Hippocampal atrophy rates and CSF biomarkers in elderly APOE 2 normal subjects

Abstract

Objective: To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. Methods:We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimer's Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF ␤-amyloid (A␤), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status.Results: APOE2 carriers demonstrated slower rates of hippocampal atrophy (p ϭ 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was Ϫ33 mm 3 /year (95% confidence interval Ϫ65 to ϩ0.4), or Ϫ0.5%/year, compared to Ϫ86 mm 3 /year (95% confidence interval Ϫ102 to Ϫ71), or Ϫ1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p ϭ 0.23) or overall cognitive change (p ϭ 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF A␤ (p ϭ 0.01), lower p-tau (p ϭ 0.02), and marginally lower tau (p ϭ 0.12). Conclusion:A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology. Neurology The association between APOE genetic polymorphisms and differing risks of developing Alzheimer disease (AD) has been well-described, 1,2 although the mechanism remains unclear. Approximately 70% of the population carry the common APOE3/3 genotype, 25% carry at least one APOE4 allele, and 5% carry an APOE2 allele.3 Even before clinical evidence of memory impairment, APOE4 carriers demonstrate more rapid rates of memory decline.4-7 On the other hand, carrying an APOE2 allele is associated with slower rates of memory decline 8 and is considered protective against the development of AD.

The APOE paradox: do attentional control differences in mid-adulthood reflect risk of late-life cognitive decline

“…The current results, however, contrast with past research suggesting e2 is protective (Chiang et al, 2010;Farrer et al, 1997;Helkala et al, 1996;Lippa et al, 1997;Wilson et al, 2002). The results reported here are based on a small sample of e2 carriers, but contribute to the small number of studies that have explored e2 effects on cognition prior to older-adulthood (Alexander et al, 2007;Alexopoulos et al, 2011).…”

Total ApoE and ApoE4 Isoform Assays in an Alzheimer's Disease Case-control Study by Targeted Mass Spectrometry (n = 669): A Pilot Assay for Methionine-containing Proteotypic Peptides

“…For instance, in animal models expressing different human ApoE isoforms, the rate and kinetics of amyloid ␤ oligomers are depend on the allele following the order 4Ͼ3Ͼ2 (78 -81). The same influencing order is found for brain amyloid ␤ accumulation across cognitively normal individuals as demonstrated by imaging studies (82)(83)(84)(85). Thus, a large body of evidence converges on a pivotal role of ApoE in the neurodegeneration process associated with a possible disruption of ApoE levels in the cerebrospinal fluid (7, 86 -95).…”

Hippocampal Volume Differences Between Healthy Young Apolipoprotein E ε2 and ε4 Carriers

“…It is of note that neither APOE 4 nor APOE 2 carriers differed significantly in hippocampal volume and memory function from the healthy young 3 homozygotes, who were enrolled in the study [5], though the 3 homozygotes had higher hippocampal volume compared to 4 carriers and lower compared to participants possessing the 2 allele (data not shown). Interestingly, it has recently been reported that elderly healthy APOE 2 carriers have slower rates of hippocampal atrophy compared to 33 homozygotes [20]. Differences in rates of atrophy in hippocampus between young individuals, possessing the APOE 2 allele, and 3 and 4 carriers warrant investigation especially in the light of the observation that brain mass begins to decline at the age of 20 years [5].…”