Autobiographical Memory Performance in Alzheimer’s Disease Depends on Retrieval Frequency

Abstract

Alzheimer’s disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot’s gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.

Keywords

Alzheimer’s disease autobiographical memory cognitive impairment multiple trace theory retrieval frequency Ribot’s Law standard model of memory consolidation

INTRODUCTION

Alzheimer’s disease (AD) is a slowly progressive disease of the brain that is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures,including the hippocampus in the earliest stages [1]. Up to now, the specific contribution of medial temporal lobe structures and the time course of its involvement in encoding and retrieval of declarative knowledge (i.e., episodic and semantic memory) is still inconclusive [2 –4].

The neuropsychological assessment of remote memory is an essential part of evaluating AD patients and can be accomplished using tests of autobiographical memory and past public knowledge, such as those for famous personalities and events. Recent findings based on a large sample of patients in different stages of AD, mild cognitive impairment (MCI), and cognitively unimpaired individuals suggest that the examination of autobiographical memory loss can facilitate the clinical diagnosis and staging of AD [5].

The concept of amnestic MCI (aMCI) is still under debate as findings concerning the temporal stability of memory decline are ambiguous [6]. Nevertheless, aMCI seems to be the nosological entity that most appropriately represents the pre-dementia stage of AD [1, 7].

Individuals with dementia due to AD typically develop retrograde amnesia. Retrograde amnesia is characterized by a loss of autobiographical memories [8 –24], a loss of public knowledge [10 , 23–30], and an inability to recognize famous faces [23 , 31–34].

Empirical evidence suggests a pattern of retrograde amnesia consistent with Ribot’s Law [35] according to which remote memories are typically preserved better than recent memories. However, other studies report no such temporal gradient in patients with AD (for review, see [16, 36]). Therefore, the course and mechanism of retrograde amnesia remain inconclusive.

In a recent study, we found the typical decline in recall of autobiographical episodes and semantic information in patients with early dementia of Alzheimer type (eDAT) and aMCI compared to healthy subjects. Moreover, we observed an increased preservation of remote than more recent memories [15]. However, an assessment of memory for famous public events revealed that the memory loss of aMCI and eDAT patients exhibited no temporal gradient as observed for the autobiographical memory [30].

These inconsistent findings can be considered a challenge for prevalent theoretical accounts of long-term memory formation. Basically, the literature comprises two competing theories which can explain the time gradient in retrograde (autobiographical) amnesia. According to the Standard Model of Memory Consolidation (SMC) [37, 38], memories initially depend on the hippocampal complex but gradually become stored in the neocortex during the consolidation process, rendering them hippocampus-independent [37, 38]. When the hippocampal complex becomes damaged during the course of AD, recent memories depending on the hippocampus will be lost, while remote memories depending on the neocortex will be spared.

According to the Multiple Trace Theory (MTT) [39, 40], however, the hippocampal complex remains involved in the recollection of remote autobiographical (i.e., episodic) memories, so that principally both recent and remote memories are affected by AD-related hippocampal damage. However, as older memories, according to theory are characterized by more and stronger hippocampal-neocortical traces, they are less susceptible to hippocampal damage than more recent memories and therefore will be affected later on in the course of disease [39, 41].

Although both the SMC and MTT can explain the temporal gradient in the recall of autobiographical information, they cannot account for the uniform impairment in the retrieval of semantic knowledge and the autobiographical context of historic events stemming from different phases of life as recently observed in our study [30].

As attempt to reconcile and integrate the putatively contradicting findings, in the present work we started from the notion that the extent of retrograde amnesia is essentially mediated by the frequency of former memory retrieval rather than the mere age of the respective memories as proposed by the SMC [37, 38] and MTT [39, 40].

More specifically, one can plausibly assume that all types of memories initially depend on the hippocampus [42 –45], and their retrieval continues to depend on the hippocampus as long as the neocortical network is not strong enough to store the information on its own. Thus, less frequently recalled information about public events may always depend on the hippocampus, whereas more frequently recalled remote autobiographical knowledge may be stored in a neocortical network and is thus less susceptible to early hippocampal damage due to AD. Loss of memory for public events, therefore, will not be temporally graded but instead related to the degree of hippocampal damage resulting from AD.

