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RESEARCH ARTICLE |
a Sanders-Brown Center on Aging, College of Medicine, Lexington, Kentucky
b Department of Preventive Medicine, College of Medicine, University of Kentucky, Lexington
c Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina
d Institute on Aging, University of South Florida, Tampa
Kathryn P. Riley, 303 Sanders-Brown Building, University of Kentucky, Lexington, KY 40536-0230 E-mail: kriley{at}aging.coa.uky.edu.
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Abstract |
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4 allele of apolipoprotein E (APOE) has been associated with Alzheimer's disease and with milder forms of cognitive impairment. We investigated the possibility that the absence of the 4 allele may predict the maintenance of high cognitive function among very old individuals. Methods. Our data are from the Nun Study, a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. All sisters participate in annual functional exams that include the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests. High cognitive function was defined as intact scores on five of the CERAD tests. A total of 241 participants aged 75 to 98 met this criterion at the first exam.
Results. Findings showed that 62% of the 241 participants maintained intact scores on the five CERAD tests throughout their participation in the study. Life table analyses indicated that those without the APOE 4 allele spent more time with intact cognitive function than those with the 4 allele 
. Cox regression analyses indicated that those without the 4 allele had half the risk of losing their intact status during the study when compared with those with the 4 allele (p < .01).
Discussion. Our findings suggest that the APOE 4 allele may be included among the variables that predict high cognitive function in cognitively intact, very old adults. Although the presence or absence of the 4 allele is known to be related to the risk of dementia, it also appears to be related to maintaining high levels of cognitive function in old age.
CURRENT trends in longevity point to the need for a better understanding of the complex set of factors that contribute to the functional ability and quality of life of aged individuals. In recent years, the concept of successful aging has captured the interest of increasing numbers of gerontologists (Baltes 1993
; Rowe and Kahn 1987; Schulz and Heckhausen 1996; Seeman, Rodin, and Albert 1993). Rowe and Kahn 1997 have recently defined this concept as encompassing three domains: low probability of disease and disability, high cognitive and physical function, and active engagement with life. Our report addresses one aspect of successful aging by examining variables related to the maintenance of high cognitive function in a group of women over the age of 75 who were followed for more than 4 years with annual examinations of cognitive and functional performance.
Although a small number of factors have been associated with the preservation of normal cognitive function in older adults (Albert et al. 1995; Evans et al. 1993; Mortimer and Graves 1993; Rowe and Kahn 1997; Shimamura, Berry, Mangels, Rusting, and Jurica 1995; Snowdon, Ostwald, Kane, and Keenan 1989), overall there is relatively little information concerning the predictors of good cognitive function in very old adults. Variables that have been identified as risk factors for cognitive impairment and dementia also may be considered as possible predictors of successful cognitive aging. One such variable, the 4 allele of apolipoprotein E (APOE 4), has been associated with the risk and age at onset of Alzheimer's disease (Evans et al. 1997; Henderson et al. 1995; Mayeux et al. 1993; Meyer, Tschanz, and Norton 1998; Myers et al. 1996; Roses 1995; Saunders et al. 1996; van Duijn et al. 1995). The APOE 4 allele also has been linked to cognitive impairment in population-based studies of older adults (Berr et al. 1996; Corder et al. 1996; Feskens et al. 1994; Helkala et al. 1995; Hyman et al. 1996), and some studies have found an association between APOE 4 and subclinical symptoms of dementia and other forms of cognitive impairment or decline (Altstiel, Greenberg, Marin, Lantz, and Mohs 1997; Bondi et al. 1995; Haan, Shemanski, Jagust, Manolio, and Kuller 1999; Hui, Gao, Hall, Sahota, and Hendrie 1996; Jonker et al. 1998; Reed et al. 1994; Reiman et al. 1996; Yaffe, Cauley, Sands, and Browner 1997). Although some studies reported a weakening of the effect of APOE on cognitive function and dementia risk after the age of 70, other data supported a continuing effect of the 4 allele into very late life (Farrer et al. 1997; Payami et al. 1997; Rebeck et al. 1994; Smith, Thibodeau, Tsai, and Tangalos 1994).
We hypothesized that the absence of the APOE 4 allele would predict the maintenance of high cognitive function in individuals over the age of 75 (stated another way, the presence of the 4 allele would predict the loss of high cognitive function). We examined this issue in a group of women who participated in the Nun Study (Snowdon et al. 1996), a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. From among these women, we identified a group of participants whose scores on a battery of cognitive tests were all within the intact range at the first exam. The tests used to define intact cognitive function assess a variety of functions including orientation, memory, language, and visuospatial functions.
