Synergistic effects of APOE ε4 and Alzheimer's pathology on the neural correlates of episodic remembering in cognitively unimpaired older adults

Abstract

Amyloid-β (Aβ) and tau pathology begin accumulating decades before clinical symptoms and are influenced by APOE ε4, a key genetic risk factor for Alzheimer's disease (AD). Although the presence of Aβ, tau, and APOE ε4 are thought to impact brain function, their effects on the neural correlates of episodic memory retrieval in preclinical AD remains unknown. We investigated this question in 159 cognitively unimpaired older adults (mean age, 68.9±5.8 years; 57% female) in the Stanford Aging and Memory Study. Participants completed an associative memory task concurrent with functional MRI. Aβ was measured using CSF Aβ₄₂/Aβ₄₀ or Florbetaben-PET imaging and tau was measured using CSF pTau₁₈₁. Hippocampal univariate activity and cortical reinstatement - that is, reinstatement of patterns of neocortical activity that were present during memory encoding - were measured during successful memory retrieval. Analyses revealed that APOE ε4 was independently associated with greater Aβ and tau burden, and that associations of AD biomarkers with brain function and memory were moderated by APOE ε4. Among APOE ε4 non-carriers, Aβ burden was linked to a pattern of hippocampal hyperactivity. Among APOE ε4 carriers, CSF pTau₁₈₁ was linked to weaker cortical reinstatement during memory retrieval and lower memory performance. Thus, abnormal AD biomarkers and genetic risk synergistically impact neural and behavioral expressions of memory in preclinical AD. These findings highlight the critical role of APOE ε4 in moderating effects of AD pathology on brain function and identify candidate mechanisms that may contribute to increased risk of memory impairment in preclinical AD.

Figure 1.. Associations between APOE ε4 and AD biomarkers.

(A) Boxplots of CSF Aβ₄₂/Aβ₄₀ by APOE ε4 (p < .001; n=113) and (B) CSF pTau₁₈₁ by APOE ε4 (p = .008; n=113), stratified by amyloid status. P-values were determined using linear regression models including age and sex as covariates as well as amyloid status in (B).

Figure 2.. Associations between age, fMRI retrieval measures, and memory.

(A) Task paradigm. Concurrent with fMRI scanning, participants studied word-face and word-place pairs and were tested using an associative cued-recall test in which they indicated the category associated with the presented word. (B) Scatterplots show associations of age with associative d’ (p < .001; n=159), (C) hippocampal activity (p = .153; n=159), and (D) reinstatement strength (p < .005; n=158). (E) Scatterplots show associations of hippocampal activity with cortical reinstatement (p < .001) and (F) associative d’ (p < .001) and (G) association of cortical reinstatement strength with to associative d’ (p < .001; n=158). Hippocampal activity is plotted as the contrast estimate for associative hits > all misses. Reinstatement strength is plotted as the mean standardized residual, controlling for classifier accuracy during memory encoding. Plots show linear model predictions (black line) and 95% confidence intervals (shaded area). P-values were determined using linear regression models including age and sex as covariates, and education in models with memory as the outcome.

Figure 3.. Associations of hippocampal activity with APOE ε4 and AD biomarkers.

Interactions of APOE ε4 with (A) CSF Aβ₄₂/Aβ₄₀ (p = .045; n=113), (B) Aβ status (p = .061; n=136), and (C) CSF pTau₁₈₁ (p = .055; n=113). Hippocampal activity is plotted as the contrast estimate for associative hits > all misses. Scatterplots show linear model predictions (black line) and 95% confidence intervals (shaded area). P-values were determined using linear regression models including age and sex as covariates.

Figure 4.. Associations of cortical reinstatement strength with APOE ε4 and AD biomarkers.

Associations of cortical reinstatement strength with (A) APOE ε4 (p < .001; n=156), (B) Aβ status (p = .247; n=135), and (C) CSF pTau₁₈₁ (p = .023; n=113). (D) Interaction of APOE ε4 with Aβ status (p = .027), such that associations with APOE ε4 are observed in Aβ+ (p = .005) but not Aβ− (p = .331). (E) Interaction of APOE ε4 with CSF pTau₁₈₁ (p = .007), such that associations with pTau₁₈₁ are observed in ε4 carriers (p = .005) but not non-carriers (p = .543). Reinstatement strength is plotted as the mean standardized residual, controlling for classifier accuracy during memory encoding. Scatterplots show linear model predictions and 95% confidence intervals (shaded area). P-values were determined using linear regression models including age and sex as covariates. (F) Unique and shared variance in reinstatement strength explained by age, sex, hippocampal activity, Aβ status, and CSF pTau₁₈₁ in APOE ε4 carriers and (G) in APOE ε4 non-carriers.

Figure 5.. Associations of episodic memory with APOE ε4 and AD biomarkers.

Associations of episodic memory (associative d’) with (A) APOE ε4 (p = .035; n=157), (B) Aβ status (p = .070; n=136), and (C) CSF pTau₁₈₁ (p = .023; n=114). (D) Interaction of APOE ε4 with Aβ status (p = .224). (E) Interaction of APOE ε4 with CSF pTau₁₈₁ (p = .002), such that CSF pTau₁₈₁ was negatively related to associative d’ in ε4 carriers (p < .001) but not non-carriers (p = .429). Scatterplots show linear model predictions and 95% confidence intervals (shaded area). P-values were determined using linear regression models including age, sex, and education as covariates. (F) Unique and shared variance in associative d’ explained by age, sex, education, hippocampal activity, reinstatement strength, and CSF pTau₁₈₁ in APOE ε4 carriers and (G) in APOE ε4 non-carriers.