Recently, the idea of a transitional phase from healthy aging to Alzheimer’s disease (AD) was increasingly investigated. This precursory stage has mostly been described as mild cognitive impairment (MCI). As early AD symptomatology is most prominently related to deficiencies in episodic memory function, those are of special interest for an early diagnosis of AD and also for the definition of MCI as a putative AD prodrome. Because the AD-related neuropathology begins in the perirhinal cortex (Braak and Braak, 1991; Delacourte et al., 1999), an examination of the cognitive functions relying on this cortical region in MCI patients might further substantiate cognitive changes during the early pathologic stages of AD.

Numerous findings from behavioral, electrophysiological and imaging studies argued for a dual-process model of recognition memory (Yonelinas, 2002), dissociating an acontextual feeling of knowing (familiarity) that something has occurred before from the conscious retrieval of contextual details (recollection). Recent neuroanatomical models assume a functional dissociation within the medial temporal lobe (MTL) with regard to recollection and familiarity. Data from patients suffering from MTL lesions (e.g., Aggleton and Brown, 1999; Bowles et al., 2007) and functional imaging data (for an overview, see Eichenbaum et al., 2007) indicate that a recollection deficit is associated with damage to the hippocampus while lesions to the surrounding medial temporal lobe cortex (MTLC; i.e., the perirhinal and entorhinal cortices) trigger a familiarity deficit.

Familiarity and recollection have been differentiated electrophysiologically using event-related potentials (ERPs). An early old/new effect (hits – correct rejections; Rugg et al., 1998), which peaks at frontal electrode sites at about 400 ms after stimulus onset, has been related to familiarity processing and can be dissociated from a later effect emerging at about 500 ms over the left parietal scalp that is associated with recollection-based processing (Friedman et al., 2010). At least for recollection, this functional mapping onto divergent MTL structures has been corroborated by studies that showed the absence of the late parietal ERP effect when hippocampal tissue was damaged (Düzel et al., 2001; Addante et al., 2012). For familiarity, Bowles et al. (2007) reported the lack of a behavioral correlate in a patient with a lesion sharply restricted to the MTLC, leaving hippocampal tissue intact. Effects similar to the ERP early old/new effect have been described in the MTLC with intracranial recordings (Grunwald et al., 1998; Fernandez and Tendolkar, 2006) and with magnetoencephalography (Düzel et al., 2003; Gonsalves et al., 2005). However, the link between the MTLC and the scalp-recorded electrophysiological correlate of familiarity is so far missing.

From a developmental perspective, a large body of literature reports concordantly that in comparison to younger adults memory performance in older adults is associated with an impairment of recollection while familiarity seems to be unaffected or even boosted (e.g., Yonelinas, 2002; Dennis and Cabeza, 2008). In line with this observation, structural imaging results show that the hippocampus, constituting the crucial structure for recollection (Eichenbaum et al., 2007), is more severely affected by age-related volume loss than the MTLC (Raz et al., 2005), which has been related to familiarity-based processing.

Electrophysiological investigations of the differential vulnerability of recognition memory processes in aging found an exclusive reduction of the recollection-related ERP effect. Friedman et al. (2010) reported a frontal old/new effect from adolescence onwards and a parietal old/new effect across age groups but drastically reduced in old age. However, it has been shown that very high-performing older adults still display a preserved parietal old/new effect indicating that recollection might be intact in certain older subpopulations (Duarte et al., 2006; Wang et al., 2011).

When this age-related cognitive decline in aging is superimposed by AD, cognitive abilities may gradually deteriorate because of the progressive nature of neuropathological changes in AD. In the prodromal phase of AD, neuropathological changes have already evolved to a point where specific mild cognitive symptoms are found, however, they may not be severe enough to be diagnosed as dementia. This transitional phase has been described phenomenologically as MCI. Different MCI subtypes have been differentiated depending on the extent of cognitive malfunctions, meaning if only one or several cognitive domains are compromised (Petersen, 2004). A singular memory impairment is characterized as single-domain amnestic MCI (aMCI). If multiple cognitive domains are impaired, this is classified as multiple-domain MCI (mdMCI). In comparison to aMCI, this subtype might not constitute a prodromal phase specific to the development of AD (Petersen, 2004). If MCI is accompanied by typical changes of biomarkers for AD, the terms “MCI due to AD” or “prodromal AD” have been proposed (Dubois et al., 2010; Sperling et al., 2011).

