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To examine whether reported age at onset (AAO) of dementia symptoms among participants with Alzheimer’s disease (AD) is later for those with fewer years of education and, if so, to see if it is attributed to delayed detection of symptoms.
National Alzheimer’s Coordinating Center Minimum Data Set (N=21,880 participants) and Washington University Alzheimer’s Disease Research Center (N=1,449 participants).
Reported AAO of dementia symptoms is slightly earlier for participants with more education. Participants with fewer years of education show greater clinical severity of AD at first assessment.
Symptoms of AD are recognized later among those with less education.
Low educational level is a risk factor for incident Alzheimer’s disease (AD).1 However, among individuals with the E280A PS1 mutation, all of whom would be expected to develop familial early-onset AD if they were to live long enough, we found that later reported age at onset (AAO) of dementia symptoms occurred for participants with lower education.2 Similar findings have been reported for most3,4 studies of individuals with clinical or autopsy-diagnosed sporadic AD. One investigation,4 using a regional sample of participants, reported that lower education was associated with both a later age at onset of symptoms and with greater severity of AD at presentation as reflected in scores on the Blessed-Roth Dementia Rating scale.5 These results suggest that it is not the onset of AD that is delayed, but that dementia symptoms are detected later among individuals with lower education.4
We sought to confirm these findings by examining whether age at onset of dementia symptoms and severity of dementia at first assessment, using alternate measures of dementia severity, were associated with education in two additional samples: one comprised of data from participants with a clinical diagnosis of AD enrolled in 30 Alzheimer’s Disease Centers (ADCs) across the United States, and a second made up of data from a single ADC.
Inclusion criteria for both samples were (1) receiving a clinical diagnosis of AD at the most recent clinical assessment, and non-missing data on (2) number of years of education and (3) AAO of symptomatic AD (ie, dementia onset).
The NACC sample was drawn from the 2003 Minimum Data Set (MDS), which contains information for all participants enrolled in Alzheimer’s Disease Centers (ADCs) supported by the National Institute on Aging. Education is coded as the highest grade or number of years of regular school completed. Participants in the data set were not evaluated or enrolled using a uniform protocol, and therefore variables in the MDS may reflect slightly different information content. The AAO variable refers to the reported onset of dementia symptoms, rather than the age at diagnosis. Data from participants enrolled in the Washington University Alzheimer Disease Research Center (ADRC) were removed from the NACC sample, because these data were analyzed separately.
Participants were enrolled in the longitudinal studies of the WU ADRC. Details concerning participant recruitment, enrollment, and assessment have been published.6 Amount of formal education is recorded as the total number of years of education completed. Information from the participant and the collateral source, typically a family member or close friend, is used by a research-trained clinician in assessing the absence or presence of dementia and, when present, to diagnose the likely cause of dementia and its severity using the Clinical Dementia Rating (CDR) scale.7
SAS/STAT PROC LIFETEST8 was used to estimate the survival curves of reported AAO of dementia symptoms for the education groups using the Kaplan-Meier Product-Limit method. Cox proportional hazard models9 using SAS/STAT PROC PHREG8 were used to test the effect of education together with demographic variables (sex, race, and birth cohort) on the survival functions of AAO. Three categories were used to reflect amount of education: Low = less than 8 years, Moderate = 8–11 years, and Normative = 12 or more years. Two birth cohorts were created, before 1920 and 1920 or after, based on a median split of the birth years in the NACC sample. To adjust for differences across the centers, ADC was used as strata in the proportional hazard models8 conducted with the NACC sample.
Reported onset of dementia symptoms occurred prior to first ADC assessment for most participants in both the NACC (97.6%) and WU samples (97.9%). ANOVA was used to examine education group differences in time from reported AAO to first assessment. Mini-Mental State Exam10 (MMSE) scores and CDR were used to assess differences between the education groups in the degree of impairment cognitive at first assessment. MMSE data were available for 86% of the NACC sample, but because the MMSE was not administered at WU until 1996, for only 35% of WU participants. CDR data were available for all WU participants, but were not reported to NACC until September, 2005, and therefore, were not available in the 2003 NACC dataset used here.