In a recent study [24], we examined the recall of past public events in AD patients and an age-, education-, and gender-matched sample of HC individuals. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. According to our reasoning above, these findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early hippocampal damage related to AD.

In the present work, we examined the recall of autobiographical incidents in aMCI subjects, eDAT patients, and an age-, education-, and gender-matched sample of HC individuals using a German version of the Autobiographical Memory Interview (AMI) [14]. We hypothesized that HC individuals will generally show better memory performance than both patient groups regardless of the age of the corresponding memories. Moreover, patients with aMCI and eDAT as well as HC individuals should exhibit a better recall of frequently retrieved memories than seldomly-retrieved ones.

METHODS

Participants

Our study included 60 participants (29 females and 31 males) with a mean age of 72.5±5.3 years. All participants had normal or corrected-to-normal visual acuity and sufficient hearing ability. No participants had a physical handicap that affected his or her ability to perform the tasks or any indication of other neurological or psychiatric disorders unrelated to his or her diagnosis. To exclude symptoms of depression, all participants completed the German 15-item version of the Geriatric Depression Scale (GDS; exclusion criterion GDS >5) [46]. The local ethical committee at the University Hospital of Tübingen approved the study. All participants signed an informed consent form after receiving a detailed explanation of the study.

Patients with aMCI or eDAT

Patients with aMCI or eDAT were recruited from the Memory Clinic of the Department of Psychiatry and Psychotherapy at the University Hospital of Tübingen. They underwent physical, neurological, neuropsychological, and psychiatric examinations as well as brain imaging. Patients with evidence of any brain disease other than potential very early signs of AD (e.g., mild hippocampal atrophy) were excluded. Routine laboratory tests included Lues serology and analysis of vitamin B12, folic acid, and thyroid-stimulating hormone levels.

The diagnostic criteria for eDAT were defined according to the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer’s Disease and Related Disorders Association [47, 48]. All of these patients had a score of 4 on the Global Deterioration Scale [49].

The diagnosis of aMCI was defined according to the Mayo criteria [48, 50], which include the presence of a memory complaint (corroborated by an informant), objectively impaired memory function, preserved general cognitive function, intact activities of daily living, and the absence of dementia. All patients in this group met the new MCI-core clinical criteria according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) clinical research criteria for MCI due to AD [51]. Although NIA-AA criteria do not explicitly exclude deficits in cognitive domains other than memory, we focused on memory impairment, as pre-dementia AD is most frequently characterized as an amnestic syndrome [1 , 51].

Healthy control group

HC individuals had no history of neurological or psychiatric disease or any sign of cognitive decline, as confirmed by a detailed clinical interview.

Neuropsychological assessment

All healthy control individuals and the patient groups performed the Mini-Mental State examination (MMSE) [52].

Both patient groups underwent a neuropsychological examination that included the German version of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD) [53], including the MMSE, a 15-item short version of the Boston Naming Test (BNT), a semantic word fluency test (animals, 1 minute), word list learning (10 words, three trials), word list recall after distraction, word list recognition (10 target and 10 distractor words), figure copying, and delayed figure recall. For the CERAD test battery normative values for subjects ≥50 years, adjusted for age, gender, and education, are provided by the Basel Memory Clinic [54].

All participants took part in the AMI [14]. The AMI is a semi-structured interview consisting of two parts that independently test recall for the two components of autobiographical memory: (a) autobiographical incidents and (b) personal semantic information. To ensure comparability to our recent findings on contextual (i.e., autobiographical) memory [24], we focused on the autobiographical incidents questionnaire to assess autobiographical memory from three life periods (childhood, early adulthood, and recent life) and related patterns of memory deficits.

The autobiographical incident questionnaire requires subjects to recall and describe nine personally experienced life episodes (i.e., three from each life period). Subsequently, a rater classifies each description according to standardized criteria. Within this classification, three points correspond to a correct episodic autobiographical memory that is specific in time and place. Two points are given for a personal but non-specific event or a specific event for which time and place are not recalled. One point corresponds to a vague personal memory. Zero points are given for no response or a response based on semantic memory. Informants, e.g., spouses or life-long companions, were asked to verify the accuracy of the memory reports.

