. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol. 2010 Aug;67(8):949-56. PubMed.

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  1. The Stanford Neurology Department held a journal club meeting on this paper, conducted by Geoffery Kerchner, M.D. This meeting brought out some concern that several conclusions appear faulty, controls are missing, and the comparison datasets are not defined or controlled. The analysis of ApoE genotype was only for “ε4 carrier status,” not by specific genotype, and the paper even reported that the carrier status indeed seemed to account for a substantial portion of the results.

    This journal club provided an opportunity for me to present and discuss an analysis of the exact same ADNI dataset CSF protein values reported in this paper (114 normal individuals, 200 MCI, 102 mild AD) that we conducted at the Stanford/VA Aging Clinical Research Center (with Art Noda, Beatriz Hernandez, and Jerome Yesavage). In our separate analysis, a major issue we see is that ApoE genotype may explain most of the CSF Aβ variation that occurs in the ADNI data reported in this paper. (See table.) As per our analysis, the ApoE genotype, not diagnosis, explains the CSF-Aβ divergences seen in the ADNI study. The abundance of the ApoE4/4 individuals in the AD group (22/102 subjects = 22 percent) versus their infrequency in the normal group (2/102 subjects = 2 percent), as well as similar variation in the same direction for ApoE3/4 (which is typical for both normal and Alzheimer’s groups), accounts for most of reported variance in this paper. Specifically, in our analysis, there is large significance for the comparisons for ε3/3 versus ε3/4 and ε3/3 versus ε4/4. (See table: normal versus mild AD) However, when changes for specific ApoE genotypes are examined independently, the differences between diagnostic groups for CSF Aβ is not significant (p >0.14 for all comparisons).

    In the paper, the absence of a control group description for the MCI subjects from Ghent (first non-ADNI comparison group) makes the interpretation of that dataset problematic, especially since their distribution was even further separated from the normal circles relative to the ADNI group. Further, the autopsy group (second comparison group) samples were collected within a year of death; thus, this replication group is probably a severely demented group, which may have had different levels of CSF proteins. The paper provides no ApoE genotype information to see how this critical factor could have affected the analyses of these two comparison groups.

    Our analysis of the ADNI data with respect to specific genotypes implies that it is not clear that CSF Aβ contributes any more information to diagnosis than do ApoE genotype and age. The relationship between a person’s ApoE genotype (not simply “carrier status”) and CSF Aβ must be studied more carefully, with respect to age and Alzheimer disease diagnosis, before any clinician should consider use of CSF Aβ as a diagnostic indicator. What is really missing in studies that have been conducted to date is how CSF Aβ levels change with respect to age in normal individuals according to ApoE genotype, particularly in subjects with the ApoE4/4 genotype. Peskind et al. (Peskind et al., 2006) have already shown that CSF Aβ42 shows a significantly and substantially greater decrease with age in subjects with an ApoE4 allele, and this work needs to be extended to a large population of subjects with the ApoE4/4 genotype across a broad age range.

    Another issue is CSF tau. This measure is highly related to cognitive impairment along the continuum from normal through MCI to mild dementia. The analysis of the ADNI data shows this relationship. (See table: normal versus mild AD) Of note, CSF tau appears to peak in mild dementia but may decline as neurons degenerate. The question then is whether CSF tau contributes any more information to estimation of clinical status than a proper medical history or cognitive testing.

    More generally, the attitude toward genotyping is an important issue in the medical community. The ApoE4/4 individuals seem to represent a group with extremely significant Alzheimer’s-related morbidity that is not getting proper attention. A consideration for research into preventive agents for AD is to focus on the ApoE4/4 individuals, who have a relatively more specific variety of AD that would likely facilitate study in this area greatly.

    References:

    . Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol. 2006 Jul;63(7):936-9. PubMed.

  2. Reply to comment by Wes Ashford
    Although it is true that ApoE genotype is associated with differences in CSF biomarker levels (e.g., Morris et al., 2010), our previous and more recent work has shown that it is not the most important measure for determining the likelihood of someone who is cognitively normal (clinical dementia rating, CDR, of 0) progressing to the earliest stages of AD dementia (CDR 0.5), at least over a several-year period of time (Fagan et al., 2007). In one part of our 2007 study, 61 cognitively normal elders were clinically followed for an average of three to four years after CSF collection. Thirteen of these individuals progressed to CDR >0 in that time span, while 48 remained clinically normal. There was no difference in the percentage of E4+ individuals in the two groups (each group comprised 31 percent E4+). Cox proportional hazard models revealed that education and the CSF tau/Aβ42 and ptau181/Aβ42 ratios, but not ApoE genotype, significantly predicted conversion from CDR 0 to CDR >0. In fact, after adjusting for the demographic variables (age, education, gender, and ApoE genotype), the hazard ratios of the two CSF measures actually increased (HR of tau/Aβ42 increased from 2.42 [95 percent CI: 1.15-5.08] to 5.21 [95 percent CI: 1.58-17.22]; HR of ptau181/Aβ42 increased from 1.78 [95 percent CI: 1.00-3.16] to 4.39 ([95 percent CI: 1.62-11.86]). This initial study was not suitably powered to test the effect of the various allele combinations.

    We are currently investigating this issue in a much larger cohort of clinically normal individuals with longitudinal follow-up. In these recent studies, we have found very similar results to the 2007 study, indicating that the tau/Aβ42 ratio is very predictive of which cognitively normal, CDR 0, individuals, will go on to progress to CDR >0. However, now the number of CDR 0 individuals we have followed is 164 instead of 61. Again, ApoE genotype was not predictive of who would progress over a three- to four-year period of time. In another study, we found that ApoE genotype did not contribute significantly in persons with elevated amyloid burden (as detected by amyloid imaging, PIB-PET) to the prediction of progression from cognitive normality to incident cognitive impairment and symptomatic AD (Morris et al., 2009). In our Adult Children Study (P01 AG026276), we are assessing the effect of parental family history of AD, as well as ApoE genotype, on the time course of fluid and imaging biomarkers of AD starting from middle age (age 45-74 years; 300 cognitively normal participants). We expect to learn much about the role ApoE genotype (and other factors) play in the initial appearance and subsequent development of AD neuropathology and its behavioral sequelae.

    References:

    . APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.

    . Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007 Mar;64(3):343-9. PubMed.

    . Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009 Dec;66(12):1469-75. PubMed.