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. Author manuscript; available in PMC: 2024 Feb 1.
Published in final edited form as: Neuropsychology. 2022 Nov 28;37(2):194–203. doi: 10.1037/neu0000866

Past and future episodic detail retrieval is reduced among clinically normal older adults at higher genetic risk for late-onset Alzheimer’s disease

Mónica C Acevedo-Molina 1, Sean Thayer 1, Kiley Horn 1, Hanna Nkulu 1, Lee Ryan 1,2,3, Jessica R Andrews-Hanna 1,2,4, Matthew D Grilli 1,2,3
PMCID: PMC10129290  NIHMSID: NIHMS1872571  PMID: 36442007

Abstract

Objective:

Remembering and imagining personal events that are rich in episodic (i.e., event-specific) detail is compromised in older adults who have mild cognitive impairment, a known risk factor for Alzheimer’s disease dementia. Less clear is whether lower episodic detail generation is associated with higher risk for Alzheimer’s disease dementia before mild clinical decline is detectable.

Methods:

We compared past and future autobiographical thinking in clinically normal older adult carriers of the Alzheimer’s disease associated apolipoprotein E e4 allele (APOE4) (n = 39) to demographically and neuropsychologically similar non-APOE4 carriers (n = 43).

Results:

APOE4 carriers showed a significant reduction for episodic details when remembering past events (d = .47) and imagining future events (d = .46), but not for non-episodic details.

Conclusions:

These findings suggest that APOE4 is associated with a selective reduction of episodic detail during past and future autobiographical thinking among clinically normal older adults. Reduced episodic detail generation, therefore, may be an early cognitive associate of higher risk for Alzheimer’s disease dementia.

Keywords: neuropsychology, autobiographical memory, future thinking, apolipoprotein E, aging

1. Introduction

The human mind has an impressive capacity to remember the past and imagine the future in rich episodic detail, meaning in a vivid, event-specific way (Suddendorf & Corballis, 2007). It is well established that older adults with mild cognitive impairment, a known risk factor for Alzheimer’s disease dementia, show reduced episodic detail while remembering and imagining personal events, compared to clinically normal older adults (Leyhe et al., 2009; Murphy et al., 2008; Barnabe et al., 2012). This cognitive reduction is potentially highly impactful, as generating episodically detailed past and future personal events influences decision making (Schacter, Benoit, & Szpunar, 2017; Mok et al., 2020), problem-solving (Halford et al., 2021; Sheldon, McAndrews & Moscovitch, 2011), and identity (Eustache, Viard, & Desgranges, 2016; Addis & Tippett, 2004). Considering the importance of episodic detail retrieval to daily functioning, and evidence of robust reductions already at the stage of mild cognitive impairment, it is critical to reveal how early these deficits are detectable.

1.2. Reduced past episodic detail retrieval among APOE4 carriers

Recent work suggests that alterations in episodic detail may in fact be associated with known markers of Alzheimer’s disease risk in clinically normal older adults. Of relevance to the present study, we recently found that clinically normal older adult carriers of the e4 allele of the apolipoprotein E gene (APOE4) recall past events in less episodic detail relative to demographically similar non-carriers of APOE4, whereas non-episodic narrative content, like background knowledge, is unaffected (Grilli et al., 2018). Given that APOE4 accounts for as much as half of all late-onset cases of Alzheimer’s disease (Corder et al., 1993; Saunders et al., 1993), these findings suggest that altered autobiographical thinking may be part of the protracted trajectory of cognitive decline leading to clinical symptoms (Caselli et al., 2019), and may be evident before many standard cognitive test scores are affected. This conclusion is supported by additional work on subjective cognitive decline (Bruss, Waldemar, & Vogel, 2021) and the relationship between preclinical amyloid and autobiographical knowledge (Buckley et al., 2014).

1.3. Future episodic detail generation among APOE4 carriers

In light of the potential significance of reduced episodic detail to detecting the cognitive impact of higher Alzheimer’s disease risk in clinically normal older adults, we aimed to replicate and extend our earlier findings in the present study by examining future-oriented autobiographical thinking. Some theories propose that the brain mentally constructs past and future events (or atemporal scenes) using similar cognitive processes, and an overlapping brain network (Andrews-Hanna & Grilli, 2021; Addis, 2021; Mullally & Maguire, 2014; Irish, 2020). However, whether APOE4 status, or any Alzheimer’s disease risk factor for that matter, impacts future-oriented episodic detail generation in clinically normal older adults is not known. Closing this gap would reveal whether the effect of APOE4 on episodic detail has a broad impact on many forms of autobiographical cognition that support daily functioning, such as goal achievement and weighing immediate versus delayed rewards (Schacter et al., 2012).

