Alzheimer's disease (AD) is the major form of age-related dementia worldwide, accounting for more than two-thirds of all dementia cases. The disease is characterized by a progressive loss of cognitive and intellectual functioning (Gilman, Reference Gilman1997). A number of risk factors for AD have been identified. The prevalence of AD increases with age, diabetes, depression, family history of Parkinson's disease and following head injury or exposure to solvents (Jorm et al., Reference Jorm1991; van Duijn et al., Reference van Duijn, Stijnen and Hofman1991; Ott et al., Reference Ott1995; Yoshitake et al., Reference Yoshitake1995; Devanand et al., Reference Devanand1996). Published research further suggests that low education levels are associated with increased prevalence of clinical AD (Gatz et al., Reference Gatz, Svedberg, Pedersen, Mortimer, Berg and Johansson2001; Qiu et al., Reference Qiu, Backman, Winblad, Aguero-Torres and Fratiglioni2001; Ravaglia et al., Reference Ravaglia2002). Women also have a higher risk for developing the disease than men, with the risk being markedly increased following menopause (Sherwin, Reference Sherwin2002; Sherwin Reference Sherwin2003). Additionally, slightly more severe cognitive deficits have been reported in AD in women compared to men (Buckwalter et al., Reference Buckwalter, Sobel, Dunn, Diz and Henderson1993, Henderson and Buckwalter, Reference Henderson and Buckwalter1994). These epidemiological trends may be a consequence of reproductive hormonal changes. Specifically, menopause results in a marked diminution in gonadal estrogen production in women (see Sherwin, Reference Sherwin2003, for a review). Estrogen plays a pivotal role in the maintenance and function of neuronal circuits in the brain and in resistance to neuronal damage (McEwen, Reference McEwen2001). The neuroprotective properties of estrogen are thought to be mediated at least in part by anti-amyloidogenic, anti-oxidative and ant-inflammatory mechanisms (reviewed in Barron et al., Reference Barron, Fuller, Verdile and Martins2006a). However, limited and somewhat mixed data exist regarding the association between endogenous levels of estrogen and cognitive decline (Manly et al., Reference Manly2000; Schupf et al., Reference Schupf2003). Based on some of our own findings, we here consider the factors that may be useful in predicting memory decline as a risk factor for Alzheimer's disease in older post-menopausal women.
We have previously noted the relationship between reproductive hormones (estrogen, leutinizing hormone (LH) and follicle stimulating hormone (FSH)) and global cognitive status in a large cohort of over 500 postmenopausal women (Rodrigues et al., Reference Rodrigues2008). However, with respect to the symptomatology of early stage AD, specific deficits in episodic learning and memory are the most commonly occurring cognitive signs of the disease (Collie and Maruff, Reference Collie and Maruff2000; Remy et al., Reference Remy, Mirrashed, Campbell and Richter2005). We have noted a lack of independent or combined association between endogenous estrogen status and episodic memory capacity in the same cohort of over 500 older postmenopausal women studied by Rodrigues et al. (Reference Rodrigues2008). This finding was observed despite the fact that the relatively large dataset allowed for the application of powerful statistical techniques, specifically with respect to multiple linear regression. This outcome is consistent with our previous report (Rodrigues et al., Reference Rodrigues2008) that estrogen did not have a statistically significant impact on global cognitive status in the same cohort; instead, gonadotropins, LH and FSH showed significant associations with global cognition. Further, gonadotropins have been reported to exert a significant role in AD risk and pathogenesis (reviewed in Barron et al., Reference Barron, Verdile and Martins2006b). However, in contrast to our findings, other studies have reported that endogenous estrogen does exert a significant effect on cognition (Drake et al., Reference Drake2000; Senanarong et al., Reference Senanarong2002; Wolf and Kirschbaum, Reference Wolf and Kirschbaum2002; Yaffe et al., Reference Yaffe, Lui, Grady, Cauley, Kramer and Cummings2000), and that estrogen shows no associations with gonadotropin levels (Hoskin et al., Reference Hoskin, Tang, Manly and Mayeux2004; Tsolaki et al., Reference Tsolaki2005). The discrepancies that exist in these studies merit further consideration, specifically with respect to issues concerning sample size, age of cohort, presence of other AD-associated risk factors (including the APOE ϵ4 allele) and the type of cognitive capacity being evaluated.
A specific threshold for estrogen may exist in relation to its influence on cognition: it is possible that clinically measurable effects of estrogen on cognition may only occur at higher concentrations (for example, after exogenous estrogen administration), compared with levels that are naturally present in post-menopausal women. In this context, it is relevant that several studies using measures of episodic memory have found an improvement in cognitive performance after exogenous estrogen replacement therapy (Phillips and Sherwin, Reference Phillips and Sherwin1992; Kampen and Sherwin, Reference Kampen and Sherwin1994; Jacobs et al., Reference Jacobs1998; Burkhardt et al., Reference Burkhardt2004). Indeed, considering the substantial number of investigations into the effects of estrogen administration on memory in post-menopausal women, it is perhaps surprising that relatively little evidence exists concerning the relationship between endogenous estrogen concentration and episodic memory. Exogenous treatments of estrogen in post-menopausal women may better match the naturally occurring biological levels found in pre-menopausal women, and may be more likely to have a significant impact on memory and learning. Further, given that the findings the we note here were obtained in a relatively older cohort (aged 75–86 years; Rodrigues et al., Reference Rodrigues2008), it is possible that women's endogenous estrogen levels in the earlier post-menopause years are more strongly associated with episodic memory functioning.
