As a number of drug candidates to prevent, slow, or even halt Alzheimer's disease are being developed, a new urgency is driving efforts to develop tests that can diagnose the disease in its earliest stages. Those tests likely will come from a combination of cognitive psychology, molecular biology, genetics, and neuroimaging. A group of recent papers addresses various possibilities, particularly in the area of neuropsychological testing.

Wanted: The Right Test Combination. Unevenness Is Hint

In this month's Neuropsychology, Mark Jacobson and colleagues at the VA Medical Center in San Diego, California, and the University of California there, show that differential scores from several cognitive tests may allow researchers to distinguish people with preclinical AD from normal subjects.

The researchers chose to compare abilities on verbal versus visuospatial tasks. For 20 patients clinically diagnosed with AD, the researchers retrospectively analyzed test scores available from the period several years before diagnosis. They matched each patient in this preclinical AD group with a control person (by age, years of education, and Dementia Rating Scale score at the time of testing), who had not since progressed to clinical AD. Then they determined an asymmetry score, reflecting the difference between the verbal and visuospatial test scores, for each subject.

Both groups had similar mean scores on the individual tests. However, further analysis revealed significantly larger asymmetry scores in the preclinical AD group than the control group. Within this group, there was also a subgroup of patients who had larger discrepancies between verbal and visuospatial scores than others. Such within-group differences would have been obscured without the asymmetry analysis.

"Use of difference scores or contrast measures may be more sensitive than analyses of single test means in identifying subgroups of at-risk individuals with subtle, lateralized cognitive changes. Additionally, cognitive asymmetry might prove useful in populations with a relatively high base rate of preclinical AD, such as [ApoE4] carriers or those with a strong family history of AD. Finally, use of non-memory measures in conjunction with recall measures might improve our ability to detect preclinical AD," the authors write.

In this month's Archives of Neurology, Richard Camicioli and colleagues at Oregon Health Sciences University in Portland and elsewhere, describe a broader assessment of testing strategies. Camicioli et al. set out to determine whether several of the risk factors for Alzheimer's-poor performance on memory tests, reduced hippocampal volume, and gait impairment-are independent of each other. For example, memory loss might result from a shrinking hippocampus rather than being an independent factor, making measuring both redundant. They followed 108 patients in a prospective, longitudinal, observational study for a mean follow-up period of 6 years. Their outcome measure was any cognitive impairment as determined by the Clinical Dementia Rating Scale, and this was analyzed against a baseline memory test (delayed recall), a hippocampal volume assessment by MRI, and a test of gait speed (time to walk 30 feet). Analysis included adjustments for age, sex, depression, and apoE genotype.

The researchers found that both memory test performance and hippocampal volume at baseline were independent predictors of progression to a classification of "questionable dementia" (48 subjects) in a mean (SD) of 3.7 (2.4) years. These two risk factors, along with gait speed, also predicted progression to a classification of "persistent cognitive impairment" (38 subjects) in a mean (SD) of 4.4 (2.4) years.

"Assessment of risk factors for the development of cognitive impairment in elderly persons will need to include cognitive and motor measures as well as neuroimaging. A combined approach will be useful for studies targeting preventive therapies for those at highest risk prior to the onset of AD," conclude the authors.

Neuropsychological Tests Pay Attention To ApoE

Also in the April Neuropsychology, Raja Parasuraman and Pamela Greenwood of Catholic University, in Washington, D.C., and Trey Sunderland of the U.S. National Institute of Mental Health in Bethesda, Maryland, review the data linking the apoE gene, attention, and brain function, and suggest how psychophysical tests of attention might aid in early diagnosis of AD.

Having one or both copies of the E4 allel of the apoE gene confers an increased risk of late-onset AD. Parasuraman et al. point out that it has also been demonstrated that otherwise healthy people with one or both copies of the E4 allele show alterations in brain morphology (e.g., reduced hippocampal volume) and metabolism (reduced in temporo-parietal cortex). However, neuropsychological studies have produced discrepant results, with some finding lower scores for E4 carriers, especially in memory, but others reporting no significant differences.

The authors cite recent reports, including several of their own, that point to subtle cognitive deficits not easily seen on standard neuropsychological tests. In particular, there is evidence of differences in attention and working memory between those who carry the E4 allele and those who don't. In this review, the authors focus on the component of attention termed "selection," which they define as "the preferential processing of particular stimuli that are relevant to an organism's current goal." (By the taxonomy the authors use in this discussion, the other components of attention are vigilance and executive control.)

Two specific assays of attention selection on spatial tasks seem to be impaired in E4 carriers: covert attentional shifting (i.e., paying attention to things outside the central, focal part of the visual field) and dynamic spatial scaling (i.e., the ability to adjust the area of attentional focus depending on the needs of the task). Interestingly, the authors note, the same pattern of deficits is seen in clinically diagnosed, mildly demented AD patients.

How might the apoE4 gene produce changes in attentional shifting and scaling? Parasuraman and colleagues review the disparate-and sparse-data from neuroimaging, physiological, and pharmacological studies and suggest that the E4 gene product may impair cholinergic neurotransmission from the basal forebrain to cortical association areas. Intriguingly, several studies have shown that deficits in the cholinergic innervation of posterior parietal cortex produces deficits in attention shifting and scaling performance.

The authors acknowledge that much work remains to be done in elucidating the expression and activity of the apoE gene products, but they suggest the hopeful possibility that further study of attention and brain function in apoE4 carriers might lead to neuropsychological tests that can help detect AD in its earliest stages.—Hakon Heimer


  1. 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.

  2. 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.

  3. 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).

  4. Charcot noted that pathological aging was associated with cerebral atrophy, and commented that "Senile atrophy is usually complete; when partial it affects the left hemisphere." Jacobson et al examines asymmetry in cognitive performance using more traditional neuropsychological measures in people with preclinical cognitive decline (as determined prospectively). The paper by Jacobson provides data indicating that early dementia evolves asymmetrically. Post analysis showed that cognitive asymmetry was a less sensitive but more specific predictor than the CVLT, a verbal memory measure. This observation may improve targeting of therapies in clinical trials of pre-symptomatic individuals, if confirmed and extended.

    Reference: J.M. Charcot. Clinical Lectures in the Diseases of Old Age. William Wood and Co, NY, 1881, (translated by Leigh H. Hunt)

     ‑ Richard Camicioli

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  5. 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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Primary Papers

  1. . Do neuropsychological tests detect preclinical Alzheimer's disease: individual-test versus cognitive-discrepancy score analyses. Neuropsychology. 2002 Apr;16(2):132-9. PubMed.
  2. . Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol. 2002 Apr;59(4):601-6. PubMed.
  3. . The apolipoprotein E gene, attention, and brain function. Neuropsychology. 2002 Apr;16(2):254-74. PubMed.