Diminished Learning Over Repeated Exposures (LORE) in preclinical Alzheimer's disease

Abstract

Introduction We determine whether diminished Learning Over Repeated Exposures (LORE) identifies subtle memory decrements in cognitively unimpaired (CU) older adults with Alzheimer's disease (AD) biomarker burden. Methods Ninety‐four CU participants (mean age = 77.6 ± 5.02) completed a challenging associative memory test, at home, monthly, for up to 1 year (mean = 9.97 months) on a study‐issued iPad. Learning curves for face‐name memory were computed for two versions completed monthly: same face‐name pairs (A‐A‐A) and alternate face‐name pairs (B‐C‐D). Positron emission tomography (PET) imaging characterized global amyloid (Pittsburgh Compound‐B (PiB); amyloid beta (Aβ)+/−) and regional tau burden (flortaucipir). Results Diminished LORE for same (but not alternate) face‐name pairs was associated with greater amyloid and tau burden. Aβ+/− group differences for same face‐name pairs emerged by the fourth exposure and was of medium‐to‐large magnitude (Cohen's d = 0.66; 95% confidence interval [CI] = 0.25‐1.08). Discussion Subtle decrements in learning related to AD pathological burden in CU are detectable over short time‐intervals (ie, months). Implications for prevention trial design are discussed.

Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

“…Improvement over cognitive testing sessions in the absence of an intervention is thought to reflect practice, also referred to as learning or retest effects, which have typically been viewed as source of error or bias in the context of cognitive testing. There is, however, a growing body of literature suggesting that quantifying PE, and particularly lower or reduced PE, could provide a meaningful clinical marker of (early) subtle decrements in learning and memory performance in preclinical stages of AD (Duff et al, 2007 ; Hassenstab et al, 2015 ; Jutten et al, 2020a ; Lim et al, 2020 ; Samaroo et al, 2020 ). One potential explanation for this is that individuals with reduced PE do not optimally benefit from previous exposure to test material, suggesting worse consolidation and retention of recently learned information induced by deficits in the integrity of their learning and memory system.…”

“…PE have typically been viewed as a source of bias (Salthouse, 2012 ), but several studies showed that characterizing PE could provide an indicator of cognitive impairment and, more specifically, that lower PE reflect a decreased ability to benefit from previous experience when re-exposed ot the same stimuli (Duff et al, 2007 , 2012 ; Jutten et al, 2020a ). PE have been reported for the individual C3 and CBB measures when administered in clinically unimpaired (CU) adults (Baker et al, 2019 ; Samaroo et al, 2020 ; Stricker et al, 2020 ). Interestingly, the study by Samaroo et al revealed diminished PE on the FNAME test in CU with high levels of amyloid compared to CU with low levels of amyloid, which was evident from only 4 months of repeated assessments.…”

“…First, we investigated the nature and magnitude of PE that arose from monthly repeated exposure to at-home C3 assessments over 1 year. Upon seeing improvement, we investigated whether PE on computerized testing could be observed over the first 3 months, as we expected that the PE signal would be strongest over the first 4–5 assessments (Watson et al, 1994 ; Calamia et al, 2012 ; Samaroo et al, 2020 ). Next, we examined the relationship of individual variation in shorter term PE (i.e., 3 months) with (1) AD biomarker burden measured using neuroimaging and (2) cognitive decline on standard paper-pencil cognitive testing over 1 year (Petersen et al, 2021 ).…”

Unsupervised mobile cognitive testing for use in preclinical Alzheimer's disease

“… 3 By allowing participants to complete study assessments using their own electronic device, data collection exponentially increases, improving clinical trial efficiency. Interest in using digital and remote assessments is growing and multiple studies have demonstrated the feasibility and validity of computerized assessments in supervised 4 , 5 , 6 and unsupervised settings 7 , 8 using personal devices. 9 , 10 Several of these assessments are designed for specific symptomatic groups (e.g., for detection of mild cognitive impairment [MCI]) 9 or broad populations.…”

Using Digital Tools to Advance Alzheimer’s Drug Trials During a Pandemic: The EU/US CTAD Task Force

“…The C3 has also been shown to provide reliable data when participants complete the assessments at home on an iPad ( 18 ). The remote use of C3 allows for more frequent assessments, which provide new information about subtle cognitive changes ( 19 ).…”