Retrieval frequency of the reported episodes was operationalized by a paired comparison analysis. More specifically, participants conducted pairwise comparisons between all reported events in which they intuitively indicated which one of the respective double they remembered more frequently during their lifetime. These comparisons allowed an individual ranking of the episodes, indicating how many times each of the events was more frequently remembered than another event (ranking 0–8). In order to enhance power for statistical analyses, the ranking levels (0–8) were reduced to the three classes “high” (comprising level 6–8), “medium” (comprising level 3–5), and “low” frequency (comprising level 0–2), resulting in an equal number (three) of life episodes in each frequency category for each participant.

Data analysis

The statistical software package SPSS (version 20) was used for data analyses. For all tests, the level of statistical significance was set to p < 0.05. Levene’s test served to assess homogeneity of variances.

Individual z-scores of the CERAD data were computed by comparing patient data for each variable with data from the norm population provided by the Basel Memory Clinic which allows to control for age, gender and education level [54]. Z-scores are expressed in terms of standard deviations from their means. Resultantly, these z-scores have a distribution with a mean of 0 and a standard deviation of 1. A positive z-score indicates the observed value is above the mean, while a negative z-score indicates that the observed value is below the mean. Usually z-scores below –1.5 or –1.0 are considered to reflect impaired test performance [55].

We compared the groups in terms of age, education, and neuropsychological performance (CERAD z-scores) by means of a one-way analysis of variance (ANOVA) followed by post hoc pairwise group comparisons by means of the Tukey test. Bonferroni adjustment was performed to correct for type I errors introduced by the use of multiple tests. Pearson product-moment correlation coefficients were calculated to measure the relationship between neuropsychological performance (i.e., z-scores of the CERAD subtests) and AMI-scores in the patient groups.

We used the Pearson chi-square test to detect group differences in gender distribution and the nonparametric Kruskal-Wallis H test to detect group differences in GDS scores.

Multivariate (three-factorial) repeated measures analysis of variance (MANOVA) with time segment (childhood, early adulthood, and recent life) and retrieval frequency (high, medium, or low) as within-subject factors and group (HC, aMCI, or eDAT) as a between-subject factor was calculated to examine the main effects and interactions among group, time segment, and retrieval frequency on performance in contextual memory tasks. Significant effects of the omnibus MANOVA were specified by post-hoc tests in a hierarchical manner, comprising of one-way ANOVAs and subsequent paired t-tests, using Bonferroni adjustments to control for alpha error accumulation. Mauchly’s test was used to evaluate violations of the sphericity assumption. In case of violation, we report Greenhouse-Geisser corrected degrees of freedom.

Differences in the three time segments between groups were assessed using one-way ANOVA. To test the effect of retrieval frequency on contextual memory paired samples t-tests were performed within each group (retrieval frequency high versus medium, high versus low, medium versus low). To test for a temporal gradient of memory impairment (i.e., better preservation of remote than recent memory), paired samples t-tests within each group were used to investigate memory recall (childhood vs. early adulthood and recent life; early adulthood versus recent life).

Wilcoxon signed rank test was conducted in all groups (i.e., HC, aMCI, and eDAT) to assess differences in frequency statements between childhood, early adulthood and recent life.

RESULTS

Clinical and demographic characteristics of the participants

Basically, HC and patient groups did not significantly differ in age, education, and gender distribution (Table 1). Also, GDS scores were not significantly different between groups and well below the cut-off score of 6. Thus all participants were free of relevant signs for depression. Patients with eDAT had lower MMSE scores (i.e., a greater impairment in global cognition) than aMCI patients and HC individuals, while patients with aMCI had lower MMSE scores than HC individuals (F = 69.61; p < 0.001).

Neuropsychological performance in the CERAD test battery

Table 2 presents the means and standard deviations (SDs) of age-, gender-, and education-corrected z-scores of the CERAD subtests in the patient groups.

Except for Word List Intrusion patients with aMCI performed better on all scores of the CERAD test battery than the eDAT individuals.

Correlating CERAD performance measures and AMI scores in patients with aMCI, we found asignificant correlation between delayed verbal recall and contextual memory for early adulthood (r = 0.586; p = 0.007) as well as between word list recognition and contextual memory for recent events (r = 0.518; p = 0.019). In patients with eDAT contextual memory for recent events correlated significantly with delayed verbal recall (r = 0.623; p = 0.004).

We did not find any other significant correlation between CERAD performance measures and AMI scores in patients with eDAT and aMCI (r scores ranged from –0.354 to 0.319; all p > 0.5).

