Short-term practice effects in Subjective Cognitive Decline: Moderators, prognostic value, and relationship to biomarker status

/ABSTRACT Subjective cognitive decline (SCD), or self-reported persistent changes in cognitive capacity without the presence of objective cognitive impairments, is regarded as the first manifestation of preclinical or asymptomatic Alzheimer’s disease (AD) – falling between normal cognition and Mild Cognitive Impairment (MCI). Although SCD has potential to be a point of intervention for future clinical trials for disease modifying treatments for AD, the heterogenous nature of its etiology and cognitive trajectory requires new methods to better characterize this group if they are to have prognostic value in clinical trials. We have previously shown that short-term practice effects (STPE) are markers of diagnosis, clinical progression, and response to treatment in MCI and AD, though STPE as a predictive tool in SCD has been largely unexplored. An opportunity therefore exists to examine the benefit of using STPE to predict future change in cognition with greater specificity in a less symptomatic condition along the AD continuum. The principal objectives of this new application are to show that individuals with SCD possess smaller STPE than their cognitively normal peers (Specific Aim 1), and that these STPE are related to plasma biomarkers of AD (Specific Aim 2). This proposal will also investigate whether STPE are related to cognitive change and amyloid progression over 24 months (Specific Aim 3). Such findings in SCD would extend our previous work on STPE in symptomatic AD populations. In addition to practice effects being mostly unexamined in SCD, another innovative aspect of this proposal includes our use of a plasma biomarker for phosphorylated tau (pTau-217). Although pTau-217 has emerged as the superior biomarker for amyloid positivity and early prediction of AD, few studies of pTau-217 have been undertaken in SCD – especially longitudinally – and none have examined the relationship to practice effects. Further, to date, the literature on practice effects has been primarily conducted in Caucasian populations, whereas we are proposing to enrich our study sample with a broader racial/ethnic representation to ensure that the primary results will generalize to a more representative sample of the U.S. population. By achieving the aims of this proposal, we foresee multiple benefits. This work could better inform individual patients with SCD about their likelihood of future cognitive changes and disease progression. Additionally, should a combination of STPE and plasma biomarker assessment lead to more precise prediction of cognitive trajectories, SCD could become an ideal condition to consider for clinical trials of disease modifying treatments for MCI and AD. Given the clinical benefits that STPE may possess for diagnosis and prognosis of subjective cognitive decline and cognitive disorders in late life, this project is consistent with the mission of the National Institute on Aging. Project Number: 1R01AG099149-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Dustin Hammers (+1 co-PI) | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $607,706 | Activity Code: R01 | Study Section: Cognitive Disorders and Brain Aging Study Section[CDBA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301522