We required that the participants have intact cognitive test scores in order to select participants without significant cognitive impairments acquired before the start of the study. Our aim was to exclude individuals who could be classified as having mild cognitive impairments, that is, impairment in an area of cognitive function without meeting criteria for dementia. Recent findings on mild cognitive impairment show that approximately 10 to 15% of individuals with this condition convert to dementia on an annual basis (Jack et al. 1999; Petersen et al. 1997, Petersen et al. 1999). Thus, a sizeable proportion of these individuals may be seen as having an incipient dementia at a time when their cognitive deficits are mild and still limited in scope. In the present article, our analyses focused on a group of women who had intact scores on all cognitive tests in our battery, thus excluding individuals who may have had mild cognitive impairment. Therefore, our selection criteria are intentionally more stringent than criteria that exclude individuals who are diagnosed as having possible or probable dementia used in many studies because these criteria could include persons with mild cognitive impairment.
In this study, we report our findings on the relationship of APOE to the maintenance of intact cognitive function across four annual cognitive exams. Findings on the effects of the presence or absence of the APOE 4 allele on the incidence and prevalence of dementia in the full population also are presented, along with findings on the individuals who have mild cognitive impairments.
Throughout their adult lives, the women in our study had equal access to healthcare services and comparable financial, social, and spiritual support systems. They refrained from smoking, limited their alcohol intake, and were nulliparous. Although this unique set of features may limit the generalizability of findings from this population, these characteristics also increase the comparability of sisters across age ranges and birth cohorts, which is of particular value to the present investigation. Finally, because the overwhelming majority of the women who participate in the Nun Study are college educated and have been engaged in intellectually stimulating vocations, they may represent a group with high potential for successful cognitive aging.
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Methods |
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Study Population
Participants in the Nun Study (Snowdon 1997; Snowdon et al. 1996, Snowdon et al. 1997) are Catholic sisters who are members of the international congregation of School Sisters of Notre Dame living in seven regions in the United States. At the first exam in 1991–1993, the 678 participants who agreed to participate in all phases of the Nun Study were 75 to 102 years old (
). Attained educational levels among the participants range from grade school through doctoral level; 85% hold at least a bachelor's degree.
Participants were included in the present set of data analyses if they met the following selection criteria: First, each participant had to have been known for the APOE genotype and fully assessed on at least the first two exams, which provided follow-up data for a minimum of two points in time. The current observation period ended after the fourth exam, yielding a maximum of four points of follow-up. In addition, we excluded any participant who missed an exam at any point during her follow-up period. A total of 540 women met this initial set of selection criteria from among the 678 original participants in the Nun Study (88 sisters died before the second exam, 14 withdrew, 1 was out of the country on mission at the time of the second exam, 3 had incomplete exams, and 32 did not have APOE genotypes available). The age range for this group of 540 participants at Exam 1 was 75 to 98.
We divided the primary sample into two groups. The group of primary interest consisted of participants who met all of the selection criteria described earlier and who had intact scores on all five cognitive tests at the first exam. There were 241 women in this cognitively intact group. Among the remaining 299 women, 80 were classified as demented at Exam 1, and 219 were classified as impaired but not demented at Exam 1. These 219 participants, who had at least one impaired cognitive test score but did not meet clinical criteria for dementia, were included in data analyses for comparison purposes.
Measures
The variables used in all analyses were obtained from the convent archives, the annual exams of cognitive and physical function, and the APOE genotyping described next.
Apolipoprotein E genotyping.
Apolipoprotein E genotyping was performed using genetic material from buccal cells collected from living participants or from frozen or paraffin-embedded brain tissue obtained at autopsy. The laboratory methods used to derive the genotype are described in detail by Saunders et al. (Mayeux et al. 1998; Saunders et al. 1996). Those who performed the genotyping were unaware of the participants' cognitive test scores.
On the basis of the six standard APOE genotypes (2/2, 2/3, 2/4, 3/3, 3/4, 4/4), we used a dichotomous variable coded as presence or absence of any 4 allele.
Cognitive function and dementia.