Autobiographical episodic memories

We found a significant main effect of group (F = 49.90; p < 0.001) and time segment (F[2,114] = 8.44; p < 0.001) on contextual memory task scores (Table 3; Fig. 1). A one-way ANOVA showed that recall of contextual memory differed significantly between all groups in all time segments:childhood (F[2,57] = 4.998; p = 0.010), early adulthood (F[2,57] = 9.443; p < 0.001), and recent life (F[2,57] = 64.320; p < 0.001).

Patients with eDAT performed worse than HC individuals in recall of autobiographical incident memories from childhood (p = 0.011), early adulthood (p < 0.001), and recent life (p < 0.001). The recall of incident memories for recent life was significantly impaired in eDAT subjects compared to aMCI patients (p = 0.007) whereas within both patient groups no significant differences could be observed for the time segment childhood (p = 0.741) and early adulthood (p = 0.153). Patients with aMCI performed worse than HC individuals in recall of autobiographical incident memories from early adulthood (p = 0.045) and recent life (p < 0.001) whereas a stable trend was observable for the time segment childhood (p = 0.065).

The group×time segment interaction was also significant (F[4,228] = 8.44; p < 0.001), indicating the presence of a temporal gradient. Paired t-tests showed a temporal decline (i.e., better preservation of remote than recent memory) in eDAT patients and patients with aMCI. In patients with eDAT, contextual memories were more detailed for childhood compared with early adulthood (p < 0.001), childhood compared with recent life (p < 0.001), and early adulthood compared with recent life (p = 0.004). In aMCI patients contextual memories were more detailed for childhood compared with early adulthood (p = 0.007), childhood compared with recent life (p < 0.001), and early adulthood compared with recent life (p < 0.011).

In HC subjects personal incident recall did not differ significantly between childhood and early adulthood (p = 0.162), and childhood compared with recent life (p = 0.208). However, personal incident recall was slightly worse in early adulthood compared with recent life (p = 0.005).

We also found a significant main effect of retrieval frequency (F[2,114] = 89.267; p < 0.001) on the autobiographical incidence memory task scores (Table 4; Fig. 2).

HC individuals reported more detailed memories when retrieval frequency was high compared with medium (p < 0.001) or low (p < 0.001) and when retrieval frequency was medium compared with low (p < 0.001). Patients with aMCI described more detailed memories when retrieval frequency was high compared with medium (p < 0.001) or low (p < 0.001) and when retrieval frequency was medium compared with low (p = 0.004). Subjects with eDAT stated more detailed memories when retrieval frequency was high compared with medium (p < 0.001) or low (p < 0.001) and when retrieval frequency was medium compared with low (p < 0.001).

Finally, the data revealed a significant time segment×retrieval frequency interaction (F =5.268; p < 0.01). Wilcoxon signed ranks test indicated that patients with eDAT recalled memories from childhood more often (i.e., higher rank) than from recent life (p = 0.034) and more often from early adulthood compared to recent life (p = 0.022). Patients with aMCI recalled memories from childhood more often than from early adulthood (p = 0.040) and from recent life (p = 0.014). HC individuals recalled memories from childhood more often than from recent life (p = 0.033) and more often from early adulthood than from recent life (p = 0.017; Fig. 3).

DISCUSSION

The current study examined whether the extent and severity of retrograde amnesia is mediated by the frequency of memory retrieval or whether it depends on time course as proposed by the SMC [37, 38] and MTT [39, 40]. To test this hypothesis, we adopted an innovative approach to assess retrograde memory by evaluating the recall of autobiographical incidents as a function of their retrieval frequency and age.

The main findings were as follows: (1) Autobiographical memory differs significantly between patients with eDAT, subjects with aMCI and HC individuals. (2) In both patient groups impairment in autobiographical memory retrieval follows Ribot’s gradient, wherein remote memories are better preserved than more recent ones. (3) In all groups memory performance, as indicated here by the vividness of recalled events, depends on retrieval frequency. (4) Remote memories are recalled more often than recent ones.

