We found a faster rate of cognitive decline in incident AD patients with higher educational attainment compared to those with lower education. This association was particularly noted in the specific domains of executive speed and memory. Only incident AD patients were used in these analyses. Subjects were assessed at points surrounding the time at which incident AD was noted. The association between education and cognitive decline was still noted after controlling for differential cognitive performance at the initial visit and was not accounted for by literacy, vascular comorbidity, or depression.
Some previous studies have noted a similar association between education and rates of cognitive decline in AD. One study4
followed 143 patients with probable AD for an average of 3 (up to 5) years with the Folstein Mini‐Mental State Examination (MMSE)42
and the Mattis Dementia Rating Scale26
and found faster rates of decline for higher education subjects. The patients were clinic based, and those with very mild or very severe dementia were excluded. The study controlled for average dementia severity throughout the course of the disease but not baseline cognitive performance. Another study followed 132 probable AD patients semi‐annually for an average of 2.5 years (up to 7.5). A random effects model demonstrated faster rates of cognitive decline in patients with higher education.5
The patients in that study were self referred to a university based AD research centre and the MMSE was used as the cognitive outcome. Another study examined the effect of education in word list learning and animal fluency scores of 22 patients with dementia identified in a community based study.7
Higher education subjects with dementia (but not controls) had greater cognitive decline from their estimated premorbid cognitive ability levels. Other investigators followed 494 participants with AD semi‐annually for up to 4 years.8
Rates of decline for a composite measure of global cognition accelerated more rapidly for higher education subjects. These participants were recruited from an AD research centre and health care facilities in the Chicago area. In a previous report6
from the present cohort, 177 patients with AD were followed for 2.4 years and a memory score (the total recall of the Selective Reminding Test23
) was used as the cognitive outcome. In order to control for baseline cognitive performance, subjects were stratified into two groups based on their baseline memory performance. Using GEE, faster rates of memory decline were demonstrated for higher education subjects (but only for the subgroup with lower baseline memory performance). Most of the subjects in that report were prevalent cases and the effect of education in other cognitive domains was not examined. A recently published study examined rates of change performance in four cognitive tests over a 9 year period before AD incidence, for 215 future community based (south‐western France) AD patients.9
Higher education subjects experienced faster decline in the few years preceding dementia onset for all neuropsychological tests (including visual‐spatial memory, verbal fluency, abstract reasoning, and global cognition).
Using MMSE as the cognitive measure, a previous study reported slower rates of decline in higher education AD patients (mixture of mild and moderate levels of severity) seen in an AD research centre.14
Two previous reports have detected no significant association between education and rates of cognitive decline in AD, but the validity of their results is limited by their very low power: 28 AD patients in one16
and 16 in the other.15
The relationship was equivocal in some other reports. A study followed 410 AD patients (self referred to an AD research centre) with 17 cognitive function tests (from which a composite cognitive score was derived) annually for an average of 3.8 assessments.18
Using a random effects model the authors demonstrated faster cognitive decline in patients with higher education. However, after controlling for demographics and premorbid reading activities, the association with education did not remain significant. In another report,17
161 AD patients were followed for 2.2 (maximum 6) years with the Blessed Memory Information and Concentration Test.31
Using a random effects model the authors reported borderline non‐significant (p
0.06) faster rates of decline for higher education subjects; the AD patients were recruited from a mixture of different sources (physicians' private practices, AD research centre, community and nursing homes).
Confidence in the present findings is strengthened by several factors. This is one of the largest studies examining this hypothesis and provided sufficient power for detection and more precise calculation of effects of interest as well as the ability to control for potential confounders. The large range and variety of education in our multiethnic population offers the advantage of higher power and generalisability. Clinical diagnosis was based on uniform application of widely accepted criteria via a consensus diagnostic conference procedure. Evaluations were performed approximately every 1.5 years for an average of 5.6 (and up to 13.3) years, which provides multiple assessments of cognitive performance and therefore permits more accurate slope calculations. We used a comprehensive battery of cognitive assessment, permitting evaluation of a full range of cognitive domains. Previous reports studied more impaired AD patients (either prevalent cases or patients seeking medical attention) capturing the part of disease course corresponding to more advanced stages, while the design of the present study enables testing of the hypothesis during earlier stages of disease. In contrast to most previous studies which included AD patients who were self referred to clinics or university based AD research centres, the current investigation was performed in a representative sample of a multiethnic community, which provides increased generalisability of the findings.
The cognitive reserve (CR) hypothesis has been proposed as one possible explanation for the association between higher education and faster cognitive decline. The CR hypothesis suggests that there are individual differences in the ability to cope with AD pathology.1,2,43
The neural substrate of CR may take the form of a higher number of healthy synapses or neurons resulting in an increased number of remaining available synapses or neurons when a certain percentage has been affected by a pathological process. Alternatively, even if the number of neurons or synapses is the same, more efficient circuits of synaptic connectivity or more efficient use of alternative brain networks might exist in subjects with higher CR. Lower linguistic ability (as expressed by idea density and grammatical complexity) in early life has been associated with late life worse cognitive performance and heavier AD‐type neuropathological burden at autopsy.44
Therefore, it is also conceivable that CR related factors may even affect the development of AD pathology.