We further observed in this cohort (Rodrigues et al., Reference Rodrigues2008) that the possession of an APOE ϵ4 allele did not have a statistically significant impact on verbal episodic memory performance. This finding is again consistent with our previous investigation of global cognitive status in this cohort of older post-menopausal women (Rodrigues et al., Reference Rodrigues2008). This point notwithstanding, considerable empirical evidence exists regarding the APOE genotype and its role in modifying the risk of age-related cognitive decline and AD. However, the presence of the ϵ4 allele is associated with less than 50% of the population of patients with AD (Evans et al., Reference Evans1997). Furthermore, this allele may not be a significant risk factor in all ethnic groups (Evans et al., Reference Evans2003). In this cohort of post-menopausal women, other modulating factors such as education, age and other relevant biomarkers may have attenuated the impact of APOE genotype. We believe that this issue also warrants further discussion and investigation.
Elderly people have an enhanced risk of depressive disorders and symptoms (Wells et al., Reference Wells1989; Judd and Akiskal, Reference Judd and Akiskal2000; Judd et al., Reference Judd2000). Moreover, a number of studies have reported a potentially important link between age-related depression and memory decline (Kral, Reference Kral1983; Alexopoulos et al., Reference Alexopoulos, Young and Meyers1993; Devanand et al., Reference Devanand1996). In our cohort (Rodrigues et al., Reference Rodrigues2008), depression was found not to be a significant factor associated with episodic learning or memory performance. The existing literature suggests that symptoms of depression can have quite specific effects on elements of cognitive functioning. This consideration might be highly relevant in this context.
Our data were consistent with established findings linking increased age, reduced educational level and increased blood-borne beta amyloid to lower episodic memory capacity. Further, one element of memory capacity that was evaluated (delayed recognition performance) was significantly associated with statin use and with hypertension status in this cohort (Rodrigues et al., Reference Rodrigues2008). Statins are used as pharmaceutical agents to reduce plasma levels of cholesterol, by inhibiting the activity of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme. Accumulating evidence suggests that the use of statins lowers the risk of dementia, most likely via amyloid-related mechanisms (Jick et al., Reference Jick, Zornberg, Jick, Seshadri and Drachman2000; Fassbender et al., Reference Fassbender2001; Pedrini et al., Reference Pedrini, Carter, Prendergast, Petanceska, Ehrlich and Gandy2005). Statins may also improve endothelial homeostasis by increasing the accessibility of nitric oxide (Vaughan, Reference Vaughan2003), which may facilitate chemical messaging between cells.
Our findings indicated that hypertension was a risk factor for lower episodic memory capacity. A number of previous studies have linked high arterial blood pressure to increased risk of late-life dementia and cognitive decline (Knopman et al., Reference Knopman2001; van Dijk et al., Reference van Dijk2004; Whitmer et al., Reference Whitmer, Sidney, Selby, Johnston and Yaffe2005). Indeed, studies have reported that hypertension may increase the rate of cognitive decline both in patients with AD (Hanon et al., Reference Hanon, Seux, Lenoir, Rigaud and Forette2003) and in controls (Bellew et al., Reference Bellew, Pigeon, Stang, Fleischman, Gardner and Baker2004). However, other studies have indicated no significant association between hypertension and age-related decline in cognitive performance (Farmer et al., Reference Farmer1987, Reference Farmer, Kittner, Abbott, Wolz, Wolf and White1990; Scherr et al., Reference Scherr, Herbert, Smith and Evans1991; van Boxtel et al., Reference van Boxtel, Buntinx, Houx, Metsemakers, Knotterus and Jolles1998). With respect to our own findings pertaining to hypertension, high blood pressure may cause cerebrovascular disease (particularly ischemia), including relatively minor but chronic disturbances in cerebral perfusion, producing unfavorable effects on brain cell metabolism (Elias et al., Reference Elias, Wolf, D'Agostino, Cobb and White1993). These changes may increase the likelihood that individuals with incipient AD pathology will express symptoms of dementia, including cognitive decline. Hypertension may also accelerate the AD process directly (Skoog and Gustafson, Reference Skoog and Gustafson2003), insofar as similar biological mechanisms may be involved in the pathogenesis of both hypertension and AD.
In summary, we have noted here that, in our cohort (Rodrigues et al., Reference Rodrigues2008) age, beta amyloid concentration and hypertension were negatively associated with episodic memory function, whereas education and statin use had positive associations with episodic memory. A relationship between endogenous estrogen and memory functioning was not evident. In future, additional insight will be gained from extended longitudinal investigations of similar cohorts, employing a wider range of cognitive and functional assessments in enriched groups of individuals who are at increased risk of prodromal AD. Further, although a wealth of literature exists on the relationship between reproductive hormones and cognitive decline, AD risk and AD pathogenesis, the precise role of estrogen still remains unclear. This is reiterated in the controversy that exists concerning the putative benefits of hormone replacement therapy for improving cognitive capacity and as a therapeutic for AD (for recent review and meta analysis, see Hogervorst et al., Reference Hogervorst, Yaffe, Richards and Huppert2009). It is clear that in future large clinical studies which control for a number of relevant factors (as adumbrated herein) are required to address some of the discrepancies in the extant literature (Manly et al., Reference Manly2000; Schupf et al., Reference Schupf2003).
Conflict of interest
None.
