Functional Asymmetry During Working Memory and Its Association with Markers of Alzheimer’s Disease in Cognitively Normal Older Adults

Article type: Research Article

Authors: Li, Jinghang^{a; 1} | Mountz, Elizabeth J.^{a; 1} | Mizuno, Akiko^b | Shah, Ashti M.^c | Weinstein, Andrea^b | Cohen, Ann D.^b | Klunk, William E.^{b; d} | Snitz, Beth E.^{b; d} | Aizenstein, Howard J.^{a; b} | Karim, Helmet T.^{a; b; *}

Affiliations: [a] Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA | [b] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [c] Physician Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [d] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: Helmet T. Karim, PhD, Assistant Professor of Psychiatry and Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA. Tel.: +1 412 246 6814; E-mail: hek26@pitt.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer’s disease (AD). This process is variable and has been associated with asymmetric hypometabolism. Objective:We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults. Methods:We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aβ, cerebral glucose metabolism, white matter hyperintensities, APOE ɛ4 allele status, DSST reaction time, age, sex, education, and cognitive function. Results:Asymmetry was not associated with several factors including cognitive function, Aβ, and white matter hyperintensities. The presence of at least one ɛ4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation). Conclusions:Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults.

Keywords: Alzheimer’s disease, amyloid, asymmetry, functional brain activation, preclinical Alzheimer’s disease, working memory

DOI: 10.3233/JAD-230379

Journal: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1077-1089, 2023