuropsychological testing may help indicate when it is time to start medication.
Along these lines, researchers at the Catholic University of America and the National Institute of Mental Health's Geriatric Psychiatry Branch are similarly interested in cognitive precursors to full-blown Alzheimer's Disease, and in linking them to carriage of a crucial genetic marker for AD. In their article, Raja Parasuraman, Ph.D., Pamela Greenwood, Ph.D., and Trey Sunderland, M.D., integrate disparate research findings (in everything from neuropsychology to neuroimaging, molecular biology and psychopharmacology) in hope of widening this avenue of investigation.
Parasuraman et al. explain that everyone has a gene called ApoE (short for Apolipoprotein E), which switches on production of a protein that helps carry cholesterol in the blood. However, the ApoE gene has three variations, or alleles. One seems to protect a person from AD (the å2, or epsilon 2, allele); another (å3) is most frequently inherited and confers an intermediate level of risk; the third (å4) confers the highest risk.
Parasuraman et al. note that carriers of the higher-risk ApoE allele have deficits in spatial attention and working memory that are qualitatively similar to those seen in AD patients, even though these carriers are healthy, middle-aged and asymptomatic. The authors speculate that the ApoE-attention link may possibly derive from altered transmission of acetylcholine, a key brain chemical, to the brain's posterior parietal cortex. This multi-function area helps manage spatial attention (shifting attention to different locations in the visual field), which is disrupted in AD.
The authors suggest that studying attention and brain function in carriers of the higher-risk ApoE allele may enhance understanding of the preclinical phase of Alzheimer's Disease and lead to better methods for early AD detection.
One speculation centers around the idea that AD may be similar to schizophrenia in that relatives who are unaffected nevertheless show some of the physiological markers of the disease. In the case of the å4 allele, carriers may show some of the attentional changes but never develop Alzheimer's Disease. Like the San Diego team, Parasuraman et al. are studying people longitudinally to evaluate this hypothesis.
Articles: Mark W. Jacobson, Ph.D.; Veterans Affairs San Diego Healthcare System; Dean C. Delis, Ph.D., and Mark W. Bondi, Ph.D., Veterans Affairs San Diego Healthcare System and the University of California, San Diego; and David P. Salmon, Ph.D., University of California, San Diego; "Do Neuropsychological Tests Detect Preclinical Alzheimer's Disease: Individual-Test Versus Cognitive Discrepancy Score Analyses." Also: Raja Parasuraman, Ph.D., and Pamela M. Greenwood, Ph.D., Catholic University of America; Trey Sunderland, M.D., National Institutes of Health, "The Apolipoprotein E Gene, Attention, and Brain Function."
Both articles appear in Neuropsychology, Vol. 16, No. 2.
(Full text of the articles is available from the APA Public Affairs Office and at
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