Mid-life plasma Aβ-40:Aβ-42 ratio, but not plasma Aβ-42 level alone, was associated with significantly worse late-life decline in global cognition, after adjustment for multiple potential confounders. Similarly, a greater temporal increase in Aβ-40:Aβ-42 ratio – but not Aβ-42 itself – from mid-life to later-life also predicted a significantly faster rate of cognitive decline.
When comparing estimates associated with the mid-life plasma Aβ-40:Aβ-42 ratio vs. the change in plasma Aβ-40:Aβ-42 ratio since mid-life, temporal change since mid-life appeared to be a slightly stronger predictor of decline on one of the cognitive measures. Furthermore, the association between accelerated cognitive decline and the observed temporal increases in plasma Aβ-40:Aβ-42 ratio is compelling biologically, as it is compatible with a plausible mechanism. Specifically, decreases in CSF and plasma Aβ are expected over time as soluble Aβ peptide gradually accrues into insoluble Aβ plaques in the brain – a probable early event in AD pathogenesis.22
Indeed, CSF Aβ42 is observed to decline during development of amnestic MCI and AD. To the extent that peripheral decline in Aβ-42 may be greater than that of Aβ-40,23
a temporal change in the Aβ-40:Aβ-42 ratio may provide a stronger indication of this pathology than Aβ-42 itself or a single measure of the Aβ-40:Aβ-42 ratio.
To our knowledge, no prior studies involving large cohorts have addressed the predictive ability of both mid-life plasma Aβ and change in plasma Aβ since mid-life, with regard to decline on repeated cognitive measures. Thus, our findings contribute uniquely to the literature. Nevertheless, results from recent investigations involving older subjects appear consistent with our findings on the Aβ-40:Aβ-42 ratio, indicating that this may be the most valuable predictor in terms of plasma Aβ. Graff-Radford et al.7
observed an association (p=0.02) between lower late-life Aβ-42:Aβ-40 ratio (i.e., higher
Aβ-40:Aβ-42 ratio) and subsequent decline on the Mattis Dementia Rating Scale24
among 379 persons (median age=77 years at blood draw) administered cognitive testing approximately 5 years apart. Similarly, Sun et al.10
reported a cross-sectional association between higher late-life Aβ-40:Aβ-42 ratio and poorer cognition among depressed elders (mean age=73.8 years). Most5,7,8
but not all4
studies of dementia that have addressed ratios between plasma Aβ-40 and Aβ-42 have identified significant associations. Overall, it appears that longitudinal studies measuring the Aβ-40:Aβ-42 ratio may hold the most promise for using plasma Aβ to identify persons at risk for late-life cognitive dysfunction.
In addition to measuring change in Aβ over 10 years, the present study has several strengths. First, measuring mid-life Aβ values likely yields less confounding due to age (and the accompanying variability in levels with aging3,9
) or other related health variables (e.g., vascular disease). In addition, we adjusted for a variety of potential confounders, including depression, heart disease, hypertension and dyslipidemia. While we did not collect data on some vascular measures (e.g., white matter lesions), it is reassuring that we found no change in estimates after controlling for lifetime history of a wide array of cardio- and cerebrovascular factors. This was especially important, as vascular disease may affect plasma Aβ levels,4,25
and cardiovascular disease may have an independent path to cognitive decline.26
Finally, the use of repeated cognitive measures allowed evaluation of differences in paths of change.
Limitations should also be considered. First, overall CVs for plasma Aβ-40 and Aβ-42 were high, due to plate-to-plate variation. Measurement variation could result in underestimation of relations between plasma Aβ and cognition. However, within-plate measurement error was low, and analyses corrected for the between-plate variation. Moreover, there was excellent within-pair reliability; thus, analyses of intra-individual change in Aβ would be less affected by measurement variability. Finally, generalizability is a concern in our population of largely Caucasian, female health professionals. Although biological mechanisms among these women are likely similar to those in the general population, research addressing diversity is needed: e.g., studies may examine differing impacts of mid-life plasma Aβ on age-of-onset of cognitive decline among ethnic minorities.
In conclusion, this prospective study provides preliminary evidence that higher plasma Aβ-40:Aβ-42 ratios at mid-life and later-life, as well as increases in the Aβ-40:Aβ-42 ratio between mid-life and later-life, may predict cognitive decline. These associations require confirmation in other large-scale, longitudinal studies. Interestingly, mid-life Aβ-40:Aβ-42 alone predicted later-life cognitive decline, suggesting that this ratio may prove valuable for early identification of those at high risk of cognitive impairments. Nonetheless, more work is needed to address whether changes in plasma Aβ-40:Aβ-42 ratio since mid-life are ultimately more sensitive predictors than Aβ-40:Aβ-42 ratio at a single timepoint. The benefits of such work are clear. Plasma biomarkers could aid in targeting prevention within large populations, by identifying high risk individuals years before clinical symptoms are evident.