The Relationship between Short- and Long-Term Memory Is Preserved across the Age Range.

Both short- and long-term memories decline with healthy ageing. The aims of the current study were twofold: firstly, to build on previous studies and investigate the presence of a relationship between short- and long-term memories and, secondly, to examine cross-sectionally whether there are changes in this relationship with age. In two experiments, participants across the age range were tested on contextual-spatial memories after short and long memory durations. Experimental control in stimulus materials and task demands enabled the analogous encoding and probing for both memory durations, allowing us to examine the relationship between the two memory systems. Across two experiments, in line with previous studies, we found both short-term memory and long-term memory declined from early to late adulthood. Additionally, there was a significant relationship between short- and long-term memory performance, which, interestingly, persisted throughout the age range. Our findings suggest a significant degree of common vulnerability to healthy ageing for short- and long-term memories sharing the same spatial-contextual associations. Furthermore, our tasks provide a sensitive and promising framework for assessing and comparing memory function at different timescales in disorders with memory deficits at their core.

Transient beta activity and cortico-muscular connectivity during sustained motor behaviour.

Neural oscillations are thought to play a central role in orchestrating activity states between distant neural populations. For example, during isometric contraction, 13-30 Hz beta activity becomes phase coupled between the motor cortex and the contralateral muscle. This and related observations have led to the proposal that beta activity and connectivity sustain stable cognitive and motor states - or the 'status quo' - in the brain. Recently, however, beta activity at the single-trial level has been shown to be short-lived - though so far this has been reported for regional beta activity in tasks without sustained motor demands. Here, we measured magnetoencephalography (MEG) and electromyography (EMG) in 18 human participants performing a sustained isometric contraction (gripping) task. If cortico-muscular beta connectivity is directly responsible for sustaining a stable motor state, then beta activity within single trials should be (or become) sustained in this context. In contrast, we found that motor beta activity and connectivity with the downstream muscle were transient. Moreover, we found that sustained motor requirements did not prolong beta-event duration in comparison to rest. These findings suggest that neural synchronisation between the brain and the muscle involves short 'bursts' of frequency-specific connectivity, even when task demands - and motor behaviour - are sustained.

Vividness of visual imagery questionnaire scores and their relationship to visual short-term memory performance.

Mechanisms underlying visual imagery, the ability to create vivid mental representations of a scene in the absence of sensory input, remain to be fully understood. Some previous studies have proposed that visual imagery might be related to visual short-term memory (STM), with a common mechanism involving retention of visual information over short periods of time. Other observations have shown a strong relationship between visual imagery and functional activity in the hippocampus and primary visual cortex, both regions also associated with visual STM. Here we examined the relationship of visual imagery to STM and hippocampal and primary visual cortex volumes, first in a large sample of healthy people across a large age range (N = 229 behavioural data; N = 56 MRI data in older participants) and then in patients with Alzheimer's disease and Parkinson's disease (N = 19 in each group compared to 19 age-matched healthy controls). We used a variant of the "What was where?" visual object-location binding task to assess the quality of remembered information over short delays. In healthy people, no evidence of a relationship between the vividness of visual imagery and any visual STM performance parameter was found. However, there was a significant positive correlation between visual imagery and the volumes of the hippocampus and primary visual cortex. Although visual STM performance was significantly impaired in patients with Alzheimer's disease, their vividness of visual imagery scores were comparable to those of age-matched elderly controls and patients with Parkinson's disease. Despite hippocampal volumes also being reduced in Alzheimer's patients, there appeared to be no impact on their self-reported visual imagery. In conclusion, visual imagery was not significantly related to visual STM performance, either in healthy controls or Alzheimer's or Parkinson's disease but it was related to hippocampal and visual cortex volume in healthy people.

Reduced cortico-muscular beta coupling in Parkinson's disease predicts motor impairment.