Investigating future thinking also can shed light on the cognitive processes that contribute to reduced episodic detail generation. Revealing the cognitive mechanisms through which higher Alzheimer’s disease risk can affect remembering is important for test development and could lead to more precise clinical endpoints. One candidate cognitive process for reduced episodic detail is the ability to bind elements during event construction (Gaesser et al., 2013; Romero & Moscovitch, 2012), a cognitive process also known as “relational processing” (Eichenbaum, 1993). Relational processing involves integrating perceptual and conceptual details within elements of an event (e.g., what an individual was wearing) and across elements of an event (e.g., the people, place, and time of an event) to construct a holistic, complex mental experience (Addis, 2018; Gaesser et al., 2013; Romero & Moscovitch, 2012). The role of relational processing in remembering is difficult to isolate, given that event memories may become more unified over repeated retrievals, and demands on relational processing might be reduced and uneven across memories (Addis, 2018). Imagining novel events requires that within-element and across-element details from past events are bound together in a way never done before (Gaesser et al., 2013; Romero & Moscovitch, 2012; Wiebels et al., 2020). Therefore, examining future thinking is a theory-driven way to evaluate relational processing’s candidacy as a cognitive mechanism behind the APOE4-associated reduction in episodic detail generation.

1.4. Present study

To investigate the impact of APOE4 status on past and future thinking, and to gain insight into the role of relational processing in this reduction, we adopted an autobiographical thought task that measures both past and future thinking, and does so in a way that ensures future thinking places higher demands on relational processing (Addis et al., 2010). We hypothesized that if reduced episodic detail generation reflects a core feature of APOE4’s impact on autobiographical cognition at non-clinical stages, clinically normal APOE4 carriers should show reduced episodic detail generation not only while remembering personal events, but also while imagining novel future personal events. We also hypothesized that if relational processing is a primary source of the APOE4-associated reduction in episodic detail, clinically normal APOE4 carriers should show a greater disruption to episodic detail generation while imagining future events, in comparison to their deficit while remembering past events.

2. Methods

2.1. Participants

Eighty-five older adults were enrolled in the present study. To be eligible, participants had to be between the ages of 60–80 and clinically normal based on an established actuarial, profile-based approach using a comprehensive battery of neuropsychological tests (Bondi et al., 2014). Neuropsychological eligibility was based on two test scores in learning and memory (total learning and long delay free recall from the California Verbal Learning Test, Second Edition (Delis, Kramer, Kaplan, & Ober, 2000), processing speed/executive functioning (Trail Making Test A and B, Reitan & Wolfson, 1985), and language (total naming on the Boston Naming Test, (Kaplan, Goodglass, & Weintraub, 2001), and total category fluency on the Animal trial of the Controlled Oral Word Association Test (Benton, Rey, & Sivan, 1994)). In this actuarial approach, individuals are considered clinically normal if neither of the following were met: (1) they performed more than 1 standard deviation below the age-corrected (and education-corrected if available) normative mean on both scores in one cognitive domain, or (2) they performed more than 1 standard deviation below the age-corrected (and education-corrected if available) normative mean on one test in three cognitive domains. Notably, in this actuarial approach, subjective cognitive decline does not factor into a determination of mild cognitive impairment. In addition, to be included participants had to score below the cutoff score of 16 for depression on the Center for Epidemiological Studies Depression Scale (Randlof, 1977), they had to deny a remarkable history of neurologic conditions that could have cognitive effects, and they had to report being independent in activities of daily living. Informed written consent was provided by all participants and all study procedures were in compliance with the Institutional Review Board at the University of Arizona.

Of the 85 participants enrolled, 82 completed the task requirements. One person did not return for their second session. We discontinued two additional participants before completing the past and future thinking task because of confusion about the task.

