Apolipoprotein (APOE), vitamin B12, and folate were examined in relation to free recall among 167 community-based older adults (M=82.81 years). Cognitive support at encoding and retrieval was also taken into account. Participants were classified as APOE ε4 or non-ε4 allele carriers, and as either low or normal vitamin B12 or folate status. A significant association was identified between low vitamin B12, and the ε4 genotype in respect to free recall, but only in circumstances of low cognitive support. This result was retained having removed incident dementia cases up to six years following testing. A similar, but nonsignificant, trend was evident in relation to folate. The research is discussed with reference to vulnerability models, and genetic influences on brain reserves. ApoE, B vitamins, and episodic memory 3 Introduction Psychosocial models of life stress propose that the vulnerability of an individual faced with a stressful life event to adverse health consequences, is moderated by the combined influence of pre-existing personal dispositions and prevailing social conditions (e.g., Dohrenwend & Dohrenwend, 1981). Individuals of a particular disposition may be more vulnerable to negative outcomes if detrimental social conditions exist. A parallel exists between these vulnerability models and research investigating genetic associations with cognitive function in old age, and the extent to which non-genetic factors may influence such associations. It is possible that individuals of a particular genetic disposition are more vulnerable to cognitive deficits in later life given certain environmental conditions. Here, we test this vulnerability hypothesis in non-demented adults aged 75 years and older. Specifically, we investigated episodic memory performance in relation to apolipoprotein E (APOE), and two nutritional variables, vitamin B12 and folate. We evaluated how far APOE genotype and low B vitamin levels rendered individuals vulnerable to episodic memory deficits in old age. Also, task demands were taken into account by varying the level of cognitive support at the encoding and retrieval phases of the episodic memory task. Manipulation of such support is of interest as earlier work (Bunce, 2001a, b) suggests the tasks most sensitive to underlying physiological mechanisms in older adults, are those placing the greatest demands on cognitive processes (i.e., low cognitive support). Here, we ask if vitamin B12 or folate, and APOE genotype interact to influence episodic memory in very old age, and whether cognitive support affects that relationship. APOE is involved in cholesterol transportation, and is determined by the combination of three alleles, ε2, ε3, and ε4. There is clear evidence that possession of the ε4 allele is a risk factor for dementia (for a review see Farrer, Cupples, Haines et al., 1997). However, work investigating whether the presence of the ε4 allele confers a greater vulnerability to cognitive impairment among non-demented older adults, is more equivocal. For example, individuals possessing the ε4 allele exhibited more precipitous decline in face and word recognition (Small, Basun, & Bäckman, 1998), delayed word recall (Hyman, Gomez-Isla, Briggs et al., 1996), factor scores for episodic memory and processing speed (Hofer, Christensen, MacKinnon et al., 2002), memory and nonmemory composite measures (Jonker, Schmand, Lindeboom, Havekes, & Launer, 1998; Mayeux, Small, Tang, Tycko, & Stern, 2001), digit symbol and visuospatial skills (Mortensen & Hogh, 2001), and verbal and nonverbal reasoning (Deary, Whiteman, Pattie et al., 2002). By contrast, there is work suggesting no ApoE, B vitamins, and episodic memory 4 association between the ε4 allele and decline in fluid intelligence (Pendleton, Payton, van den Boogard et al., 2002), composite visuospatial and language factors (Mayeux et al., 2001), and proxy measures of IQ (Deary, Whalley, St. Clair et al., 2003). Cross-sectional work found no association between APOE and episodic, semantic, or working memory, perceptual speed or visuospatial ability, after controlling for dementia (Bennett, Wilson, Schneider et al., 2003). Regarding measures of global cognitive performance, some studies suggest decline to be greater in ε4 carriers (e.g., Bretsky, Guralnik, Launer, Albert, & Seeman, 2003; Fillenbaum, Landerman, Blazer et al, 2001; Jonker et al., 1998), whereas others show no such differentials (Winnock, Letenneur, Jacqmin-Gadda et al., 2002). Given those equivocal findings, research that has investigated APOE in the presence of another deleterious physiological factor suggests that ε4 carriers are indeed more vulnerable to cognitive deficits. For instance, cognitive impairment was greater in ε4-carrying older adults suffering peripheral vascular disease, and atherosclerosis (Haan, Shemanski, Jagust, Manolio, & Kuller, 1999), olfactory dysfunction (Borenstein Graves, Bowen, Rajaram et al., 1999), and low estrogen use (Yaffe, Haan, Byers, Tangen, & Kuller, 2000). To date, little research has investigated nutritional factors and APOE ε4 in respect to cognitive performance in older adults. Earlier work suggests two B vitamins, B12 and folate, may provide a particularly worthwhile avenue for exploration. For instance, among older adults vitamin B12 and folate have been associated cross-sectionally with episodic memory (e.g., Hassing, Wahlin, Winblad, & Bäckman, 1999; Wahlin, Hill, Winblad, & Bäckman, 1996), spatial, and working memory ability, and verbal fluency (Lindeman, Romero, Koehler et al., 2000; Robins Wahlin, Wahlin, Winblad, & Bäckman, 2001), and also with spatial copying skills (Riggs, Spiro, Tucker, & Rush, 1996). Intervention studies (e.g., Martin, Francis, Protetch et al., 1992; Meadows, Kaplan, & Bromfield, 1994) have established a link with improved cognition in demented or cognitively impaired individuals, and low levels of those nutrients have also been associated with an increased risk of developing Alzheimer’s disease (e.g., Wang, Wahlin, Basun et al., 2001). More broadly, there is evidence suggesting subclinical differences in those B vitamins may influence cognitive performance (see Calvaresi & Bryan, 2001). Together, those findings raise the possibility that possession of the ε4 allele and low B vitamin levels will increase vulnerability to cognitive impairment due to their combined deleterious effect on neural structures and processes. However, no empirical research has tested this possibility. Here, we address this shortfall in a population-based sample of ApoE, B vitamins, and episodic memory 5 dementiaand depression-free adults aged 75 years and over. As noted earlier, there is evidence that demanding task conditions are more sensitive to underlying physiological mechanisms than those that are less demanding. Therefore, we manipulated the level of task demands by varying cognitive support at both the encoding and retrieval phases of an episodic free recall task. Finally, given the possibility that cerebro-, and cardiovascular diseases are related to both APOE, and vitamin B12 and folate levels, we took those influences into account in our investigation.