In accordance with previous studies [16 , 56] (and not surprisingly), patients with aMCI and eDAT basically showed impaired autobiographical memory. In the literature, autobiographical memory deficits in AD are commonly ascribed to neuropathological changes and neurodegeneration within medial temporal structures, brain regions that are indispensable for memory formation and that are affected early in the disease process [57, 58]. Neuroimaging studies of autobiographical memory have highlighted the involvement of a large core brain network, involving the hippocampus and parahippocampal gyrus, the medial and ventrolateral prefrontal cortex, the precuneus, the retrosplenial/posterior cingulate cortex, the lateral temporal cortex, as well as the temporo-parietal junction [3 , 59–61]. More specifically, empirical evidence suggests that the posterior cingulate cortex, a region densely connected with medial temporal cortex, plays a crucial role in autobiographical memory retrieval [62]. Furthermore, positron emission tomography (PET) imaging data indicate that amyloid accumulation is concentrated in the posterior cingulate cortex in early AD [63]. Finally, functional imaging studies suggest this region to be vulnerable for early metabolic changes in AD [64, 65]. Taken together, the literature strongly suggests that neuropathological changes take place in a widespread network involved in autobiographical memory retrieval during AD, which might account for the observed memory impairments in patients compared to controls.

In both our aMCI and eDAT participants we found an impairment of recalling autobiographical incidents. The impairment was less pronounced for remote compared to recent memories. Coherently, we found positive correlations between contextual memory performance for more recent incidents (i.e., early adulthood and recent life) and delayed verbal recall and recognition scores in the neuropsychological examination with the CERAD test battery in the patient groups. An analogue time gradient was not observed in the HC group, which exhibited equal memory performance across all life periods.

This finding is well in line with a substantial number of studies reporting a pattern of retrograde amnesia in AD patients consistent with Ribot’s Law [11 , 67]. Disturbances in the consolidation of autobiographical incidents occur at the beginning of AD-associated hippocampal degeneration [1, 68]. In this sense, our findings support the SMC [37 , 70] which basically states that memory consolidation initially depends on hippocampal integrity [3, 60]. Interestingly, there is evidence that hippocampal dependency of memories decreases over time in favor of consolidation and storage in neocortical structures [3, 60]. Thus, episodic memory of early adulthood and childhood is better preserved during the course of AD, as these memories have been consolidated and stored in the neocortex, and hereby have become independent of the hippocampus [3, 60]. Accordingly, an impaired ability to remember remote incidents in AD as observed in the present study is probably due to the spreading of the neurodegenerative process to the neocortex, as has been shown in previous studies [71].

Of special importance, in addition to the temporal decline of vividness in autobiographical memories from recent to remote events observed in our patient groups, the effect of life period on memory perseveration was significantly modulated by retrieval frequency. Patients with eDAT as well as aMCI, and also HC individuals, described personal circumstances surrounding a public event in greater detail when memory for the event was retrieved more frequently. As we could show that remote memories are recalled more often than recent ones, the temporal gradient of memory decline in the patient groups could be explained by the effect of retrievalfrequency.

In the case of the patients, this finding supports the hypothesis that more frequently retrieved knowledge possibly becomes more independent of the hippocampal complex. While frequently retrieved episodes become integrated into existing neocortical memory structures, seldomly-retrieved knowledge remains more dependent on hippocampal structures and therefore preserve its susceptibility to early neurodegenerative damage to the hippocampus.

The observable temporal decline in recall of autobiographical incidents may be also due to increasing pathological changes in the hippocampus. Recent and thus unconsolidated memories, which are not stored in the neocortex, may be more susceptible to hippocampal disruption, rendering them less detailed, less accessible, and therefore less likely to be retrieved. Thus, during the course of AD, the positive effect of retrieval may be counteracted by increasing neurodegenerative processes in the hippocampal complex.

In summary, our results provide strong evidence that cognitive activity (i.e., memory retrieval) delays the onset of memory decline in persons who develop AD [72, 73] and conclusively suggest that frequently retrieved autobiographical episodes become more independent of the hippocampus and thus better protected against the early damage of AD.

This has important influence for clinical practice as consistently disappointing results from drug trials with various agents have led to considerable doubt that disease-modifying treatments can show a positive effect on cognition and daily functioning by the time dementia is fully developed [74]. As efforts in this direction are increasingly being shifted to the pre-dementia or even the pre-symptomatic stage, non-pharmacological interventions, and particularly cognition-based interventions, should be recognized as an important adjunct or alternative topharmacological treatments for protecting cognitive decline or for delaying onset of dementia.

Disclosure statement

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/15-1071r1).

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