Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, Baxter LC, Rapcsak SZ, Shi J, Woodruff BK, Locke DE, Snyder CH, Alexander GE, Rademakers R, Reiman EM. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med. 2009 Jul 16;361(3):255-63. PubMed.

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  1. This is a very elegant and important study. The researchers studied 815 participants using a mixed model approach for cross-sectional and longitudinal data to assess the potential effects of ApoE ε4 (ApoE4) on longitudinal decline in memory in the absence of mild cognitive impairment or Alzheimer disease (AD). In ApoE4 carriers, longitudinal decline in memory, as assessed with the Auditory-Verbal Learning Test (AVLT-LTM), started earlier (before age 60) and showed a greater acceleration than in non-carriers. These data are consistent with earlier studies of this group showing a more rapid decline in memory in ApoE4 carriers that was correlated with reduced cerebral metabolism 5-10 years before the onset of cognitive symptoms (see Baxter et al., 2003; Caselli et al., 2004; Caselli et al., 2007; and Caselli et al., 2008). Interestingly, as presented by van der Flier during the first ApoE symposium during ICAD 2009 and published by her group earlier this year (van der Vlies et al., 2009), cognitive decline in early AD is ApoE4-dependent. In a study including 99 patients with early onset AD and 192 patients with late-onset AD, patients with early onset AD showed a more rapid cognitive decline, as assessed by the change in scores on the Mini-Mental State Examination (MMSE), and in this group, non-ApoE4 carriers showed a greater cognitive decline than non-ApoE4 carriers. In ApoE4 carriers, there was no difference in the rate of cognitive decline between early and late-onset AD.

    As presented in the second ApoE symposium during ICAD 2009, we have follow-up data on our study showing detrimental effects of ApoE4 on performance in a translational test of object recognition (Novel-Image-Novel-Location [NINL]) in 116 non-demented healthy elderly study participants (mean age 81 years) (Berteau-Pavy et al., 2007) who were invited to return six and 18 months after the baseline session. Using a longitudinal study design, effects of ApoE4 on NINL test performance were assessed in study “dropouts,” participants who did not return for the second and/or third session(s), and “finishers,” participants who returned for all sessions. While the dropout rate was higher in ApoE4 than non-ApoE4 carriers, and ApoE4 carriers with a low NINL score were more likely to drop out of the study than those with a high NINL score, in finishers ApoE4 carriers had higher NINL scores than non-ApoE4 carriers, and the scores of these ApoE4 finishers did not decline over the 18 months of the study.

    Together, these results show that although the direction of these ApoE4 effects might depend on the study population (healthy elderly without MCI, MCI, early AD, or late AD), and the cognitive measure used, these results have important implications for clinical trials and emphasize the importance to assess ApoE genotype. For example, in the promising Dimebon data from Doody et al. (see Doody et al., 2008), a different proportion of ApoE4 carriers in the two treatment groups could have either contributed to the observed effect or have masked a larger therapeutic effect. In addition, and perhaps more importantly, the treatment response to Dimebon, as seen for several other drugs, might depend on ApoE4 status as well.

    References:

    Baxter LC, Caselli RJ, Johnson SC, Reiman E, Osborne D. Apolipoprotein E epsilon 4 affects new learning in cognitively normal individuals at risk for Alzheimer's disease. Neurobiol Aging. 2003 Nov;24(7):947-52. PubMed.

    Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004 Jun 8;62(11):1990-5. PubMed.

    Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, Woodruff BK, Alexander GE, Osborne D. Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol. 2007 Sep;64(9):1306-11. PubMed.

    Caselli RJ, Chen K, Lee W, Alexander GE, Reiman EM. Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Arch Neurol. 2008 Sep;65(9):1231-6. PubMed.

    van der Vlies AE, Koedam EL, Pijnenburg YA, Twisk JW, Scheltens P, van der Flier WM. Most rapid cognitive decline in APOE epsilon4 negative Alzheimer's disease with early onset. Psychol Med. 2009 Nov;39(11):1907-11. PubMed.

    Berteau-Pavy F, Park B, Raber J. Effects of sex and APOE epsilon4 on object recognition and spatial navigation in the elderly. Neuroscience. 2007 Jun 15;147(1):6-17. PubMed.

    Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D, . Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet. 2008 Jul 19;372(9634):207-15. PubMed.

    View all comments by Jacob Raber

  2. Caselli and colleagues show that in asymptomatic, clinically normal individuals with a mean age about 60, ApoE4 carriers have an increased mean rate of longitudinal decline on an auditory verbal learning test. Effects are ApoE4 dose-dependent. This decline, studied in a large cohort of individuals, supports the idea that a greater percentage of ApoE4 carriers are developing “preclinical” Alzheimer disease at an earlier age than non-carriers. Prior data show that amyloid deposition in the brain as reflected by amyloid imaging and a decline in CSF Aβ42 begins to occur in some ApoE4 carriers in their fifties. These data are consistent with there being subtle learning-related changes that begin to occur either about the same time or just after this pathology is beginning to build up.

    View all comments by David Holtzman

  3. A group of researchers at the Arizona Alzheimer’s Consortium led by Richard Caselli and Eric Reiman have been recruiting and following a large number of middle-aged persons who are either heterozygous or homozygous for the ApoE ε4 allele. Their current findings, based on extensive longitudinal study, make a very important observation about the relationship between carriage of the ε4 allele and cognition. While their subjects were still clinically normal, those with one or two copies of the ε4 allele experienced a decline in their delayed recall ability at an average age of 60 years. This observation is very valuable because it adds confirmatory weight to several suspicions about the relationship between ApoE ε4 carriage and Alzheimer’s disease. First, the results are consistent with the view that among the earliest clinical impacts of ApoE ε4 carriage is anterograde amnesia. This is of critical importance because it shows that ApoE accelerates the temporal profile of pathological AD. These findings support the contention that carriage of an ε4 allele lowers the age of onset of AD, on average. Furthermore, the results lend support to the use of ApoE genotype as a proxy for incipient AD.

    View all comments by David Knopman

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