Parasuraman R, Greenwood PM, Sunderland T.
The apolipoprotein E gene, attention, and brain function.
Neuropsychology. 2002 Apr;16(2):254-74.
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The three papers examine the important issue of whether subtle changes in psychometric measures can provide predictors as early as 3-5 years before patients develop an "end point" such as mild dementia or mild cognitive impairment (MCI). Many studies have performed these types of analyses, and much research suggests that changes in memory (particularly sensitive measures of memory acquisition and delayed recall) and in complex tasks requiring judgment and problem solving (executive function) are among the best and most robust predictors. Two of the three new papers (Jacobson and Marquis) agreed that measures of delayed recall were among the most sensitive. To this they add measures of asymmetric cognitive performance (Jacobson), gait speed, and hippocampal volume measures (Marquis).
A general problem inherent to studies of very early diagnosis and predictors is how to define absolute (preclinical) normality, an intermediate degree of decline in cognition on the road to AD, and then the stage of very mild but recognizable AD. The concepts of MCI and of CDR 0.5 are attempts to codify a transitional stage between normal and clear-cut AD. The types of cognitive deficits identified in all three studies are precursors of AD, and appear to be precursors of (formally defined) MCI. This raises the thorny question of whether these early deficits are not quite consistent with normal/optimal aging and represent "very mild MCI".
The relationship between ApoE4 and predictors of dementia is a tricky one. In principle, if a group of older people begin to show structural brain changes and cognitive deficits that definitely presage MCI and/or AD, then one would expect them to progress to AD, regardless of whether they possess the E4 allele (e.g. the Marquis study). Studies have yielded mixed findings about whether E4 accelerates the progression to develop AD, either in normals or in MCI. This debate is likely to continue until we have a clear idea of exactly what E4 does to promote AD.
This is a very good overview of the use of psychophysics to probe cognitive tasks that might be sensitive to early changes in AD. The finding that specific aspects of visual attention vary as a function of apoE genotype is especially intriguing. The mechanisms proposed by the investigators are obviously speculative but reasonable. I wonder about their argument for early effects on the cholinergic system, because most of the evidence now seems to indicate no decline, and maybe even an increase, in cholinergic innervation during early stages. But I think the use of sensitive cognitive tasks to probe early deficits is highly promising.
This very interesting article presents important knowledge on how the apoE isoforms affect brain function, memory, and memory dysfunction.
The functional aspect is a major plus, as it extends the simplistic consideration of seeing the role of apoE in Alzheimer's merely through the prism of the amyloid hypothesis. The field's current inability to advance the understanding of Alzheimer's disease and find a cure requires the withdrawal of the amyloid concept (Koudinov and Koudinova, 2002). The Parasuraman article widens the horizon of fresh ideas.
The authors' major functional suggestion is apoE?related modulation in the cholinergic system. This elucidation of this perspective for the mechanism of ApoE's effect relies mostly on future genetic studies but understates other possibilities already in hand.
One such possibility, the biochemical link betweem apoE and neural cholesterol homeostasis (Koudinov and Koudinova '2001), likely stays beyond the article scope as 'cholesterol' is not mentioned once in the entire article. If it were there, the functional triangle comprising apoE, cholesterol, and neuronal function would not only complete the picture, but would also raise further questions on the neurodegeneration specificity (Koudinov et al. '2002).
Alzheimer disease (AD) is defined by verbal memory loss in its early stages. However, changes in attention also occur. The study of attention in Alzheimer disease may have both theoretical and practical relevance (Della Sala, 2001). Sund et al. extensively review changes in attention in AD. They also provide data linking changes in covert orienting and a novel spatial scaling of attention task with the APOE e4 allele in non-demented (possibly pre-symptomatic) research subjects as well as work revealing impairment in attention in patients with diagnosed AD. While the authors acknowledge that their findings need to be extended, they remain of great interest. At the most simplistic level, such novel cognitive tasks might be helpful in predicting the onset of dementia in at-risk populations, complementing and extending more traditional neuropsychological, neuroimaging and clinical predictors (Marquis et al, 2002). The relationship between APOE, cholinergic function and attention is discussed, and supports inclusion of attention measures in clinical trials. The paper is comprehensive and should assist, and indeed inspire, further study of attention as a cognitive marker in aging and dementia. ‑ Richard Camicioli
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