Sixty-five percent of participants were women, 83% were Caucasian, and 51% were born prior to 1920. Seventy-three percent of participants had 12 or more years of education, 19% had 8 to 11 years, and 8% had less than 8 years. Reported AAO was younger with increasing amount of education (log-rank test, p<.001; Figure, Panel A). This finding was confirmed in the Cox proportional hazards analysis when differences between the individual survival curves were tested controlling for sex, race, birth strata, and ADC (Table). The Moderate and Normative education groups showed a slightly faster rate of reported age of AD onset over time compared to the Low education group, and the Normative group had a slightly faster rate than the Moderate group (Table). Male sex and white race were associated with earlier, and birth prior to 1920 was associated with later, ages of reported onset. The mean±SD number of years from AAO to age at first assessment at the ADC was similar for the Normative (4.25±3.3), Moderate (4.29±3.2), and Low (4.28±=3.5) education groups (p=.71), although mean±SD MMSE scores at first assessment differed (p<.001) across the groups (Normative=18.0±7.2; Moderate=15.3±6.7; Low=12.9±6.3).
Sixty-three percent were women, 89% were Caucasian, and 38% were born before 1920. Over two-thirds (68%) had 12 or more years of education, 26% had 8 to 11 years, and 6% had less than 8 years. The finding in the NACC sample of an earlier AAO with increasing education was replicated in the WU sample (log-rank test, p<.001; Figure, Panel B). Given the decreased statistical power in the WU sample, the Cox proportional hazard model adjusting for demographic factors did not show significant differences between the individual survival curves associated with each of the educational groups. However, the hazard ratios representing the differences in AAO between the Moderate and Low, and Normative and Low, education groups (Table) were of approximately the same magnitude as those in the NACC sample. There was no meaningful difference between the Normative and Moderate educational groups. Male sex and White race were associated with earlier, and being born before 1920 was associated with later, AAO (Table).
Like the NACC sample, there was no significant difference between the Normative (3.7±3.1), Moderate (3.9±3.3), and Low (3.9±2.5) education groups in the mean±SD number of years from reported onset of AD symptoms to first assessment (p=.69). However, participants with Low education (45%) were more likely than those in the Moderate (28%) or Normative (17%) education groups to receive a CDR score indicating moderate or severe dementia (CDR 2 or 3) at their first assessment (p<.001), consistent with their lower (p<.001) mean±SD MMSE scores at that assessment (Normative=23.0±5.2; Moderate=19.7±5.0; Low=17.1±4.7).
Identification of factors that delay recognition of dementia symptoms is important in targeting individuals for treatment. As have others,3,4 we found that years of education has a modest association with AAO, such that reported onset of dementia symptoms is slightly earlier for participants with greater amounts of education. Together with the finding that the time from reported onset of symptoms to first assessment does not vary by education, these results suggest that individuals of varying educational levels do not differentially delay seeking medical attention after noticing symptoms, but that symptoms are recognized later among those with fewer years of education, as suggested by an earlier report.4
Persons with more education may be more likely to regularly be engaged in cognitive tasks or occupational roles that emphasize subtle changes in cognitive functions, leading to their earlier detection.4 Therefore, in assessing for dementia among persons with lesser amounts of formal education, clinicians may need to individualize their assessment procedures, such that changes attributable to memory and thinking problems in the cognitive, recreational, and social activities that the individual regularly engages are detected. Because recognition of early dementia symptoms may be associated with amount of formal education, these results also suggest caution among researchers when using self or proxy reports of memory impairment, and statistical adjustment for level of education may be appropriate depending on the research question.
As has been found in other studies, more recent birth years were associated with earlier ages at reported onset.3 Greater awareness of dementia, increasing recognition that AD is not an inevitable consequence of normal aging, and the development of better diagnostic tools over the years may account for earlier reported AAO in the later birth cohort.
Limitations of the study include differences across the ADCs in how AAO was assessed. Unfortunately, there is currently no universal, standardized way to measure age at onset of dementia symptoms. Further, reports of AAO are likely to be imprecise. The study sample consisted of individuals with an AD diagnosis who were enrolled in an ADC, and thus it is unclear the extent to which these results would generalize to all individuals with an AD diagnosis. In addition, enrollment in an ADC may itself be influenced by factors related to education, such as economic status.
Supported by grants P50 AG05681 and P01 AG03991 (WU ADRC) and U01 AG016976 (NACC) from the National Institute on Aging, Bethesda, MD. We are grateful to the staff of the National Alzheimer’s Coordinating Center for their contributions. Catherine Roe had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.