Long-range communication through the motor system is thought to be facilitated by phase coupling between neural activity in the 15-30 Hz beta range. During periods of sustained muscle contraction (grip), such coupling is manifest between motor cortex and the contralateral forearm muscles-measured as the cortico-muscular coherence. We examined alterations in cortico-muscular coherence in individuals with Parkinson's disease, while equating grip strength between individuals with Parkinson's disease (off their medication) and healthy control participants. We show a marked reduction in beta cortico-muscular coherence in the Parkinson's disease group, even though the grip strength was comparable between the two groups. Moreover, the reduced cortico-muscular coherence was related to motor symptoms, so that individuals with lower cortico-muscular coherence also displayed worse motor symptoms. These findings highlight the cortico-muscular coherence as a simple, effective and clinically relevant neural marker of Parkinson's disease pathology, with the potential to aid monitoring of disease progression and the efficacy of novel treatments for Parkinson's disease.

Gamma oscillations modulate working memory recall precision.

Working memory (WM)-the ability to keep information in mind for short periods of time-is linked to attention and inhibitory abilities, i.e., the capacity to ignore task-irrelevant information. These abilities have been associated with brain oscillations, especially parietal gamma and alpha bands, but it is yet unknown whether these oscillations also modulate attention and inhibitory abilities. To test this, we compared parietal gamma-transcranial alternating current stimulation (tACS) to alpha-tACS and to a non-stimulation condition (Sham) in 51 young participants. Stimulation was coupled with a WM task probing memory-based attention and inhibitory abilities by means of probabilistic retrospective cues, including informative (valid), uninformative (invalid) and neutral. Our results show that relative to alpha and sham stimulation, parietal gamma-tACS significantly increased working memory recall precision. Additional post hoc analyses also revealed strong individual variability before and following stimulation; low-baseline performers showed no significant changes in performance following both gamma and alpha-tACS relative to sham. In contrast, in high-baseline performers gamma- (but not alpha) tACS selectively and significantly improved misbinding-feature errors as well as memory precision, particularly in uninformative (invalid) cues which rely more strongly on attentional abilities. We concluded that parietal gamma oscillations, therefore, modulate working memory recall processes, although baseline performance may further influence the effect of stimulation.

The Effect of Transcranial Random Noise Stimulation on Cognitive Training Outcome in Healthy Aging.

Background and Objective: Aging is associated with a decline in attentional and executive abilities, which are linked to physiological, structural, and functional brain changes. A variety of novel non-invasive brain stimulation methods have been probed in terms of their neuroenhancement efficacy in the last decade; one that holds significant promise is transcranial random noise stimulation (tRNS) that delivers an alternate current at random amplitude and frequency. The aim of this study was to investigate whether repeated sessions of tRNS applied as an add-on to cognitive training (CT) may induce long-term near and far transfer cognitive improvements. Methods: In this sham-controlled, randomized, double-blinded study forty-two older adults (age range 60-86 years) were randomly assigned to one of three intervention groups that received 20 min of 0.705 mA tRNS (N = 14), 1 mA tRNS (N = 14), or sham tRNS (N = 19) combined with 30 min of CT of executive functions (cognitive flexibility, inhibitory control, working memory). tRNS was applied bilaterally over the dorsolateral prefrontal cortices for five sessions. The primary outcome (non-verbal logical reasoning) and other cognitive functions (attention, memory, executive functions) were assessed before and after the intervention and at a 1-month follow-up. Results: Non-verbal logical reasoning, inhibitory control and reaction time improved significantly over time, but stimulation did not differentially affect this improvement. These changes occurred during CT, while no further improvement was observed during follow-up. Performance change in logical reasoning was significantly correlated with age in the group receiving 1 mA tRNS, indicating that older participants profited more from tRNS than younger participants. Performance change in non-verbal working memory was significantly correlated with age in the group receiving sham tRNS, indicating that in contrast to active tRNS, older participants in the sham group declined more than younger participants. Interpretation: CT induced cognitive improvements in all treatment groups, but tRNS did not modulate most of these cognitive improvements. However, the effect of tRNS depended on age in some cognitive functions. We discuss possible explanations leading to this result that can help to improve the design of future neuroenhancement studies in older populations.