Demographics for the 82 participants, split by APOE4 status, are shown in Table 1. These individuals were recruited from existing databases in which APOE status was already known through cheek swab or dried blood spot samples (i.e., in our laboratory, and with GeneMatch, Langbaum et al., 2019). This enabled us to target a planned ratio of approximately 50:50 APOE4 carrier versus non-carrier status, while matching on basic demographics. We achieved this plan by conducting multiple waves of email and phone invitations that were balanced on APOE status, and by monitoring enrollment numbers by APOE status. No individual was from Grilli and colleagues (2018). Table 1 shows that the APOE4 carriers did not significantly differ from the APOE4 non-carriers on age, gender, education, or intelligence, p’s > .21. Table 1 also reports the breakdown of heterozygotes and homozygotes for APOE4.

Table 1.

Sample characteristics by APOE status

Variables Carriers (N=39)a Non-Carriers (N=43) Effect Sizes (Cohen’s d)
Demographics
Age M(SD) 69.2(6.9) 68.5(5.1) .12
Education 16.7(2.0) 16.9(1.6) .10
Male N(%) 16(41) 12(28) Odds ratio = 1.80
Race N(%)
Black or African 2(5) 0
American
White 37(95) 42(98)
Asian 0 1(2)
Ethnicity N(%)
Hispanic or Latino 2(5) 1(2)
Not Hispanic or Latino 37(95) 42(98)
Neuropsychological testing scores Mraw(SD)
CVLT-2
Trials 1–5 50.3(10.6) 51.6(8.4) .14
Long Delay Free Recall 11.1(3.3) 12.1(2.8) .34
BNT 57.5(2.1) 57.9(2.0) .18
Animal Fluency 21.4(4.4) 22.5(5.1) .25
Trails A 32.3(10.4) 30.6(7.7) .18
Trails B 79.0(35.1) 66.6(23.8) .42
WAIS-IV VCI 121.5(9.6) 123.8(11.9) .22
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a.

Among the APOE4 carriers 5 participants were homozygotes and 34 participants were heterozygotes.

b.

A total of 49 participants were tested prior to the COVID-19 pandemic; 33 participants were tested during the pandemic with enhanced health measures in place.

2.2. Sample size determination.

The present study is part of a larger project involving behavioral testing and a functional magnetic resonance imaging session. We aimed to recruit 85 participants for the project, knowing that a small number of participants might need to be removed for various reasons. For the present study, we knew a priori that with a sample size ≥80, and α = .05, we had high power (1 – β) = .95, to detect an interaction between task (past vs. future) and APOE4 status for episodic detail generation, assuming a small to medium effect (partial η2 = .04).

2.3. Procedures.

2.3.1. Past and future thinking task.

We used an adapted version of the recombination task developed by Addis and colleagues (Addis et al., 2010). In our version, the task unfolded over two sessions, separated by five to seven days. In session 1, participants were asked to generate 16 memories from approximately the past five years. Participants were informed that each memory must contain what they considered a “very vivid and detailed” person, object, and place, and that these details could not repeat across memories. To facilitate retrieval, participants were cued with 16 pictures (selected with Google Image searches), which roughly corresponded to the meaning of 16 words selected from the Clark and Paivio norms (Clark & Paivio, 2004) that were high on frequency (mean = 1.84), imageability (mean = 5.91), and concreteness (mean = 6.71). Participants were told that they need not rely on pictures to cue retrieval. The first trial was for practice, and therefore there were 15 critical memory generation trials.

Between session 1 and 2, an experimenter randomly selected five memories to serve as memory trials. These people, object, and place detail triplets were preserved. The future thinking trials were created by re-sorting the people, objects, and places from the remaining 10 memories. The experimenter ensured that each recombined triplet was entirely new. Five of these recombined triplets were randomly selected as future thinking trials, two were selected for practice, and 3 were available in case a selected triplet was reported as improbable.

In session 2, participants were informed that they would be asked to revisit some memories retrieved in session 1, and imagine several new events happening in approximately the next five years. Participants were shown the triplets using slides on PowerPoint, along with the instruction to either remember the previously generated past event from the past five years or imagine a future event happening in the next five years involving the newly combined person, place, and object. The order of the past and future thinking trials was quasi-randomized such that no more than two trials of either task were presented sequentially. Participants were instructed to focus on the details that described the unique features of the event. They also were told that they needed to describe the three details presented in the triplet. They were given four minutes per trial. If presented with an improbable future event (e.g., imagining a future event with someone who passed away), participants were asked to inform the experimenter, who would select a new triplet. The participants’ responses were audio recorded.

