Both hyper- and hypo-activation to cognitive challenge are associated with increased beta-amyloid deposition in healthy aging: A nonlinear effect

Abstract

Beta-amyloid (Aβ) positive individuals hyper-activate brain regions compared to those not at-risk; however, hyperactivation is then thought to diminish as Alzheimer's disease symptomatology begins, evidencing eventual hypoactivation. It remains unclear when in the disease staging this transition occurs. We hypothesized that differential levels of amyloid burden would be associated with both increased and decreased activation (i.e., a quadratic trajectory) in cognitively-normal adults. Participants (N = 62; aged 51-94) underwent an fMRI spatial distance-judgment task and Amyvid-PET scanning. Voxelwise regression modeled age, linear-Aβ, and quadratic-Aβ as predictors of BOLD activation to difficult spatial distance-judgments. A significant quadratic-Aβ effect on BOLD response explained differential activation in bilateral angular/temporal and medial prefrontal cortices, such that individuals with slightly elevated Aβ burden exhibited hyperactivation whereas even higher Aβ burden was then associated with hypoactivation. Importantly, in high-Aβ individuals, Aβ load moderated the effect of BOLD activation on behavioral task performance, where in lower-elevation, greater deactivation was associated with better accuracy, but in higher-elevation, greater deactivation was associated with poorer accuracy during the task. This study reveals a dose-response, quadratic relationship between increasing Aβ burden and alterations in BOLD activation to cognitive challenge in cognitively-normal individuals that suggests 1) the shift from hyper-to hypo-activation may begin early in disease staging, 2) depends, in part, on degree of Aβ burden, and 3) tracks cognitive performance.

Tau Accumulation in Clinically Normal Older Adults Is Associated with Hippocampal Hyperactivity

“…One hundred and twenty normal older adults (aged 63-90, M ϭ 75.22, SD ϭ 6.6, female ϭ 80) were recruited from the Harvard Aging Brain Study, an ongoing study designed to further our understanding of normal aging and preclinical Alzheimer's disease (Dagley et al, 2017). All participants were fluent English speakers and had normal or correctedto-normal vision.…”

“…The development of positron emission tomography (PET) agents for amyloid-␤ and tau (Klunk et al, 2004;Xia et al, 2013) enables in vivo assessment of these pathologies and their relationships to fMRI activity during memory formation. Previous studies in preclinical AD have yielded variable reports on the relation between amyloid-␤ PET and hippocampal fMRI activity Mormino et al, 2012;Oh and Jagust, 2013;Vannini et al, 2013;Elman et al, 2014;Sperling et al, 2014a;Rieck et al, 2015;Lockhart et al, 2017;. One potential reason for the discrepancies between studies may be that hippocampal hyperactivity begins later in the course of preclinical AD after amyloid-␤ has started to accumulate, and might be more closely related to the spread of tau pathology (Sperling et al, 2014a).…”

“…One interpretation is that increased fMRI activity can be compensatory (Kircher et al, 2007;Miller et al, 2008;Mormino et al, 2012;Elman et al, 2014). Elman et al (2014) demonstrated that clinically normal older adults with amyloid-␤ accumulation show compensatory activity in neocortical brain regions outside of the default-network, including so-called task-positive brain regions (Fox et al, 2005). These compensatory increases in activity are associated with better memory performance.…”

Mapping of impaired functional connectivity during memory phases in Alzheimer's disease and its association with cortical β-amyloid

“…It was once argued that amyloid pathology and neurodegeneration have adverse, in part synergistic, effects on prospective cognition (48). In addition to the linear relationship found between Aβ and cognition (49), Aβ load was revealed for its nonlinear role in moderating the BOLD activation effect on behavioral task performance (50,51). Taken together, these ndings suggested the involvement but lack of direct and consistent effect of Aβ on the cognitive de ciency.…”

Functional signature of conversion in Mild Cognitive Impairment patients

“…studies showing that the decreased FC between central hubs of the DMN correlates with enhanced Aβ deposition(Buckner RL et al 2005)(Elman et al 2016;Foster et al 2018;Grothe et al 2016;Koch et al 2010;Mutlu et al 2017;Mormino et al 2011;Palmqvist et al 2017). The link between the presence of hyper-connectivity and enhanced signs of tau-pathology is less explored.…”