Temporal orienting in Parkinson's disease.

Temporal orienting of attention can affect multiple stages of processing to guide adaptive behaviour. We tested whether temporal expectation in different task contexts is compromised in individuals with Parkinson's disease (PD). In Experiment 1 two temporal-orienting tasks were used: a speeded task emphasizing motor preparation and a non-speeded task emphasizing perceptual discrimination using rapid serial visual presentation. In both tasks, auditory cues indicated the likelihood of a target appearing after a short or long interval. In the speeded-response task, participants used the cues to anticipate an easily detectable target stimulus. In the non-speeded perceptual-discrimination task, participants used the cues to help discriminate a target letter embedded in a stream of letters. Relative to healthy participants, participants with PD did not show altered temporal orienting effects in the speeded-response task. However, they were impaired in using temporal cues to improve perceptual discrimination. In Experiment 2, we tested whether the temporal-orienting deficits in the perceptual-discrimination task depended on the requirement to ignore temporally distracting stimuli. We replicated the impaired temporal orienting for perceptual discrimination in an independent group of individuals with PD, and showed the impairment was abolished when individuals were on their dopaminergic medication. In a task without any distracting letters, however, patients off or on medication benefited normally from temporal orienting cues. Our findings suggest that deficits in temporal orienting in individuals with PD interact with specific task demands, such as the requirement to select target from temporally competing distractors.

Superior short-term memory in APOE ε2 carriers across the age range.

The Apolipoprotein-E (APOE) gene is now known to be associated with individual differences in cognitive health in ageing. However, while the APOE ε4 allele confers significantly increased risk of developing Alzheimer's disease (AD), the APOE ε2 allele is hypothesized to be protective against the development of AD. This is in line with neuroimaging and pathological findings associated with ε2 APOE allele, which go in the opposite direction to those observed in AD-related pathology. However, the precise impact of this allele on cognition remains inconclusive, with some small-cohort studies raising the possibility of an advantageous memory performance in these individuals. Here, we tested short-term memory (STM) performance in a large cohort of individuals, 300 of which were ε2/ε3 carriers. Their performance was compared to 554 ε3/ε3 carriers. We included participants from a wide age range spanning young, middle-aged and elderly adults. All of them performed a STM task that has previously been shown to be sensitive to subtle changes in memory in various patient and at-risk cohorts. Individuals carrying the APOE-ε2 allele exhibited a significant memory advantage, regardless of STM task difficulty and across all ages. The observed memory advantage was present across the age range, suggestive of a phenotypical effect of this allele on cognition, possibly independent of any effects of this genetic allele that occur later life in these individuals.

A new toolbox to distinguish the sources of spatial memory error.

Studying the sources of errors in memory recall has proven invaluable for understanding the mechanisms of working memory (WM). While one-dimensional memory features (e.g., color, orientation) can be analyzed using existing mixture modeling toolboxes to separate the influence of imprecision, guessing, and misbinding (the tendency to confuse features that belong to different memoranda), such toolboxes are not currently available for two-dimensional spatial WM tasks. Here we present a method to isolate sources of spatial error in tasks where participants have to report the spatial location of an item in memory, using two-dimensional mixture models. The method recovers simulated parameters well and is robust to the influence of response distributions and biases, as well as number of nontargets and trials. To demonstrate the model, we fit data from a complex spatial WM task and show the recovered parameters correspond well with previous spatial WM findings and with recovered parameters on a one-dimensional analogue of this task, suggesting convergent validity for this two-dimensional modeling approach. Because the extra dimension allows greater separation of memoranda and responses, spatial tasks turn out to be much better for separating misbinding from imprecision and guessing than one-dimensional tasks. Code for these models is freely available in the MemToolbox2D package and is integrated to work with the commonly used MATLAB package MemToolbox.

Different patterns of short-term memory deficit in Alzheimer's disease, Parkinson's disease and subjective cognitive impairment.

