Top-down attention and Alzheimer's pathology impact cortical selectivity during learning, influencing episodic memory in older adults

Abstract

Human aging affects the ability to remember new experiences, in part, because of altered neural function during memory formation. One potential contributor to age-related memory decline is diminished neural selectivity -- i.e., a decline in the differential response of cortical regions to preferred vs. non-preferred stimuli during event perception -- yet the factors driving variability in neural selectivity with age remain unclear. We examined the impact of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity during memory encoding in 156 cognitively unimpaired older participants who underwent fMRI while performing a word-face and word-scene associative memory task. Neural selectivity in face- and place-selective cortical regions was greater during events that were later remembered compared to forgotten. Critically, neural selectivity during learning positively scaled with memory-related variability in top-down attention, whereas selectivity negatively related to early AD pathology, evidenced by elevated plasma pTau₁₈₁. Path analysis revealed that neural selectivity at encoding mediated the effects of age, top-down attention, and pTau₁₈₁ on associative memory. Collectively, these data reveal multiple pathways that contribute to memory differences among older adults -- AD-independent reductions in top-down attention and AD-related pathology alter the precision of cortical representations of events during experience, with consequences for remembering.

Keywords: Alzheimer’s disease; Psychological and Cognitive Neurosciences; Social Sciences; aging; attention; episodic memory; functional MRI; neural selectivity.

Fig. 1.. Experimental design, group-level statistical maps, and regions of interest (ROIs).

(A) Structure of study (encoding) and test (retrieval) trials in the word-picture associative memory task. (B) Group-level category effects (face vs. place) during word-picture study. (C) Group-level subsequent memory effects depicting differential activation on word-picture encoding trials for which the association was subsequently remembered vs. subsequently forgotten at test. (D) Predefined place- and face-selective ROIs: OPA, occipital place area; RSC, restrosplenial cortex; PPA, parahippocampal place area; FFA, fusiform face area; OFA, occipital face area. (E) Predefined frontoparietal dorsal attention network (DAN) and ventral attention network (VAN) ROIs: IPS, intraparietal sulcus; FEF, frontal eye fields; IFC, inferior frontal cortex; TPJ, temporoparietal junction.

Fig. 2.. Neural selectivity relates to age, top-down attention, and early AD pathology.

(A) The age-related decrease in neural selectivity at encoding is greater on subsequently remembered vs. forgotten trials. (B) Neural activity decreased more with age for preferred category than non-preferred category trials in (left) place- but not (right) face-selective regions (analyses restricted to subsequently remembered trials). Sex and years of education were included as nuisance variables. (C) Neural selectivity on remembered trials was associated with the subsequent memory effect (SME) in frontoparietal nodes of the dorsal attention network (DAN). (D) DAN SME was tightly related to face- and place-related activity on subsequently remembered trials in (left) place- and (right) face-selective regions. (E) Neural selectivity on remembered trials in (left) place- but not (right) face-selective regions significantly declined with plasma pTau₁₈₁. (F) Plasma pTau₁₈₁ negatively related to preferred neural activity (i.e., place-related activity, cool color) in place-selective regions. Age, sex, and years of education were included as nuisance variables.

Fig. 3.. Predictors on neural selectivity.

(A) Plasma pTau₁₈₁ and DAN SME partially mediated the negative relationship between age and neural selectivity (on remembered trials in place-selective regions). Sex and years of education were included as nuisance variables. ^# p = .05, ^* p < .05, ^** p < .01, ^*** p < .001. c’ = direct effect; c = total effect = a₁b₁ + a₂b₂ + c’. (B) Unique and (C) shared explained variances of predictors of neural selectivity. DAN = DAN SME (i.e., subsequent memory effect in dorsal attention network), AD = plasma pTau₁₈₁, EDUC = years of education.

Fig. 4.. Greater neural selectivity is related to better memory performance.

(A) Neural selectivity in place-selective regions predicted associative memory (overall associative d’) on remembered trials. (B) & (C) Neural selectivity in place-selective regions (i.e., Place) on remembered trials (i.e., Rem) predicts out-of-task memory performance (B, mnemonic similarity task: the similarity slope on the y-axis reflects the magnitude of the increase in performance as target–lure similarity moved from high to low; C, delayed recall). (D) Neural selectivity in place-selective regions on subsequently remembered trials was not significantly associated with executive function.

Fig. 5.. Pathways and predictors on memory performance (i.e., place associative d’).

(A) Structural equation modelling. Solid lines represent significant paths; dashed lines represent nonsignificant paths. The figure shows standardized betas. ^# p = .05, ^* p < .05, ^** p < .01, ^*** p < .001. c’ = direct effect; c = total effect = a₁b₁ + a₂b₂ + a₃b₃ + a₁d₂₁b₂ + a₃d₂₃b₂ + c’. (B) Unique and (C) shared explained variances of predictors of place associative d’. NS = neural selectivity, DAN = DAN SME (i.e., subsequent memory effect in dorsal attention network), AD = plasma pTau₁₈₁, EDUC = years of education.