The volume of MTL structures in AD and MCI was for example studied using tracing methods or voxel-based morphometry (VBM) with scans from structural magnetic resonance imaging (MRI). AD patients showed significant neuronal atrophy in the MTL including the hippocampus (e.g., Karas et al., 2004; Barbeau et al., 2008; Pihlajamäki et al., 2009; Schmidt-Wilcke et al., 2009), whereas MCI subjects displayed significant neuronal loss only in the MTLC (Kordower et al., 2001). Regionally specific atrophy within the MTL also correlated differentially with functionally distinct memory measures, e.g., delayed recognition with MTLC volume but delayed free recall with hippocampal size in a mild AD population (Wolk and Dickerson, 2011). Also using multiple behavioral recognition assessments, hippocampal volume was more strongly related to recollection and MTLC volume more strongly related to familiarity estimates (Wolk et al., 2011). Structural MRI data suggest that the differentiation of MCI subtypes based on cognitive criteria also holds for the underlying atrophy processes with more focused MTL atrophy in aMCI subjects, and more diffuse atrophy in mdMCI (Bell-McGinty et al., 2005).

The hypothesis that pronounced MTLC atrophy in aMCI leads to familiarity impairments yielded conflicting results in previous behavioral studies. Most studies investigating recollection-based memory indeed found significantly reduced recollection estimates and some of the studies found an additional deficit of familiarity estimates (e.g., Wolk et al., 2008; Ally et al., 2009; Algarabel et al., 2009, 2012) However, others reported no significant differences for familiarity measures between controls and MCI subjects (e.g., Westerberg et al., 2006; Anderson et al., 2008; Hudon et al., 2009; Serra et al., 2010). However, it might be a substantial confound that most of the studies investigated mdMCI subjects though atrophy in mdMCI is not restricted to the MTLC (Petersen, 2004; Whitwell et al., 2007).

Recently, Ally et al. (2009) investigated ERPs to verbal and visual recognition memory in healthy older adults and in a mixed group of single and multiple domain aMCI. The aMCI group showed a significantly worse performance than the control group across conditions. ERP results revealed a recollection-based parietal old/new effect for controls in the picture but not in the word condition, whereas aMCI subjects did not show any recollection correlate in either task. A frontal old/new effect that indicates familiarity-based processing was similarly present in both groups in the picture condition wheras in the word task only controls showed a significant frontal old/new effect. This suggests that aMCI patients exhibit deficient familiarity and recollection-based processing in recognition memory tasks involving word material.

To investigate more thoroughly the impact of aMCI on electrophysiological markers of recognition memory processes, a verbal yes/no recognition memory paradigm was designed to analyze alterations of the frontal and parietal ERP old/new effects indicating recollection and familiarity, respectively, in a sample of single-domain aMCI subjects. Given that also healthy older adults potentially exhibit deficient recollection (Friedman et al., 2010) there was no specific hypothesis on the parietal old/new effect. However, the frontal old/new effect was hypothesized to differ between aMCI patients and control subjects indicating differential reliance on familiarity. Moreover, these group differences should correspond to morphological changes in the MTL assessed in a VBM analysis with a reduced volume of MTLC gray matter in aMCI subjects.

This study examined behavioral and electrophysiological correlates of recognition memory in single-domain aMCI patients with an assumed selective atrophy in the MTLC. Analyses of brain morphology by means of VBM confirmed a focused GM loss in the medial and inferior temporal lobes in the aMCI group compared to the healthy controls. The analysis of recognition memory performance showed poorer discrimination ability between correctly classified old and new items for the aMCI patients, which was accompanied by prolonged reaction times. Whereas a familiarity-related early frontally distributed ERP effect was present in the control group, no reliable frontal old/new effect could be found in the aMCI patient group. Additionally, neither group showed any sign of a significant parietal old/new effect indicating a lack of recollection-based processing. The magnitude of the frontal old/new effect correlated positively with test performance and with a compound measure including eight episodic memory test scores. Moreover, correlations of the frontal old/new effect with executive functioning comprised of an analogous compound score derived from neuropsychological testing turned out to be not significant. In addition, the size of the frontal old/new effect was positively correlated with the GM volume in the MTLC.

The behavioral results of this experiment are in line with our hypotheses that aMCI patients should perform more poorly than healthy seniors. The Petersen criteria define aMCI as a pathological condition with preserved general cognition but objectively impaired mnemonic functioning (Petersen, 2004; Winblad et al., 2004). In this study, this was ensured through a careful selection process where potential subjects’ cognitive functions were screened using multiple neuropsychological measures. The aMCI patient group differed significantly from the control group in four of eight episodic memory scores where they performed at least 1.3 SD inferior to the control group. Thus, also the behavioral data of the recognition memory paradigm showed a performance advantage for the healthy seniors.