2.3.2. COVID-19 pandemic mitigation.

Eight of our participants had to complete session 2 using video conferencing (Zoom for Health), because we halted in-person research at the start of the COVID-19 pandemic, and then again briefly during a surge in infections. In-person research after the start of the pandemic involved enhanced health measures, including masks. Both pre- versus post-pandemic and in-person vs. zoom were accounted for as nuisance covariates.

2.3.4. Detail scoring.

We used the Autobiographical Interview scoring protocol developed by Levine and colleagues (Levine et al., 2002). In this protocol, trained raters break each narrative down into detail segments, and then score these segments as either “internal” or “external” to the main event being described. Internal details are typically characterized as episodic details, including event, time, place, perceptual, and thought/emotion details. External details include semantic details, along with repetitions, meta or editorial comments, and descriptions of external events. To create a more reliable estimate of internal and external detail for each participant, two trained raters who were blind to APOE4 status scored each trial. The average of the two scores was used in the analyses. Reliability between the two scorers for each participant was consistently good for internal and external details in past and future thinking trials, ICCs = .88 – .90.

2.4. Statistical analyses.

Demographic and neuropsychological data (reported in Table 1) were compared between APOE4 carriers and non-carriers using independent samples t-tests.

To test the hypotheses that the APOE4-associated reduction in episodic detail generation extended to, and may be greater for, future thinking, we ran an analysis of variance (ANOVA) with factors of group (APOE4 carriers vs. non-carrier), detail type (mean internal vs. external per memory or future thinking trial) and task (remembering versus future thinking) with pre-versus post-COVID status and in-person versus online status added as nuisance covariates.

In follow-up exploratory analyses, we asked whether the effect of Alzheimer’s disease risk would be reflected in APOE4 homozygote versus heterozygote status. Given the small sample sizes for these follow-up analyses, we used the non-parametric Mann-Whitney U test to compare APOE4 non-carriers to APOE4 heterozygotes and then homozygotes, and we collapsed across remembering and future thinking for internal and external detail generation. As another exploratory analysis, we asked whether individual differences in internal detail generation while remembering was significantly related to internal detail generation while imagining future events with a Pearson correlation analysis.

All analyses were performed with Jamovi (The Jamovi Project, 2021), which ran the afex package and the psych package in R (R Core Team, 2021). Figures were created in R using ggplot2.

2.5. Transparency and Openness.

De-identified data for the present study are deposited here: https://osf.io/gbpfa/?view_only=69c8922d834645c3b67be07a3cd74457. The design and analyses for this study were not preregistered.

3. Results

3.1. Neuropsychological profiles.

The APOE4 carriers and non-carriers did not significantly differ on any of the eight neuropsychological scores used to determine study eligibility, p’s ≥ .06 (Table 1).

3.2. Remembering versus future thinking

Figure 1 shows internal and external detail generation for remembering (A) and future thinking (B) separately. Supplementary Table 1 reports means and standard deviations. When we examined memory and future thinking trials entered into a single model, we found that while there was not a significant effect of group, F (1,78) = 1.25, p = .27, partial η2 = .02, there was a significant effect of detail type, F (1,78) = 39.9, p < .001, partial η2 = .34, and a significant interaction between group and detail type, F (1,78) = 8.39, p = .005, partial η2 = .10. Planned simple effect analyses revealed that this interaction reflected the fact that there was an overall effect of APOE4 status on internal detail, t (78) = 2.29, p = .02, but not on external detail, t (78) = 1.15, p = .25.

Figure 1.

Figure 1.

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A) Relative to non-APOE4 carriers (purple; dark grey) APOE4 carriers (yellow; light grey) tended to generate less internal (i.e., episodic) detail, but not less external (i.e., non-episodic) detail while remembering past personal events. B) Relative to non-APOE4 carriers, APOE4 carriers tended to generate less internal detail, but not less external detail while imagining future personal events. The boxes in the boxplots capture the 25th to 75th percentile, with the 50th percentile represented by the dark line intersecting the boxes. The whiskers capture 1.5 standard deviations above and below the 75th and 25th percentiles, respectively. Each participant is represented by a dot, with a minor jitter applied for visualization of all dots.

