Sequential early cognitive changes sensitive to rising beta‐amyloid and tau pathology in preclinical AD. (December 2021)

• Record Type: Journal Article
• Authors: Farrell, Michelle E.; Papp, Kate V.; Buckley, Rachel F.; Jacobs, Heidi I.L.; Schultz, Aaron P; Properzi, Michael J; Vannini, Patrizia; Hanseeuw, Bernard; Rentz, Dorene M.; Johnson, Keith A.; Sperling, Reisa A.
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 4
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.056315
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: AD clinical trials are increasingly looking towards intervention at the earliest stage of preclinical AD, when beta‐amyloid (Aβ) is emerging and tau pathology remains restricted to the MTL. While some evidence suggests subtle cognitive changes start at this early stage, it is unclear what cognitive measures may be most sensitive to emerging pathology and whether they reflect Aβ, tau or both. Method: 143 clinically‐normal adults with longitudinal PIB‐PET, FTP‐PET and cognitive data (median follow‐up: 7.68(1.17) years) were included from the Harvard Aging Brain Study (HABS). Analyses focused first on those initially PIB‐ (<Centiloid (CL) 20), then were expanded to those initially <CL 40, approximately where neocortical tau proliferation accelerates. Linear mixed effects (LME) models first assessed the neocortical PIB slope*time effect on each cognitive task across the full time‐course. FTP was introduced later (∼Year 3), so LME models assessing combined PIB+FTP effects on cognition (Year3+) were divided into prior effects (PIB slope‐Year0‐3, Year3‐FTP level) and concurrent effects (PIB slope‐Y3+, FTP slope‐Y3+). Both entorhinal (ERC) and inferior temporal (IT) FTP were tested. ROC curve analyses assessed sensitivity/specificity of each task and composite measures to PIB slope. Result: In PIB slope models across the full time‐course (Fig 1), rising PIB was robustly associated with declining processing speed (DSST, Trails A) in those <CL20 and expanded to include memory encoding (FCsrt‐FR, SRT‐tr, LM‐immed) in the <CL40 group. In the combined PIB+FTP models under CL20 (Fig 2), rising PIB slope associated with declining DSST, FCsrt‐FR, and SRT‐tr, while the only FTP effect was between rising ERC FTP and declining FCsrt‐FR. Expanding up to CL40, IT FTP became dominant and related to most cognitive tasks, but independent effects of PIB slope remained for DSST and the encoding measures. A composite measure (DSST, Trails A, FCsrt‐FR, LM‐immed) demonstrated high sensitivity and specificity (SE=.85, SP=.88, Fig 3) to PIB slope, performing better than any individual task and the PACC. Conclusion: Measures of processing speed and memory encoding were most sensitive to emerging Aβ and tau pathology, and may help to determine whether anti‐Aβ therapies administered at the first signs of Aβ and tau might preserve cognitive function.