The ERP results of the recognition memory experiment supported the hypotheses. Only the control group exhibited a significant frontal old/new effect. This corroborates recent findings of impaired familiarity in aMCI (e.g., Wolk et al., 2008; Algarabel et al., 2009). Contrary to these findings are the results of the behavioral studies by by Westerberg et al. (2006); Anderson et al. (2008), Hudon et al. (2009), and Serra et al. (2010) who reported familiarity to be preserved in aMCI patients. However, most of these studies examined recognition memory in mixed groups of multiple and single-domain aMCI patients with multiple-domain aMCI being the more frequent diagnosis. Thus, it is open to what extent these results are comparable to the current data that only incorporated subjects with a single-domain aMCI diagnosis, who are probably located at a transitional stage towards the development of AD. The outcome of patients suffering from mdMCI is less clear (Petersen, 2004; Fischer et al., 2007). The interpretation of the Anderson and Serra studies which only included single-domain aMCI patients is complicated because the Process Dissociation and the Remember/Know Procedure used in these studies have been called into question as being reliable behavioral measures of familiarity and recollection in healthy older subjects and in patients with aMCI due to intrinsic testing characteristics (e.g., Wolk et al., 2008; Serra et al., 2010). The Process Dissociation Procedure might lead to an underestimation of recognition memory performance in older adults because the exclusion condition requests to label the items from one of the two learning lists as new although they have been learned beforehand. Also, the Remember/Know procedure which assumes that the processes leading to one or the other introspectively determined judgment are independent might overestimate the impact of familiarity or recollection in subjects with specific memory problems.

The current results support the findings of Ally et al. (2009) who used a nearly identical paradigm with verbal and pictorial material in healthy older adults and aMCI patients. The current study only used verbal material and reveals an exact concordance with the Ally et al. (2009) data. They also found a significant frontal old/new effect only for the control subjects and no significant parietal old/new effect in both groups. Again, there is the question of precise comparability because Ally et al. (2009) also examined both single and multiple-domain aMCI patients. Thus the current results obtained in a more homogenous sample argue even more strongly in favor of impaired familiarity in very early developmental stages of AD caused by the neuropathological changes in the MTLC (Braak and Braak, 1991; Delacourte et al., 1999).

The scalp distribution of the familiarity effect in the control group was right-lateralized at frontal electrode sites. Usually the early old/new effect reflecting item familiarity is more mid-frontally focused (Rugg et al., 1998; Rugg and Curran, 2007). Friedman et al. (2010) compared the ERP correlates of familiarity and recollection across age groups and also found that older adults exhibited a rather right-lateralized frontal old/new effect whereas the analogous effect in adolescents and younger adults was mid-frontally focused. Identical results on topography were reported in a previous study investigating younger and older adults (Nessler et al., 2007). In both studies, it was hypothesized that the effect might have been lateralized at right hemisphere electrode sites due to additionally engaged monitoring processes to strengthen the processing of perceptual features to compensate for impaired recollection.

Neither of the groups showed a reliable old/new effect at parietal electrode sites. This indicates a lack of recollection-based processing. The study of Wolk et al. (2008) showed that MCI patients demonstrated not only familiarity but also recollection impairments relative to control subjects, in fact at least to the same extent. But here, also healthy seniors did not evoke a parietal recollection correlate. Friedman et al. (2010) clarified the developmental trajectories of familiarity and recollection in a lifespan perspective but only healthy seniors were included in their sample. A parietal old/new effect was indeed present across age groups in that study but the magnitude of the effect diminished with increasing age. Moreover, their subjects had to learn visual abstract material over four study-test cycles leading to a more pronounced recollection effect in three younger age groups with repetition but not in the senior group. Hence, the results of Friedman et al. (2010), suggest that the distorted recollection ERP correlates in old age rely on impaired recollection. An age-related decline in recollection performance is also corroborated by behavioral and imaging studies (e.g., Parkin and Walter, 1992; Cabeza et al., 2004). Recollection relies on the integrity of the hippocampus (e.g., Eldridge et al., 2000; Baddeley et al., 2001; Eichenbaum et al., 2007) and aging studies showed that especially hippocampal tissue is vulnerable to age-related shrinkage (e.g., Raz et al., 2005). Thus, the absence of an ERP correlate of recollection in healthy seniors can be accounted for by the natural decline going along with aging. Another account for the absence of a recollection correlate might be inherent in the nature of the task. Subjects had to learn a list of single words and were subsequently tested to discriminate between previously seen old words and new words. Because there was neither a subsequent query for associational information nor a source judgment, it was not necessary for the subjects to recall any further details from the study episode besides the targeted word forms to successfully accomplish this task. Thus, it might have been irrelevant for the task to engage recollective processing to retrieve any specific details. Potentially, some but not all of the participants might have initiated recollection processes, leading to greater inter-subject variability (Sugiura et al., 2007). This might have resulted in a reduction of an ERP correlate of recollection.