It has recently been proposed that short-term memory (STM) binding deficits might be an important feature of Alzheimer's disease (AD), providing a potential avenue for earlier detection of this disorder. By contrast, work in Parkinson's disease (PD), using different tasks, has suggested that the STM impairment in this condition is characterised by increased random guessing, possibly due to fluctuating attention. In the present study, to establish whether a misbinding impairment is present in sporadic late-onset AD (LOAD) and increased guessing is a feature of PD, we compared the performance of these patient groups to two control populations: healthy age-matched controls and individuals with subjective cognitive impairment (SCI) with comparable recruitment history as patients. All participants performed a sensitive task of STM that required high resolution retention of object-location bindings. This paradigm also enabled us to explore the underlying sources of error contributing to impaired STM in patients with LOAD and PD using computational modelling of response error. Patients with LOAD performed significantly worse than other groups on this task. Importantly their impaired memory was associated with increased misbinding errors. This was in contrast to patients with PD who made significantly more guessing responses. These findings therefore provide additional support for the presence of two doubly dissociable signatures of STM deficit in AD and PD, with binding impairment in AD and increased random guessing characterising the STM deficit in PD. The task used to measure memory precision here provides an easy-to-administer assessment of STM that is sensitive to the different types of deficit in AD and PD and hence has the potential to inform clinical practice.

Short-term memory advantage for brief durations in human APOE ε4 carriers.

The Apolipoprotein-E (APOE) ε4 gene allele, the highest known genetic risk factor for Alzheimer's disease, has paradoxically been well preserved in the human population. One possible explanation offered by evolutionary biology for survival of deleterious genes is antagonistic pleiotropy. This theory proposes that such genetic variants might confer an advantage, even earlier in life when humans are also reproductively fit. The results of some small-cohort studies have raised the possibility of such a pleiotropic effect for the ε4 allele in short-term memory (STM) but the findings have been inconsistent. Here, we tested STM performance in a large cohort of individuals (N = 1277); nine hundred and fifty-nine of which included carrier and non-carriers of the APOE ε4 gene, those at highest risk of developing Alzheimer's disease. We first confirm that this task is sensitive to subtle deterioration in memory performance across ageing. Importantly, individuals carrying the APOE ε4 gene actually exhibited a significant memory advantage across all ages, specifically for brief retention periods but crucially not for longer durations. Together, these findings present the strongest evidence to date for a gene having an antagonistic pleiotropy effect on human cognitive function across a wide age range, and hence provide an explanation for the survival of the APOE ε4 allele in the gene pool.

Effects of Home-Based Working Memory Training on Visuo-Spatial Working Memory in Parkinson's Disease: A Randomized Controlled Trial.

BACKGROUND: Cognitive impairment is a very frequent and severe nonmotor symptom of Parkinson's disease (PD). Early intervention in this at-risk group for cognitive decline may be crucial for long-term preservation of cognitive functions. Computerized working memory training (WMT) has been proven beneficial in non-PD patient populations, but such evidence is still needed for patients with PD. OBJECTIVE: This study aimed to evaluate the effect of WMT on visuo-spatial working memory (WM) in cognitively unimpaired patients with PD. METHODS: A single-blind randomized controlled trial encompassing 76 patients with PD but no cognitive impairment according to level II diagnostic criteria was conducted. Thirty-seven patients engaged in home-based adaptive WMT 5 times per week for a period of 5 weeks, whereas the remaining patients were in the waiting list arm of the study (control group [CG]). Working memory performance was evaluated using a computerized task before and after intervention and at 14-week follow-up, allowing to quantify the precision of WM on a continuous scale, ie, to test not only if an item was remembered but also how well the location of this item was retained. RESULTS: Coincidently, the WMT group showed slightly worse WM performance compared with the CG at baseline, which was ameliorated after WMT. This training-induced effect remained stable until follow-up. CONCLUSION: Patients showing relatively low WM performance, despite not formally diagnosable as Parkinson's disease with mild cognitive impairment (PD-MCI), seem to benefit from home-based WMT. Thus, WMT could potentially be implemented in future trials as a time- and cost-efficient route to counteract subtle cognitive changes in early disease stages. TRIAL REGISTRATION: German Clinical Trial Register (drks.de, DRKS00009379).