The cognitive test battery includes measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD; Morris et al. 1989), which assesses memory, language, visuospatial ability, concentration, and orientation. In the Nun Study, this battery is administered by two trained field gerontologists. Five of the tests from the CERAD battery were used to define intact cognitive function: Mini-Mental State Exam (Folstein, Folstein, and McHugh 1975), Delayed Word Recall (Rosen, Mohs, and Davis 1984), Boston Naming (Kaplan, Goodglass, and Weintraub 1978), Verbal Fluency (Borkowski, Benton, and Spreen 1967), and Constructional Praxis (Rosen et al. 1984). These tests were selected from the full CERAD battery because they assess a variety of cognitive abilities and because of the availability of reliable normative data.
The standard cut point of 24 or greater was used to identify intact scores for the Mini-Mental State Exam. For the other four tests, cut points that were close to, but did not exceed, the 5th percentile for the normative data described by the CERAD group (Welsh et al. 1994) were identified to classify individual test scores as intact or impaired (Snowdon et al. 1997). The cut points for intact scores were as follows: 
13 for Boston Naming, 11 for Verbal Fluency, 4 for Delayed Word Recall, and 8 for Constructional Praxis. Participants judged to be cognitively intact in the present analyses had intact scores on all five tests.
Individuals who were classified as demented in our study had each of the following conditions (Snowdon et al. 1997): (a) impairment in memory and in at least one other area of cognition, (b) impairment in social or daily function (i.e., inability to use a phone, handle money, or dress oneself), and (c) decline in function from a previous level (observed during our study for the incident dementia cases, and inferred for those dementia cases present at the first exam).
Statistical Methods
Cox proportional hazards regression was used to estimate adjusted relative risks, that is, ratios of hazard functions (Allison 1995), and the Kaplan-Meier method of estimating survival functions was used to create graphic representations of the survival curves. We verified the proportionality assumption for the Cox regression analyses with the methods described by Allison 1995. The Breslow-Day test for homogeneity was used to test for the uniformity of the odds ratios across geographic strata.
Once we determined the rate of change score for each test for each participant, we calculated simple means for the rate of change for each selected subgroup (i.e., the group with the APOE 4 allele present, and the group without the allele). To derive p values for the comparison of these unadjusted means for different groups, we used t tests. All p values reported are two-tailed. The adjusted mean rate of change and corresponding p values were derived for each group from least squares regression analyses, using the general linear models procedure in SAS (SAS Institute 1985).
We calculated the annual rate of change for each cognitive test using the test scores and time period beginning with the Exam 1, continuing up to and including the first subsequent exam in which each participant either met criteria for dementia or obtained a score of zero on that test. Thus, each participant's rate of change was based on two to four test scores, depending on the length of her follow-up and whether she became demented or received a zero score at any point during her follow-up period. This rate of change was determined by a best-fit regression line for each individual participant. For example, if Participant A never became demented and never earned a zero test score; had scores of 10, 8, 6, and 4; and the time in years since the first exam was 0, 1, 2, and 3 for Exams 1–4, a regression analysis of these data would yield a slope of –2, indicating that, on average, Participant A declined two points per year. If, for example, Participant B had the same scores but became demented by the Exam 3, then only the first three test scores would be used in the regression that calculated her rate of change. If Participant C had scores of 10, 5, 0, and 0, then only the first three scores would be used in calculating her rate of change.
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Results |
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. These frequencies are similar to those found in other population-based studies (Berr et al. 1996; Feskens et al. 1994; Hyman et al. 1996; Myers et al. 1996). The presence of the APOE 4 allele was significantly related to the presence of dementia at Exam 1 (
Presence of the APOE 2 allele was not significantly related to the incidence or prevalence of dementia in the total sample of 540 or in the other subgroups of participants described in the next section.
Table 1 presents descriptive data for the primary sample of 241 cognitively intact participants as well as the total sample of 540 participants and for the subset of 219 participants who were classified as impaired but not demented. As seen in Table 1 , the presence or absence of the APOE 4 allele was associated with mean age at Exam 1, and with years of education only in the group of impaired but not demented participants. Table 1 also shows the adjusted relative risk of developing dementia by the last exam. The presence of the 4 allele was associated with a significantly higher risk of developing dementia in the total group of 540 participants. Among the 241 initially cognitively intact participants, those with the 4 allele were more likely to become demented (12%) than those without the 4 allele 
, although this did not reach statistical significance due to lower power.
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4 status. The 4 allele was associated with excess risk of dementia in six of the seven regions. An analysis of the relationship between APOE 4 status and dementia incidence revealed no statistically significant difference in this association across the geographic regions (the Breslow-Day test for homogeneity; p = .24). Further analyses that considered the length of follow-up and adjusted for age differences revealed a similar pattern of results.
