Cognitive Aging, Alzheimers disease, and Cancer-related Cognitive Decline

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The goal of the parent grant is to study heterogeneity in cognitive aging and relationships between cancer-related cognitive decline (CRCD) and Alzheimer’s disease related dementias (ADRD). The broad research question is whether CRCD is the result of damage due to the cancer and its therapies that accelerate an underlying early ADRD or damage to similar systems as are involved in ADRD. To address this question we are testing ADRD plasma biomarkers and using the results to test the overarching hypothesis that breast cancer survivors ages 60+ with CRCD will have more plasma ADRD-pathology biomarker abnormalities than survivors with no cognitive abnormalities or contemporaneously assessed non-cancer controls. The originally proposed ADRD biomarkers in the parent grant were Aβ1-42, p-tau and neurofilament light chain [NfL]. These assays were planned in a collaborating federal laboratory where the director has left the institution. In the interim, Dr. Jeff Dage, a leading expert in plasma ADRD biomarkers, joined Indiana University (home of MPI Saykin) and the NIA National Centralized Repository for Alzheimer’s and Related Dementias (NCRAD). During the timeframe of this project there have also been significant new breakthroughs in the field of blood-based biomarkers for AD. Measures of Aβ42 and Aβ40 (reported as the 42/40 ratio), P-tau and neurofilament light chain (NfL) are now being used in clinical trials to screen for patients with AD pathology and monitor pharmacodynamic responses to new drugs. Additionally, a marker of reactive astrocytes, GFAP, has been shown to be elevated in response to amyloid pathology in the earliest stages of AD. These breakthroughs have been possible due to advances in the precision of the plasma biomarker assays, although this has also been accompanied by increased costs since the time of parent grant submission. With these rapid changes in the field, cost escalations and the implementation of the NIA NCRAD laboratory, this supplement will: 1) take advantage of the opportunity to move biomarker testing to the NCRAD laboratory, 2) use the supplemental funds to modify our assays to match the most advanced biomarkers in the field (Aβ1-42, Aβ1-40, P-tau181, NfL, and GFAP [new markers bolded]), and 3) expand the number of longitudinal samples that can be tested from two time points (n=617 samples) to a baseline sample and two longitudinal follow-up time points (n=817 samples). Responding to changes in the field that were not anticipated at the time of our parent grant submission will allow us to expand the parent grant aims to address new research questions in a robust, up-to-date manner with more sensitive assays, including use of prespecified cutoffs being established for P-tau181 in the NCRAD lab and comparison of the cancer survivor and control results to NCRAD standards. Additionally, because TLC participants were cognitively normal at baseline, adding testing of more longitudinal specimens will allow us to better understand the time course of any ADRD biomarker changes. The parent grant is now at the start of Year 3 (5/22-4/23), when all assays were planned, so the timing is ideal to use multiplex assays in the NCRAD to test all available specimens in one batch to ensure laboratory quality control. These results will provide an outstanding future resource for data sharing.