Introduction
Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease and related dementias (ADRD), including amyloid-β (Aβ42), phosphorylated tau (P-tau181), and total tau (T-tau), are known to differ by cognitive status, but their power for predicting future transitions is less established.
In multi-center studies, assay variability and demographic heterogeneity may confound true associations.
Data and Methods
We analyzed longitudinal data from National Alzheimer’s Coordinating Center (NACC) case series, including 4,077 observations from 1,595 participants across 8 Alzheimer’s Disease Research Centers (ADRCs).
We only included participants who had a CSF sample taken 6–18 months prior to a cognitive assessment.
We investigated three cognitive status transitions: Normal Cognition to Cognitive Impairment, Cognitive Impairment to Normal Cognition, and Cognitive Impairment to Dementia.
Using linear regression, we evaluated associations between transitions in cognitive status with prior-year ADRD biomarker concentrations. Models were adjusted for ADRC site, assay type, and potential demographic and medical confounders (any variable that changed the main association by 10% after adjustment).
Key Findings
1. Aβ42 was significantly lower in individuals with normal cognition who later transitioned to impaired cognition (adjusted difference: -135 (95% CI: -235, -34) compared those who remained normal.
2. A similar association was seen for individuals with impaired cognition who later transitioned to dementia (adjusted difference: -99 (95% CI: -163, -35) compared those who did not transition.
3. The opposite association was observed for individuals with cognitive impairment who later reverted to apparent normal cognition compared to those who remained impaired (adjusted difference: 115 (95% CI: 32, 197)).
4. P-tau181 (adjusted difference: 21 (95% CI: 11, 31)) and T-tau (adjusted difference: 142 (95% CI: 67, 216)) were higher in individuals with normal cognition who transitioned to cognitive impairment compared to those who did not transition.
5. Associations between P-tau181 or T-tau and transitions from cognitive impairment were in the expected direction but not statistically significant.
Conclusions
CSF ADRD biomarkers, particularly Aβ42, may be predictive of future cognitive status transitions. More work is needed to evaluate the prospective predictive power of these biomarkers accounting for the specific time between measurements, as well as for their easier-to-measure counterparts in plasma.
This study was supported by the National Institute of Aging of the National Institutes of Health through the Michigan Alzheimer’s Disease Research Center (P30AG072931), as well as the University of Michigan Alzheimer’s Disease Center, Berger Endowment (G102865/321033). The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs.