Modulation of the pupillary response by the content of visual working memory.

Studies of selective attention during perception have revealed modulation of the pupillary response according to the brightness of task-relevant (attended) vs. -irrelevant (unattended) stimuli within a visual display. As a strong test of top-down modulation of the pupil response by selective attention, we asked whether changes in pupil diameter follow internal shifts of attention to memoranda of visual stimuli of different brightness maintained in working memory, in the absence of any visual stimulation. Across 3 studies, we reveal dilation of the pupil when participants orient attention to the memorandum of a dark grating relative to that of a bright grating. The effect occurs even when the attention-orienting cue is independent of stimulus brightness, and even when stimulus brightness is merely incidental and not required for the working-memory task of judging stimulus orientation. Furthermore, relative dilation and constriction of the pupil occurred dynamically and followed the changing temporal expectation that 1 or the other stimulus would be probed across the retention delay. The results provide surprising and consistent evidence that pupil responses are under top-down control by cognitive factors, even when there is no direct adaptive gain for such modulation, since no visual stimuli were presented or anticipated. The results also strengthen the view of sensory recruitment during working memory, suggesting even activation of sensory receptors. The thought-provoking corollary to our findings is that the pupils provide a reliable measure of what is in the focus of mind, thus giving a different meaning to old proverbs about the eyes being a window to the mind.

Working Memory in Alzheimer's Disease and Parkinson's Disease.

Working memory impairments are frequently observed in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Recent research suggests that the mechanisms underlying these deficits might be dissociable using sensitive tasks, specifically those that rely on the reproduction of the exact quality of features held in memory.In patients with AD, working memory impairments are mainly due to an increase in misbinding errors. They arise when patients misremember which features (e.g., color, orientation, shape, and location) belong to different objects held in memory. Hence, they erroneously report features that belong to items in memory other than the one they are probed on. This misbinding of features that belong to different objects in memory can be considered a form of interference between stored items. Such binding errors are evident even in presymptomatic individuals with familial AD (due to gene mutations) who do not have AD yet. Overall, these findings are in line with the role of the medial temporal lobes, and specifically the hippocampus, in retention of feature bindings, regardless of retention duration, i.e., in both short- or long-term memory.Patients with PD, on the other hand, do not show increased misbinding. Their working memory deficits are associated with making more random errors or guesses. These random responses are not modulated by manipulations of their dopaminergic medication and hence may reflect involvement of non-dopaminergic neurotransmitters in this deficit. In addition, patients with PD demonstrate impairments in gating of information into relevant vs. irrelevant items in memory, a cognitive operation that is modulated by dopaminergic manipulation in line with a frontal executive effect of this neurotransmitter. Thus, although AD and PD are both associated with working memory impairments, these surface manifestations appear to be underpinned by very different mechanisms.

Neural mechanisms of attending to items in working memory.

Working memory, the ability to keep recently accessed information available for immediate manipulation, has been proposed to rely on two mechanisms that appear difficult to reconcile: self-sustained neural firing, or the opposite-activity-silent synaptic traces. Here we review and contrast models of these two mechanisms, and then show that both phenomena can co-exist within a unified system in which neurons hold information in both activity and synapses. Rapid plasticity in flexibly-coding neurons allows features to be bound together into objects, with an important emergent property being the focus of attention. One memory item is held by persistent activity in an attended or "focused" state, and is thus remembered better than other items. Other, previously attended items can remain in memory but in the background, encoded in activity-silent synaptic traces. This dual functional architecture provides a unified common mechanism accounting for a diversity of perplexing attention and memory effects that have been hitherto difficult to explain in a single theoretical framework.

