We found that all molecular biomarker variables examined predicted time from cognitive normality to incident cognitive impairment. Hence, AD biomarkers in cognitively normal persons designate a preclinical stage of AD that is marked by greater risk for developing cognitive impairment due to AD. There were no differences in the predictive ability of the biomarkers. These findings, using a larger sample size (N = 201), a longer range of follow-up times (up to 7.5 years), and measurement of CSF and amyloid imaging biomarkers within the same individuals at approximately the same time, extend our previous work that showed that both CSF biomarkers6,7
and amyloid imaging25
predict incident cognitive impairment.
Combining the biomarker values with information regarding certain participant characteristics resulted in better prediction of incident cognitive impairment for every biomarker. Our sample included adults aged 45 to 65 years, because previous work indicates that abnormal CSF Aβ42
levels can occur as early as the mid-40s,23
consistent with data from families with autosomal dominant AD mutations suggesting that abnormal levels of the biomarkers studied here may occur 25 to 30 years before the appearance of dementia symptoms.29
The present results support the hypothesis that both abnormal biomarker levels and older age are important factors in determining time to incident AD (e.g., see ).
Moreover, our examination of the relationships among the biomarkers themselves indicated that CSF Aβ42
and tau interact to predict PiB uptake values, such that individuals with abnormal PiB uptake values usually have abnormal levels of both CSF Aβ42
and tau, rather than either alone. The pattern of results found among these biomarkers implies that abnormal changes in both Aβ42
and tau occur before, or coincide with, substantial deposition of fibrillar amyloid. This result is consistent with data from autosomal dominant AD families suggesting that changes in CSF tau and fibrillar amyloid deposition lag those of CSF Aβ42
Minority participants and men developed cognitive impairment more rapidly compared with white participants and women, after adjustment for biomarker levels. The majority (80%) of our minority participants were African American. It has previously been established that African Americans have a higher incidence rate of AD compared with Caucasians.30
Because biomarker levels were included in the models, the faster time to cognitive impairment for minority participants cannot be a function of differences across the groups in average biomarker values. This is an important area for future research. Consistent with our results, a recent study suggests that the incidence of mild cognitive impairment is higher among men than women.31
However, other studies suggest either no gender difference in incident AD dementia32
or a higher incident dementia rate for women compared with men.33
Autopsy data suggest that women are more likely to show dementia symptomatology in the presence of AD pathology,34
whereas our results, using biomarkers as indicators of underlying AD pathology, suggest the opposite.
aided in prediction of cognitive impairment in models testing tau and ptau, but not models testing Aβ42
, either alone or as part of the “ratio” biomarker values (i.e., tau/Aβ42
). Levels of Aβ42
, but not levels of tau and ptau, are associated with APOE
genotypes among cognitively normal individuals.23
genotype and Aβ42
may provide somewhat redundant information, and once Aβ42
is included in a model, APOE
genotype does not add any predictive value.
As in the models testing each biomarker alone, the expanded models including participant characteristics did not differ from each other in longitudinal predictive ability. Although much more research needs to be done in comparing imaging and CSF biomarkers, these results imply that decisions about whether imaging or CSF biomarkers are obtained to determine preclinical AD may eventually rely more on factors such as acceptability of the procedure to the individual and physician, the cost of the assays, and availability.
Although nearly all biomarkers were related to change in the global cognitive functioning composite score with time, not all of the individual tests that make up the composite showed significant associations. This may be attributable to the regional distribution of neuropathology in the preclinical stages of AD. Psychometric tests that rely on integrity of regions in the limbic system and the precuneus, such as episodic memory tasks and verbal fluency tasks, are regions that also show increased amyloid deposition,35
early structural changes,36
and reduced functional connectivity, even in individuals without clinical symptoms of dementia.37
Some individuals developed cognitive impairment but had normal baseline biomarker values. There are several possible explanations for this result. First, participants may have been misdiagnosed with cognitive impairment. Second, participants may be cognitively impaired due to a non-AD mechanism, or they developed abnormal biomarker levels postbaseline. Third, the biomarkers captured here may not reflect all pathology relevant to symptomatic AD. For example, amyloid tracers that bind strongly to fibrillar Aβ plaques may be unable to detect AD characterized predominantly by diffuse Aβ plaques.38
Likewise, some participants had abnormal biomarker levels, but did not develop cognitive impairment during the follow-up period. As noted above, biomarker abnormalities may occur 25 to 30 years before the appearance of dementia symptoms.29
Additionally, cognitive and brain reserve may have important roles in determining the time that individuals with abnormal biomarker levels will remain cognitively normal.39
Finally, our results support the hypothesis that molecular biomarkers of AD signal underlying AD pathology a decade or more before the appearance of cognitive symptoms,1,2
as we found that the majority of individuals with abnormal biomarker values followed 4 to 7 years remained cognitively normal.
Limitations of our study include the use of a convenience sample, so the extent to which these results are generalizable to the larger population is unknown. Some statistically significant differences reported here may be due to chance because we conducted multiple statistical tests. With decreasing p values, the likelihood that a difference is due to chance also decreases.
We find that AD biomarker profiles are associated with incident cognitive impairment, and hence, can be used to identify cognitively normal individuals at much higher risk of symptomatic AD for secondary prevention clinical trials. However, our results suggest that accurate prediction of future symptomatic AD for a specific individual will not depend on molecular biomarkers alone, but rather, will incorporate characteristics of the individual in making the prediction.