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4 present and 4 absent) did not significantly differ on any of the tests at baseline. Table 3 also shows the adjusted mean annual point change in cognitive test scores during follow-up. Participants who did not have a copy of the 4 allele showed less decline on each test, and the differences in scores for the Mini-Mental State Exam and Delayed Word Recall reached statistical significance (ps < .05 and .01, respectively). For the data in both Table 3 and Table 4 , the two APOE subgroups were compared with respect to the annualized point change in each test using analysis of covariance with factors for APOE status, education, age, and baseline (Exam 1) test score as covariates.
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4 allele showed less decline on each test than those who had at least one copy of the 4 allele, with three tests reaching statistical significance.
Table 5 classifies the 241 initially cognitively intact participants as intact on all five cognitive tests, impaired but not demented, or demented at the last exam. Of the 241 participants who were cognitively intact at Exam 1, 65% of those without an 4 allele remained cognitively intact throughout their participation in the study compared with 41% of those with the 4 allele. Cox proportional hazard analyses showed that among the women who were intact at the first exam, participants with at least one APOE 4 allele were twice as likely to lose their intact status over time 
than were participants who did not have an 4 allele (Table 4 ). Further analyses separated the group into those under the age of 80 
and those aged 80 and older 
). The association between the 4 allele and cognitive status was substantially stronger in those 75 to 79 years old 
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4 allele and those without an 4 allele. The last conversion out of the cognitively intact state occurred at 4.4 years of follow-up. Life table analyses indicated that those without the APOE 4 allele spent more time with intact cognitive function than those with the 4 allele 
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; Welsh et al. 1994). Our results showed that among the cognitively intact participants, those with at least one copy of the APOE 4 allele were comparable with those without an 4 allele on all primary study variables measured at Exam 1. The similarity between these two APOE subgroups is probably due in large part to the requirement that these participants have intact scores on all five cognitive tests at baseline.
In contrast to these findings, individuals who were classified as impaired but not demented at Exam 1 and who had one or more copies of the 4 allele were younger and slightly better educated than those without the 4 allele. This finding is consistent with the possibility that higher education or younger age may have led to better preservation of cognitive function among those with the 4 allele. We will continue to follow this group of women with mild or limited cognitive impairments to determine if APOE status is related to their ultimate diagnosis of dementia.
Analyses of the relationship between APOE status, dementia, and geographic location revealed increased risk of dementia associated with the presence of the 4 allele in every region except Milwaukee. Although it is possible that there could be some factors that may have modified the effect of APOE on risk of dementia, given the small number of Milwaukee sisters with the APOE 4 allele, this negative finding is probably due to random variation.
Our data suggest that the effect of the 4 allele on cognitive performance is not evident in the initially cognitively intact women at Exam 1 but manifested itself as the participants were followed for an average of 4 years. The expected relationship between the APOE 4 allele and the prevalence and incidence of dementia was observed in our participants who were unselected for cognitive status (Evans et al. 1997; Mayeux et al. 1993; Roses 1995; Saunders et al. 1996).
Nearly two thirds of the women who had intact cognitive test scores at Exam 1 maintained this high level of cognitive function throughout their participation in the study. Our analyses showed that the absence of the APOE 4 allele was associated with a significant increase in the likelihood of remaining cognitively intact over time. Our findings highlight the ability of the presence of the 4 allele to predict subtle differences within the normal range of cognitive function over more than 4 years of follow-up. In our data, as in other reports, the findings were attenuated in higher age ranges (Jonker et al. 1998; Payami et al. 1997). We would note that the requirements for remaining in the cognitively intact group were quite strict: A score that fell into the impaired range on just one of the cognitive tests at any subsequent exam was enough to change a participant's classification from intact to impaired. Thus, among the women who were no longer classified as intact, the average amount of decline seen in cognitive function was small.
The fact that our participants were all women aged 75 or older, members of a religious community, and consented to participate in a longitudinal study of aging with an autopsy component sets them apart from many other groups. The selection criteria for the 241 participants in the primary sample included in the present investigation (cognitively intact individuals who were consecutively followed across four annual exams) may further limit the generalizability of our results. However, the sample included here was specifically selected to represent a group with high potential for successful cognitive aging to examine the possible impact of the APOE 4 allele on cognitive function in very late life. Thus, even though it may not be possible to generalize in a broad manner from the findings on these women, our data may in fact be useful in understanding some of the variables associated with successful aging.