This model further showed that, as intended, the recombination manipulation for the future thinking trials significantly increased difficulty for internal detail generation, as shown by a significant effect of task, F (1,78) = 25.01, p < .001, partial η2 = .24, and a significant interaction between task and detail type, F (1,78) = 40.41, p < .001, partial η2 = .34, with planned simple effect analyses showed that while internal detail generation significantly dropped from memory to future thinking, t (78) = 3.33, p < .001, external details did not, t (78) = 0.31, p = .76.

Finally, this model showed that although future thinking placed higher demands on relational processing, the effect of APOE4 status was not significantly moderated by this task manipulation. That is, there was not a significant interaction between task and APOE4 status, F (1,78) = 0.72, p = .40, partial η2 = .01, nor was there a three-way interaction between these factors and detail type, F (1,78) = 0.45, p = .50, partial η2 = .006.

Despite the lack of a significant three-way interaction, we nonetheless examined whether the effect of APOE4 status on internal detail was evident in both the remembering and future thinking tasks, given the importance of such an outcome to evaluating whether we had replicated and extended Grilli and colleagues (Grilli et al., 2018), and for estimating effect sizes for the APOE4 reduction in both remembering and future thinking. Here, we found that there was in fact a significant interaction between APOE4 status and detail type for both remembering and future thinking, when analyzed separately (remembering: F (1,78) = 6.39, p = .01, partial η2 = .08; future thinking: F (1,78) = 7.51, p = .01, partial η2 = .09). In both cases, while internal details were significantly reduced (remembering: t (78) = 2.15, p = .04, d = .47; future thinking: t (78) = 2.13, p = .04, d = .46), external details did not significantly differ by APOE4 status (remembering: t (78) = 0.63, p = .53, d = .14; future thinking: t (78) = 1.52, p = .13, d = .32).

3.3. Effect of APOE4 homozygosity vs heterozygosity

Means and standard deviations for APOE4 homozygotes and APOE4 heterozygotes are reported in Supplemental Table 2. These exploratory analyses further suggest that the reduction in internal detail generation was related to the magnitude of genetic risk for Alzheimer’s disease. Although internal details were numerically reduced in both APOE4 heterozygotes and homozygotes relative to APOE4 non-carriers, the difference was only significant for the homozygotes (heterozygotes: U = 567, p = .09, rank biserial correlation = .22; homozygotes, U = 43, p = .03, rank biserial correlation = .60). Neither APOE4 heterozygotes nor homozygotes significantly differed from APOE4 non-carriers for external detail (heterozygotes: U = 626, p = .28, rank biserial correlation = .14; homozygotes: U = 74, p = .28, rank biserial correlation = .31).

3.4. Correlation between past and future detail

While the past and future thinking findings show a consistent effect of APOE4 status, they do not inform whether individuals who tend to recall past events in less episodic detail also tend to imagine future events in the same way. We therefore conducted an exploratory analysis in which we examined the Pearson correlation between participants’ mean episodic detail generation for past events with that of their mean episodic detail for future events. Past and future episodic detail generation were highly correlated, r = .73, p < .001. As shown in Figure 2, this high correlation was evident in both APOE4 carriers (r = .71, p < .001) and non-carriers (r = .75, p < .001).

Figure 2.

Figure 2.

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Average internal detail generation per remembered past personal event was highly correlated with average internal detail generation per imagined future personal event. The shaded region represents the 95 percent confidence interval of the regression line for APOE4 carriers and non-carriers separately.

4. Discussion

The present findings strengthen the conclusion that autobiographical remembering among clinically normal older adult APOE4 carriers is selectively reduced in episodic (internal) detail relative to demographically and neuropsychologically similar non-APOE4 carriers. Not only do these findings demonstrate the replicability of this reduction, but they do so in a large sample of older adults more than double that of Grilli and colleagues (2018). The effect size for the reduction in remembering specifically (d = .47) further suggests that the impact on episodic detail generation while recalling past events is moderate. Reduced episodic detail retrieval while remembering, therefore, appears to be a robust and replicable associate of higher risk for Alzheimer’s disease, before mild cognitive impairment has emerged.

