CONTROLLED SEMANTIC RETRIEVAL IS SENSITIVE TO CHANGES IN BETA-AMYLOID LOAD IN PRECLINICAL ALZHEIMER’S DISEASE: A NEUROCOGNITIVE STRESS TEST FOR ALZHEIMER-RELATED DISRUPTIONS TO FRONTOTEMPORAL PATHWAYS

Abstract

Previous studies have characterized pathways linking frontal control systems with temporal regions involved in semantic memory storage that are critically involved in retrieval under effortful conditions. Recent findings also suggest that disruption within frontotemporal pathways are present in preclinical AD and may predict conversion to prodromal/clinical AD. Cognitive tasks placing high demands on controlled semantic retrieval may therefore be particularly sensitive markers of AD pathology in presymptomatic individuals. Cognitively normal older adults (mean age: 64.3 years) with a family history of AD and subjective memory complaints performed a semantic control task in which participants were asked to determine which word from a set of possible targets was most related to a cue word. Retrieval demands were manipulated by varying the associative strength (Strong or Weak) between cue and correct target, and semantic load was manipulated by varying the number (2 or 4) of potential targets. Two summary scores were derived from participants’ response times across conditions: 1) Controlled Retrieval (Weak 2 vs. Strong 2) and 2) Semantic Load (Strong 4 vs. Strong 2). All participants underwent Florbetapir PET beta-amyloid (Aβ) imaging at time of cognitive testing and 27 months prior to testing. Using an SUVr threshold of 1.1 in the anterior cingulate cortex, participants were classified as either Aβ+ (n=15) or Aβ- (n=23), and the two groups did not differ for age or education. The Aβ+ group performed significantly worse on Controlled Retrieval despite comparable performance on Semantic Load across groups. Twenty participants had increased SUVr levels (Δ+) from their scan 27 months earlier, whereas 18 did not. A two-way ANOVA revealed a significant interaction between change status and summary score, with the Δ+ group performing worse on Controlled Retrieval despite comparable performance on Semantic Load across groups. Results suggest that tests of controlled semantic retrieval dependent on the integrity of frontotemporal pathways are sensitive both to current Aβ status and to changes in Aβ load in preclinical AD. Impaired controlled retrieval may reflect subtle disruptions of frontotemporal pathways in preclinical AD, and may serve as a potential cognitive stress test for the detection of subtle change in presymptomatic AD.