Whilst the role of the ApoE ε4 in Alzheimer’s disease is well established, its role in cognitive decline remains uncertain (Kleiman et al., 2006; Fliesher et al., 2007). Many studies have attempted to model the effects of the ApoE ε4 to examine whether it provides independent information on risk of future cognitive decline. The outcomes of these studies have varied widely. Some studies indicate that the ApoE ε4 may accelerate decline in those with cognitive impairment or Alzheimer’s disease (Consentino et al., 2008; Fratiglioni et al., 2004). Another study reported that the ApoE ε4 does not affect patients with preclinical Alzheimer’s disease (Estevez-Gonzalez et al., 2004). The ApoE ε4 has also been shown to impair specific domains such as episodic memory (Kozauer et al., 2008). One study indicated that the ApoE ε4 provides an independent contribution to the risk of cognitive decline, especially after the age of 50 (Caselli et al., 2004). The
ApoE ε4 has also been related to a faster decline in non-demented samples (Small et al., 2004).
A recent study showed that the ApoE ε4 allele appears to accelerate cognitive decline in patients with early stage Alzheimer’s disease (Consentino et al., 2008; Fratiglioni et al., 2004). To examine the effect of ε4 on the rate of cognitive decline in patients with Alzheimer’s disease, Consentino et al.
(2008) recruited patients from two longitudinal cohort studies and one clinic-based sample. The 3 samples studied included: 199 (48%) incident Alzheimer’s disease; 215 (54%) prevalent Alzheimer’s disease, and 156 (71%) patients diagnosed with Alzheimer’s disease. Over a 4-year follow-up period, in the incident sample, the presence of the ε4 allele was associated with more rapid cognitive decline, even after demographic adjustments. In contrast, ε4 was not associated with the rate of change in either of the other groups. However, after adjustment for disease severity or exclusion of severely impaired subjects, a faster decline in e4 carriers was also apparent.
This study shows that the ApoE ε4 influences cognitive decline in the earliest stages of disease with minimal effects or none in the moderate to severe stages.
In a large epidemiological study, Jorm et al. (2007) examined the effects of ApoE ε4 allele on cognitive functioning in 6,560 subjects and observed no association. The subjects were aged 20-24, 40-44, and 60-64 and all received cognitive testing. Whilst, the cross-sectional analysis showed differences in cognitive performance across the age categories, these authors failed to find an effect of the ApoE ε4 genotype on cognitive
functioning across the age categories or an age by genotype interaction. In this study, normal cognitive ageing between the ages of 20 and 60 years could not be attributed to the effects of the ApoE ε4 (Jorm et al., 2007).
In a subsequent study, these same authors Christensen et al. (2008) re-examined the effects of the ApoE ε4 allele on cognitive function in a sample of 2,021 subjects, aged between 65-69 years. This is the age when the ApoE ε4 exerts its maximal effect (Blacker et al., 1997). Over a follow-up period of 4-years, MMSE scores were significantly lower for ε4 homozygotes than heterozygotes or non-carriers. The effects of the ApoE ε4 on cognitive decline were found on the MMSE and Symbol-Digit Modalities test, after controlling for risk factors, such as previous head injury or low education. Christensen et al. (2008) suggested that it is possible for ApoE ε4 carriers to be more vulnerable to greater cognitive decline in the presence of other risk factors between the ages of 65-69 years.
In healthy ageing, the ApoE ε4 appears to have some influence in global cognitive function, however only in some specific domains. A meta-analysis of 38 studies (Small et al., 2004) reported that ApoE ε4 carriers scored modestly but significantly poorer in the areas of global cognitive function, episodic memory and executive functioning compared to ApoE ε3/ε3 carriers. Notably, ApoE ε2 carriers performed better than the controls in global cognitive function. This is consistent with the protective effect of the ApoE ε2 against Alzheimer’s disease.
In a retrospective analysis, using patients with established Alzheimer’s disease, Estevez-Gonzalez et al. (2004) used formal assessment to examine
the association between the ApoE ε4 allele and memory profile in 24 patients in the preclinical stage of Alzheimer’s disease who were either ApoE ε4 carriers (n=13) or ApoE ε3 homozygotes. (N=11). A one-way analysis of variance comparing ApoE ε4 carriers and patients with ApoE ε3 homozygosity showed that 2 years prior to AD diagnosis both genotype groups had similar memory performance on a number of tasks, including working memory, declarative memory and non-declarative memory.
Similarly, Caselli et al. (2004) examined whether memory loss could be identified in subjects prior to the onset of MCI by recruiting 180 subjects from the community at increased risk for Alzheimer’s disease due to the presence of the ApoE ε4 allele. A total of 180 subjects (mean age=60; SD:
6.2) were classified as normal on the basis of their MMSE scores=29.6 + 0.7;
45 were ApoE ε4/ε4 homozygotes, 42 ApoE ε3/ε4 heterzygotes, and 93 ApoE ε4 non-carriers. Over the 33-month interval, carriers of the ApoE ε4 had poorer performance on multiple measures of verbal memory tests including (total score on Auditory Verbal Learning Test (AVLT); delayed recall; and Selective Reminding Test (SRT), free and cued recall) compared to non-ApoE ε4 carriers. Additionally, these authors reported that carriers of the ApoE ε4 aged between 50 to 59 showed greater declines on the AVLT delayed recall, SRT free and cued recall, and Complex Figure Test. This study suggests that prior to the onset of MCI or dementia; ApoE ε4 carriers show a modest decline in memory skills commencing from the age of 50 onwards.
2.10 Summary
To summarise, Alzheimer’s disease is considered to be a multi-factorial disease. The risk for Alzheimer’s disease is not likely to be determined in any single time period but results from a complex interplay between genetic and environmental exposures throughout one’s life (Borenstein et al., 2006). All of these factors are likely to have synergistic or additive effect on the risk of Alzheimer’s disease which increases with age.
Also, the role of ApoE ε4 status in memory function remains controversial. It is not clear whether ApoE has a direct effect on memory in the absence of disease or acts only through association with Alzheimer’s disease. This may be attributed to the small effect size related to the ApoE and that very large samples (n>1000) may be required to find subtle associations or to determine the mechanism of action. Nevertheless, several studies have reported a higher proportion of ApoE ε4 carriers in patients with advanced Alzheimer’s disease and thus remain an important risk factor for developing the disease. The next chapter examines the risk of Alzheimer’s disease associated in individuals with subjective memory complaints or mild cognitive impairment.