Consistent with the idea that past and future thinking rely on a common set of cognitive processes and underlying brain network (Andrews-Hanna & Grilli, 2021; Addis, 2021; Irish, 2020) we found that APOE4 carriers also showed a reduction in episodic (internal), but not non-episodic (i.e., external), detail while imagining future personal events. Like the memory results, the magnitude of this APOE4 effect for future thinking was moderate (d = .46). In addition, we found that episodic detail generation for past and future events were highly correlated. Both APOE4 carrier and non-carrier individuals who tended to recall past events in little episodic detail also tended to imagine future events in a less episodically rich way. This suggests that clinically normal older adults tend to be highly reliable in how vividly they typically remember the past and imagine their future.

What is the cause of the APOE4-associated breakdown in episodic detail generation? At a cognitive level, we investigated whether reduced relational processing, or event construction, could be a key source of the problem. Episodic (internal), but not external, detail generation was significantly lower for future thinking relative to remembering, indicating that the future thinking task increased demands on relational processing as intended. However, the findings appear not to support a relational processing explanation for the APOE4 effect on autobiographical thinking, because APOE4 carriers did not show a disproportionate drop from past to future thinking. Therefore, other cognitive processes involved in autobiographical thinking, such as how thoughts are searched for and narrated (Acevedo-Molina, Matijevic, & Grilli, 2020; Wank et al., 2020; Bluck et al., 2016), may be responsible for this APOE4 effect. It is also possible that mental scene construction, a specific type of relational processing not isolated in this study, is responsible for the drop in episodic detail generation (Hassabis et al., 2007). Event construction is a complex process (Gaesser et al., 2013; Romero & Moscovitch, 2012), and perhaps not all forms of relational processing within and across items and context are the same. Whereas our study involved integrating a diversity of event elements including people, places, and items, we might have found different results if we focused the role of relational processing on piecing together the core elements of the scene (Hassabis et al., 2007; Summerfield et al., 2010).

In regard to understanding the neural underpinnings of this APOE4-associated reduction in episodic detail generation, recent research has revealed that a number of brain regions, including the hippocampus and its cortical connections, are involved in remembering the past, simulating the future, and imagining novel scenes (Addis, Wong, & Schacter, 2007; Andrews-Hanna & Grilli, 2021; Hassabis et al., 2007; Maguire, 2001; Schacter et al., 2012; Summerfield et al., 2010). The medial temporal lobe subsystem of the default network, which incorporates the hippocampus and many of its cortical and subcortical connections (including the parahippocampal cortex, retrosplenial cortex, the posterior cingulate cortex, and the inferior parietal lobe), may have an essential role in the sort of cognitive demands required of retrieving and (re)binding vivid, contextualized elements of past events, future events, and atemporal scenes, possibly working collaboratively with the medial prefrontal cortex (Andrews-Hanna & Grilli, 2021; Gaesser et al., 2013; Romero et al., 2019; Sheldon et al., 2019; Summerfield et al., 2010). In fact, recent neuroimaging research using the same Autobiographical Interview scoring approach as the present study has found that individual differences in structural and functional measures of parts of the default network medial temporal lobe subsystem significantly relate to episodic (internal) detail remembering among cognitively normal older adults (Memel et al., 2020; Matijevic et al., 2022; also Setton et al., 2022, in a sex specific pattern).

The hippocampus and its cortical connections also are prime targets of Alzheimer’s disease pathology (Ingala et al., 2021; Hojjati et al., 2021). Both amyloid and tau appear to compromise portions of the default network medial temporal lobe subsystem early in the disease (Rodrigue et al. 2012; Schultz et al., 2017; Sheline et al., 2010; Foster et al., 2018; Palmqvist et al., 2017; Jones et al., 2017). Relatedly, prior studies have shown that Alzheimer’s disease risk-related neural alterations in the hippocampus and its cortical connections are linked to cognitive mechanisms that may be needed to retrieve episodic details of past events, including spatial context memory, verbal memory recall, and cognitive control (Rajah et al., 2017; Shafer et al., 2021; Westlye et al., 2012. Older adult APOE4 carriers have deficits in other hippocampally dependent memory mechanisms that may also have a role in episodic detail generation, such as autobiographical category fluency and memory consolidation (Grilli et al., 2021; Tort-Merino et al., 2020; Zimmerman & Butler, 2018). Therefore, while the present study raises doubt about the role of relational processing, other cognitive mechanisms dependent on the hippocampus and its cortical connections may account for APOE4-associated reductions in episodic detail generation. Future research also can directly investigate whether reduced episodic detail generation is connected to amyloid or tau in the default network and whether APOE4 moderates this relationship. However, we also acknowledge that neural differences have been found in APOE4 carriers that may not be specific to Alzheimer’s disease (Ryan et al., 2011). Whether reduced episodic detail generation is more generally capturing risk for cognitive decline needs to be considered.

