In a previous study, we found that adults with DS with high initial levels of plasma Aβ42, but not Aβ40 or the ratio of Aβ42/Aβ40, had a 2.5-fold increased risk of incident dementia.11
The current study extends this analysis in the same study group to show that declining levels of Aβ42 and of the Aβ42/Aβ40 ratio are also associated with increased risk of incident dementia. Among adults with DS, the association of elevated Aβ42 with increased risk of dementia is consistent with studies showing elevated plasma levels of Aβ42 in other high-risk populations. Studies of families with AD mutations have shown elevated plasma Aβ42 levels in both symptomatic and nonsymptomatic individuals.30,31
Plasma Aβ42 and Aβ42/Aβ40 ratio levels were elevated in unaffected familial AD mutation carriers compared with unaffected individuals with familial AD without mutations. However, Aβ42 levels were lower in mutation carriers with incipient AD characterized as having a Clinical Dementia Rating = 0.5, supporting the hypothesis that Aβ42 decreases prior to overt disease.30
First-degree relatives of patients with late-onset AD without known mutations or genetic variants have also been found to have increased plasma Aβ42.32
Among elderly individuals without dementia, plasma levels of Aβ42 were also increased in women with MCI, who are at high risk of progression to AD,9
and high baseline levels and greater reductions in plasma levels of Aβ42 during follow-up have been associated with greater cognitive decline.10
In contrast, a prospective study examining plasma Aβ42 showed no difference in patients with MCI who progressed to AD.16
Other studies have found that low plasma Aβ42 or a low ratio of plasma Aβ42/Aβ40 was associated with more rapid cognitive decline or with the presence of frank disease.17,18,33
These inconsistencies may be related, at least in part, to the timing of Aβ measures in relation to disease onset and progression. If conversion to AD is associated with a decline in plasma Aβ42 or in the Aβ42/Aβ40 ratio, then plasma Aβ levels may already be low in those with MCI or incipient AD. Thus, given the long preclinical period for AD, it is important to control for stage of disease, and this can best be done in prospective, longitudinal studies with repeated peptide measurements in elders who are free of cognitive impairment at their initial assessment. In the current study, the development of dementia in adults with DS who were without dementia at baseline was strongly related to decreases in plasma Aβ42, decreases in the Aβ42/Aβ40 ratio, and increases in plasma Aβ40, suggesting that change may be a more sensitive biomarker of risk than level. Compared with individuals with increasing levels of Aβ peptides, incident dementia was 2.5 to 5 times more likely among those whose plasma levels of Aβ42 or the Aβ42/Aβ40 ratio did not change or declined by more than 0.5 standard deviations. These findings parallel those from a multiethnic cohort from Northern Manhattan.12
In that study, decline in plasma Aβ42 levels and in the Aβ42/Aβ40 ratio over a 4.5-year period was associated with a 3-fold increase in the likelihood of AD. In another study, higher initial plasma Aβ42 levels and greater reductions in Aβ42 levels were associated with more rapid cognitive decline in healthy elders without dementia.10
Similarly, an increase in the plasma Aβ40/Aβ42 ratio (comparable to a decreased Aβ42/Aβ40 ratio) measured at midlife predicted greater decline in a global measure of cognition and in cognitive status as measured by the Telephone Interview for Cognitive Status.14
These findings suggest that decline in plasma Aβ42 or the Aβ42/Aβ40 ratio might serve as a sensitive biomarker for incipient AD and may reflect aggregation of Aβ42 in senile plaques.7,12
Our results are also consistent with findings from longitudinal assessments of Aβ peptides in CSF, where decreases in Aβ42 are correlated with cognitive decline in episodic memory and cognitive speed.34
Prior studies, however, have not found significant correlations between levels of CSF and matched plasma samples of Aβ42 and Aβ40,35,36
suggesting that Aβ levels in CSF and plasma are not related in a simple way and that the source of Aβ synthesis in these 2 compartments is different.36
It has been suggested that some Aβ in brain parenchyma is eliminated through the vascular spaces, contributing to Aβ levels in blood,37
but other studies suggest that platelets are a major source of Aβ in plasma unrelated to CNS processes.38
Thus, there is as yet no consensus regarding how plasma Aβ is related to progressive CNS amyloid pathology. In most previous studies, the relationship between CSF and plasma Aβ levels was examined in cross-sectional samples and compared patients with MCI or established AD with controls without dementia.35,36
Future longitudinal studies comparing sequential measures of matched plasma and CSF Aβ levels may be an effective approach to address this issue.
In the current study, increasing levels of plasma Aβ40 were associated with increased risk of AD. In cross-sectional studies, increased levels of Aβ40, along with increased levels of Aβ42, have been found in plasma of adults with DS.21–24
We are not sure what role increasing Aβ40 may play in the pathogenesis of AD in DS. We speculate that increasing levels among adults with DS without dementia, who already have very high levels of Aβ40, may be a marker of rate of aging.
These new findings add to previous evidence indicating that change in levels of Aβ peptide in both blood and CSF are sensitive to progression of neuropathology in AD, both in the general population and among adults with DS. Our study is limited by a relatively small sample size with small numbers in high-risk groups. In addition, individual differences in Aβ peptide levels, as well as changes in these levels, are imperfectly related to risk of dementia, and the determinants of individual differences in both initial levels and the trajectory of change in Aβ need to be explored further before these assays can be used to inform diagnosis or predict individual risk. Differences in the formation of oligomeric forms of Aβ, in levels of autoantibodies to Aβ, or in other protective factors may modify the effect risk biomarkers. Thus, plasma Aβ levels are not useful for predicting future onset or to confirm diagnoses for specific individuals with DS at the present time.