Previous studies have shown a relationship between APOE genotype and cognitive function in initially nondemented individuals (Bondi et al. 1995; Petersen et al. 1995; Reed et al. 1994; Small, Basun, and Backman 1998; Smith et al. 1998). For example, Reed et al. 1994 found an association between the presence of the APOE 4 allele and poorer cognitive performance in fraternal twin pairs who had normal cognitive performance at baseline.
However, some recent studies that examined the relationship between APOE and normal cognitive function excluded participants who developed dementia at any point during the reported follow-up period. Small et al. 1998 examined baseline and 3-year longitudinal cognitive performance in individuals over the age of 75 and found that those with the 4 allele showed greater decline on two measures of episodic memory. In contrast, Smith et al. 1998 did not find the presence of the APOE 4 allele to be related to poorer cognitive performance in their sample of normal controls at baseline. At issue in these and other studies is whether or not findings of a relationship between APOE 4 status and cognitive performance in nondemented individuals is a reflection of a preclinical phase of dementia or a more direct influence of APOE on cognitive performance.
Our primary research question examined whether APOE was related to the maintenance of high cognitive function in very old individuals, involving three potential cognitive status outcomes at the end of the observation time: intact on all cognitive tests, impaired but not demented, or demented. However, we also conducted a separate set of analyses that excluded all participants who developed dementia during the follow-up period of four annual exams (a total of 19 participants), consistent with the approach used in some of the literature described earlier. These findings continued to show a significant relationship between APOE 4 and maintenance of high cognitive function. The non-4 group showed significantly less decline on Mini-Mental State Exam and Delayed Word Recall. Similar to the results reported in Table 4 , Cox proportional hazard analyses showed that among the women who were cognitively intact at Exam 1, the 4 group was twice as likely to lose intact status over time, even after the 19 participants who developed dementia were removed from the analyses 
p 
. Thus, our findings of a relationship between the APOE 4 allele and cognitive performance are not likely to be explained by the presence of an imminent preclinical dementia. However, continued follow-up data will be needed to determine the ultimate diagnostic outcomes of our participants.
In general, our findings suggest that the absence of the APOE 4 allele may be included among the variables that predict the maintenance of high cognitive function in late life. The longitudinal study of individuals who reach very old age with intact cognitive functioning can lead to more precise definitions of normal cognitive function in older adults as well as provide data on predictors of successful cognitive aging. As the Nun Study progresses, we will continue to examine the relationships between APOE status and the rate and magnitude of change in cognitive function. With the average age of our participants currently at 85 years, we are increasing the amount of longitudinal data collected on participants who reach the 9th and 10th decades of life, permitting us to assess the effects of APOE in the very oldest of populations.
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Acknowledgments |
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Footnotes |
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Received for publication June 1, 1998. Accepted for publication September 1, 1999.
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References |
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4 allele on cognitive results in a group of highly performing subjects: The EVA study. Neuroscience Letters 218:9-12. [Medline]4 allele in nondemented older adults. Neurology 45:2203-2206. 4 and incidence of Alzheimer disease in a community population of older persons. Journal of the American Medical Association 277:822-824. 4 in modulating effects of other risk factors for cognitive decline in elderly persons. Journal of the American Medical Association 282:40-46. 4 dementia, and cognitive decline in a population sample. Lancet 346:1387-1390. [Medline]4 allele of apolipoprotein E with poor performance on a dementia screen in African Americans. Ethnicity and Disease 6:266-271. [Medline]4 and the rate of cognitive decline in community-dwelling elderly individuals with and without dementia. Archives of Neurology 55:1065-1069. 4 allele in patients with Alzheimer's disease. Annals of Neurology 34:752-754. [Medline]4 association with dementia in a population-based study: The Framingham Study. Neurology 46:673-677. 4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology 44:1513-1516. 4 allele. Archives of Neurology 51:1189-1192. 4 allele for apolipoprotein E. New England Journal of Medicine 334:752-758. 2 allele is associated with an increased risk of early-onset Alzheimer's disease. Annals of Neurology 37:605-610. [Medline]This article has been cited by other articles:
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  F Zhang, M Lewis, G Yang, J Iriondo-Perez, Y Zeng, and J Liu Apolipoprotein E polymorphism, life stress and self-reported health among older adults J Epidemiol Community Health, April 1, 2008; 62(4): e3 - e3. [Abstract] [Full Text] [PDF]
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