The significant positive correlations of the behavioral assessments of episodic memory capacity and the magnitude of the familiarity-related ERP correlate suggest that the decline in memory performance covaries with a decrease of the frontal old/new effect.

The supplementary examination of the GM volume of MTL structures revealed bilateral shrinkage of aMCI patients’ GM volume within the medial and inferior temporal lobe, specifically within the perirhinal cortex and the fusiform gyrus. Moreover, GM volume of MTLC structures covaried positively with the magnitude of the early frontal ERP effect. To our knowledge these are the first data which can show a direct link between the MTLC and the putative electrophysiological correlate of familiarity.

Structural alterations in medial and inferior temporal lobe have been reported in several studies investigating morphometric changes in aMCI patients, whereby volume loss in rhinal cortex and in fusiform gyrus was repeatedly found (Convit et al., 2000; Karas et al., 2004; Chételat et al., 2005; Bozzali et al., 2006; Barbeau et al., 2008; Schmidt-Wilcke et al., 2009). Moreover, in aMCI patients MTLC volumes have also been found to be positively correlated with performance in mnemonic neuropsychological tests (Meyer et al., 2013). Neither a volumetric between-group difference in hippocampal GM nor a correlation of hippocampal GM and the ERP effect could be found. Thus in the case of patients at a very early stage of presumed AD pathology, the examination of MTLC atrophy might be more useful to support an early diagnosis of AD-related neuropathology than hippocampal atrophy. On the other hand, volume loss of hippocampal GM that exceeds atrophic changes associated with healthy aging might be suited to differentiate between healthy elderly and patients only at a later stage of the neuropathological process. In addition, the present data suggest that alteration of the electrophysiological correlate of familiarity might be a suitable marker of these early subtle cognitive and anatomical changes.

Concerning the correlations of familiarity with GM volume outside the MTLC, several fMRI studies also reported activations in the medial temporal gyrus (Henson et al., 1999; Yonelinas et al., 2001; Montaldi et al., 2006), the lingual gyrus (Voss et al., 2008), the insula (Henson et al., 1999; Montaldi et al., 2006) and the dorsolateteral prefrontal cortex (Yonelinas et al., 2005) which were correlated with familiarity strength. Thus, it is well conceivable that differences in GM in these regions also contribute to a modulation of the familiarity signal.

One major critical point when examining MCI patients is who of the aMCI subjects will prospectively develop AD. This question can only be answered when longitudinal studies are conducted. There have been attempts to find predictors of subsequent conversion including volumetric measures of hippocampal and entorhinal volumes (e.g., Pennanen et al., 2004). The results of the current study suggest that the deficiency of an ERP correlate of familiarity, or at least the attenuation of such an ERP effect, might be a supplementary predictor of conversion to AD.

One potential limitation of this study is the rather small sample size of only fourteen aMCI patients and ten healthy controls. Whereas for the ERP analysis, the reported effects were statistically significant and seemed rather robust (in terms of effect sizes), for the VBM analysis, only effects with p-levels uncorrected for multiple comparisons could be reported. This might actually be due to a lack of power because of the small sample size. A second limitation might be the significantly poorer performance of the aMCI subjects in the recognition memory task. It could be a possible confound that the two groups differ in their performance levels but because the defined clinical criteria for a diagnosis of aMCI include an objective impairment in memory tests, it is not surprising that the patients yielded poorer Pr scores in the experimental task. But it is important to state that also the patient group did not operate at chance level in the recognition task (a Pr score of 0.74 is significantly different from 0.5). Finally, the current results do not allow to draw strong conclusions about the location of the neural generators of the familiarity-related early old/new effect as scalp ERPs cannot be used to determine the neural generators with high precision. However, the current electrophysiological and correlational results clearly support the notion that the familiarity-related early old/new effect relies upon the integrity of the MTLC.

The current data provide evidence that aMCI patients exhibit a specific memory-related cognitive impairment. The electrophysiological correlate of familiarity substantially differs between aMCI patients and age-matched healthy controls. Those alterations can be ascribed to neuropathological changes in the MTLC. Thus, the detection of abnormal ERP correlates of familiarity, together with a neuropsychologically based diagnosis of aMCI, might constitute an important predictor of an underlying AD pathology and if validated in further studies, may be used as a biomarker for AD.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.