Epidemiological data supporting the CR hypothesis include observations that lower educational attainment is associated with increased risk for incident dementia.11,20,45,46,47,48,49,50,51
The above observations are consistent with the prediction that people with more CR can cope with advancing AD pathology longer before it is expressed clinically. However, this would mean that when AD is clinically manifested in patients with higher education, brain pathology is already quite advanced. Actually this has been demonstrated in some imaging studies.52,53,54,55
The CR hypothesis predicts that among AD patients with similar cognitive status, those with more CR would have (or be able to tolerate) more severe degrees of brain pathology. In an MRI study of AD patients, controlling for cognitive performance, higher levels of education were associated with more severe parietal atrophy (an indirect measure of brain AD pathology).56
In a Xenon study, AD patients with higher education52
manifested more prominent cerebral blood flow deficits (and hence more AD pathology) when controlling for clinical severity. Thus subjects with higher education can manifest clinical deficits comparable to those in subjects with lower education despite higher burdens of pathological involvement. Important for the current observation, this would predict that subjects with higher education would have a heavier brain pathological burden than those with lower education when AD is first clinically manifested. Results from the Religious Order Study, including clinical and neuropathological data from 130 older Catholic clergy, contested this.57
The association between cognitive function and AD pathology was modified by education: there was less effect of AD pathology on cognitive function for each additional year of education. However, because AD pathology progresses independently of educational attainment (or CR), when pathological burden becomes more severe and widespread, sufficient neural substrate is no londer available and a faster decline may ensue.
Alternative explanations for the education effect have been suggested. One possibility is that individuals with higher education have a younger age of onset of AD12,58
so that they are already at more advanced stages when compared with low education subjects. Our results do not support this since we know that the onset of clinical AD occurred during the evaluation period for these subjects and we included age as a covariate in the analyses. It is also possible that patients with higher education perform better on cognitive tests at time of diagnosis and therefore have more room for decline. However, we included baseline scores as covariates in the analyses and the results were unchanged.
We included pre‐incidence evaluations in the analyses. We know that AD pathological changes already exist in the brain for years before the disease is clinically manifested. Several studies have shown that subtle cognitive changes antedate the clinical diagnosis of AD by many years.9,19,44
Our incident AD patients' cognitive performance 3.9 years before incidence was already 0.37 SD lower than that of age, gender, and education matched controls. In addition, rates of cognitive decline were almost identical before and after incidence. We therefore feel that data collected for a few years prior to AD clinical incidence reflect the effects of AD associated pathological changes. In supplementary analyses which included only the post‐incidence evaluations, both the direction and the magnitude of the coefficients were very similar despite the smaller number of patients included in these analyses.
Many prospective studies have suggested that higher education is associated with reduced risk of incident AD.11,20,45,46,47,48,49,50,51
Assuming that the progression of AD pathology does not differ as a function of education, this delay in clinical onset may result from differences in rate of cognitive decline, differences in the time when cognitive decline begins (“inflection point”), or a combination of both. One could therefore imagine at least four hypothetical scenarios for differential cognitive decline prior to incident AD as a function of education (fig 2). The results of the present analyses are suggestive of model B‐a in fig 2: the lower incidence of AD reported in previous studies may be the result of a later inflection point and not of a slower pre‐incidence rate of decline for higher education AD patients. Graphic representations of cognitive decline over a 9 year period before dementia incidence (deriving from actual data from a previous population based study)9
are also supportive of the above model.
Figure 2Four theoretical scenarios of association between education and rates of cognitive decline. (A) The inflection point (the time when cognitive decline begins) is the same for both high and low education subjects, but high education subjects (more ...)
This study has limitations. First, our diagnosis of AD is a clinical one. It is conceivable that some of these subjects either do not have dementia or suffer from some other type of dementia. The used standard diagnostic criteria have a sensitivity of ~81% with a specificity of ~70%.59
Therefore, despite the use of standard criteria, the diagnostic expertise of our centre, and the thorough work up, in the absence of a biomarker there is always the possibility of assessment bias. Second, because we used pre‐incidence data and the post‐incidence follow up was relatively limited (1.8 years), it is possible that we have not fully captured the later stages of the disease. However, the hypothesis tested here is most relevant to the earlier disease stages (during which subjects are still testable with neuropsychological assessments). Third, although we examined rates of decline using both linear and non‐linear (quadratic) terms, it is possible that other types of non‐linear decline may be present.8,9,60,61
Fourth, it is always possible that education is just a surrogate for some other factor that is not included in the models and is truly associated with faster rates of cognitive decline. Fifth, years of schooling cannot completely capture all aspects of educational experience (that is, different quality of education in different educational systems, etc).