An exploratory analysis revealed that APOE4 homozygosity was significantly associated with a reduction in episodic (internal) detail generation relative to APOE4 non-carriers. In comparison, heterozygosity was associate with a numerical, but not statistically significant, reduction relative to APOE4 non-carriers. One intriguing implication of these analyses is that reductions in episodic detail generation while remembering and imagining events tracks with the degree of APOE4-related Alzheimer’s disease risk, such that one allele introduces a degree of risk that is less than that of two alleles. However, these findings should be investigated further as this was an exploratory analysis based on smaller sample sizes. It would also be interesting to compare the impact of APOE4 on remembering and imagining relative to other Alzheimer’s disease risk factors in clinically normal older adults, such as subjective cognitive decline (Bruss, Waldemar, & Vogel, 2021; van Harten et al., 2018; Pike et al., 2021). Notably, although our inclusion criteria included being independent in functional activities of daily living, we did not formally assess subjective cognitive decline, which is a limitation of the present study.

Finally, it is essential to note that our study sample was not racially or ethnically diverse. Given that autobiographical memories inherently come from a person’s cultural framework and background knowledge, we might expect autobiographical memory tests to be culturally appropriate and sensitive to Alzheimer’s disease risk across groups. However, we must also acknowledge that cultural differences may influence autobiographical remembering and future thinking. For instance, Wang and colleagues (2011) examined episodic autobiographical memory specificity differences between young East Asians and European Americans and found that relative to East Asians, European Americans produced more episodic details during memory retrieval. Indeed, the social-cultural environment in which a person is raised appears to influence how they share stories. For instance, Euro-American mothers tend to engage in highly elaborative conversations with their children, which may influence their ability to recall and recount personal experiences. As a result, by the age of three, Euro-American children can recall more specific memory information relative to Chinese children (Wang et al., 2011; Wang, 2004; Han et al., 1998). Such cultural differences may be related to variability in narrative style, language use or bilingualism, self-other prioritization, and interviewer-interviewee factors (Ross & Wang, 2010). Moreover, research examining the relationship between race, ethnicity, and APOE4, in particular, has found that these factors may also influence how Alzheimer’s disease-associated cognitive risk manifests in different populations. For instance, the effects of APOE4 may be weaker among African Americans than Caucasians (Maestre et al., 1995; Tang et al., 1996). Similarly, a study by Farrer and colleagues (Farrer et al. 1997) found that APOE4 Alzheimer’s disease-associated risk was also attenuated in Hispanics. Given these findings, had our sample been more diverse, it might have been possible to see different relationships between episodic detail generation and APOE4 among different racial groups.

While questions remain, the fact that autobiographical thinking, both past and future-oriented, tends to be altered in clinically normal older adult APOE4 carriers is noteworthy. The findings from our study are especially striking in that our sample was otherwise a high functioning group of older adults with no significant differences from non-APOE4 carriers on neuropsychological scores. Given that autobiographical thinking plays a significant role in everyday decision making, planning, problem-solving, socializing and self-reflection, our findings raise the possibility that reduced episodic detail could affect these “real world” cognitive demands prior to clinical decline. Our findings also suggest that autobiographical memory testing is worth further consideration as a potentially useful clinical endpoint.

Supplementary Material

Supplemental Material

Key Points.

  • Question: Is lower episodic detail generation while imagining future events associated with higher risk for Alzheimer’s disease dementia before mild clinical decline is detectable?

  • Findings: Clinically normal older adult APOE4 carriers not only showed a reduction in episodic detail generation while remembering past events, but also while imagining future events, relative to APOE4 non-carriers.

  • Importance: Our findings suggest that reduced episodic detail generation is associated with higher risk for Alzheimer’s disease dementia in clinically normal older adults.

  • Next steps: Future research could investigate the neural mechanisms behind this Alzheimer’s risk-related selective reduction in episodic detail generation, in particular in relationship to race, ethnicity, and APOE4.

Funding Statement:

Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Number R03 AG060271 and 1UF1AG046150-01 (MDG). M.C. Acevedo-Molina was additionally supported by National Service Research Award F31 AG069443. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Declaration of interests: none

5. References

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