Accumulating evidence suggests that the presence of AD biomarkers in cognitively normal persons is a harbinger of eventual cognitive impairment,13–15
and much current effort is devoted to developing therapies that can halt the disease process. When these therapies are ready for use, it is thought that they may be most effective if administered at the time that biomarkers show abnormal values, but before dementia symptoms occur.15
However, since biomarker levels may become abnormal a decade or more before clinical symptoms appear,32
it is vital to understand the time course between abnormal biomarker values, the onset of cognitive impairment, and characteristics that influence that time course, to avoid exposing healthy individuals to medications, and their potential side effects, many years before they are needed.
Our results indicate that among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, the time to incident cognitive impairment is moderated by education and brain volume. More education and larger nWBV appear to slow the rate of impairment onset in the presence of tau-related pathology, whereas individuals with both lower levels of education and smaller nWBV have the most rapid onset. As theorized by others, greater education may provide resistance to dementia in the presence of brain damage because more education may be associated with the use of particular cognitive processing approaches or enlistment of compensatory processes, or, may serve as a proxy for another factor, such as innate intelligence.5
Individuals with larger nWBVs may have sufficient neuronal resources to continue normal functioning in the presence of AD pathology for a longer time,33
and/or, these individuals may have experienced less neuronal neurodegeneration despite having similar abnormal biomarker levels as other individuals. Education and nWBV do not interact to predict future cognitive impairment when lower levels of brain tau and ptau are present.
Previously, cross-sectional autopsy studies including individuals with dementia as well as those with normal cognition prior to death have suggested that education and brain volume interact with AD pathology to predict concurrent cognitive performance.34,35
In these studies, education was found to interact with amyloid plaque, but not tangle, pathology. 34,35
In the present study, conducted only with individuals who were cognitively normal at baseline, we found a modifying effect of education and nWBV on incident cognitive impairment for tau-based, but not amyloid-based, pathology. In fact, the main effect of Aβ42
itself was not significant in the primary multivariate analyses. This is consistent with our previous finding, using a smaller subsample of these individuals, of only a marginally significant effect (p=.09) of Aβ42
on incident AD when education and nWBV were included in the same model.36
combined with education and nWBV to predict the slope of CDR-SB scores across the follow-up period, suggesting that Aβ42
interacts with education and nWBV in a similar manner to that exhibited by tau and ptau, although as shown in , the effect is less dramatic. With a longer follow-up period, or larger sample size, it is possible that a significant 3-way interaction effect among Aβ42
, education, and nWBV would be found using the endpoint of CDR>0. The categorical variable reflecting combined levels of the biomarkers, education, and nWBV was unrelated to the slope of scores on the MMSE. As pointed out by others,37
the MMSE may be less sensitive to cognitive decline compared to global dementia severity measures such as the CDR-SB and SBT.
Interestingly, nWBV was found to be associated with incident cognitive impairment even among individuals with tau levels below the baseline median. Brain volume decline, in addition to occurring as a consequence of neuron loss in AD, also occurs as a function of normal aging.38
Although based on small sample numbers, individuals with smaller nWBV and lower tau levels who developed cognitive impairment were less likely to receive DAT diagnoses as an explanation of their cognitive problems, compared to individuals with smaller nWBV and higher tau values. This suggests that individuals with smaller nWBV may be more vulnerable to cognitive impairment due to reasons other than underlying AD. However, this interpretation should be viewed with caution, since the effect of nWBV was not significant when examined in the presence of low ptau.
Relatedly, we found no effect of age on incident impairment in the multivariate models. As previously noted, age and nWBV are tightly correlated among our participants.36
Thus, when one variable is present in the model, the other adds little additional predictive power.
There were no significant effects of APOE4
status when considered together with the CSF biomarkers in predicting incident cognitive impairment. This result is similar to our previous finding that APOE4
did not increase the predictive accuracy of CSF biomarker models for development of incident AD.36
That study also demonstrated that APOE4
was helpful in distinguishing prevalent AD from normal cognition.36
It is possible that APOE
genotype, when tested together with CSF biomarkers, might show independent effects on incident cognitive impairment in studies using a larger sample size or longer follow-up period.
Limitations of the study include the use of a convenience sample as well as a relatively short average follow-up time of 3.3 years. Given these limitations, our results provide strong support for the brain and cognitive reserve hypotheses,1,5–8
and suggest that education and nWBV are influential in mediating the time to cognitive impairment when tau-based pathology is present.