Task-irrelevant financial losses inhibit the removal of information from working memory.

The receipt of financial rewards or penalties - though task-irrelevant - may exert an obligatory effect on manipulating items in working memory (WM) by constraining a forthcoming shift in attention or reinforcing attentional shifts that have previously occurred. Here, we adjudicate between these two hypotheses by varying - after encoding- the order in which task-irrelevant financial outcomes and cues indicating which items need to be retained in memory are presented (so called retrocues). We employed a "what-is-where" design that allowed for the fractionation of WM recall into separate components: identification, precision and binding (between location and identity). Principally, valence-dependent effects were observed only for precision and binding, but only when outcomes were presented before, rather than after, the retrocue. Specifically, task-irrelevant financial losses presented before the retrocue caused a systematic breakdown in binding (misbinding), whereby the features of cued and non-cued memoranda became confused, i.e., the features that made up relevant memoranda were displaced by those of non-cued (irrelevant) items. A control experiment, in which outcomes but no cues were presented, failed to produce the same effects, indicating that the inclusion of retrocues were necessary for generating this effect. These results show that the receipt of financial penalties - even when uncoupled to performance - can prevent irrelevant information from being effectively pruned from WM. These results illustrate the importance of reward-related processing to controlling the contents of WM.

Dissociable effects of the apolipoprotein-E (APOE) gene on short- and long-term memories.

Short- and long-term memory performance as a function of apolipoprotein-E (APOE) genotype was examined in older, healthy individuals using sensitive and comparable tasks to provide a more detailed description of influences of the ε4 allele (highest genetic risk factor for Alzheimer's disease) on memory. Older heterozygous and homozygous ε4 carriers and noncarriers performed 2 tasks of memory. Both tasks allowed us to measure memory for item identity and locations, using a sensitive, continuous measure of report. Long-term memory for object locations was impaired in ε4/ε4 carriers, whereas, paradoxically, this group demonstrated superior short-term memory for locations. The dissociable effects of the gene on short- and long-term memory suggest that the effect of genotype on these two types of memories, and their neural underpinnings, might not be co-extensive. Whereas the long-term memory impairment might be linked to preclinical Alzheimer's disease, the short-term memory advantage may reflect an independent, phenotypical effect of this allele on cognition.

Binding deficits in visual short-term memory in patients with temporal lobe lobectomy.

Classical views of the medial temporal lobe (MTL) have established that it plays a crucial role in long-term memory (LTM). Here we demonstrate, in a sample of patients who have undergone anterior temporal lobectomy for the treatment of pharmacoresistant epilepsy, that the MTL additionally plays a specific, causal role in short-term memory (STM). Patients (n=22) and age-matched healthy control participants (n=26) performed a STM task with a sensitive continuous report measure. This paradigm allowed us to examine recall memory for object identity, location and object-location binding, independently on a trial-by-trial basis. Our findings point to a specific involvement of MTL in object-location binding, but, crucially, not retention of either object identity or location. Therefore the MTL appears to perform a specific computation: binding disparate features that belong to a memory. These results echo findings from previous studies, which have identified a role for the MTL in relational binding for LTM, and support the proposal that MTL regions perform such a function for both STM and LTM, independent of the retention duration. Furthermore, these findings and the methodology employed here may provide a simple, sensitive and clinically valuable means to test memory dysfunuction in MTL disorders.

Alpha Oscillations Are Causally Linked to Inhibitory Abilities in Ageing.

Aging adults typically show reduced ability to ignore task-irrelevant information, an essential skill for optimal performance in many cognitive operations, including those requiring working memory (WM) resources. In a first experiment, young and elderly human participants of both genders performed an established WM paradigm probing inhibitory abilities by means of valid, invalid, and neutral retro-cues. Elderly participants showed an overall cost, especially in performing invalid trials, whereas younger participants' general performance was comparatively higher, as expected.Inhibitory abilities have been linked to alpha brain oscillations but it is yet unknown whether in aging these oscillations (also typically impoverished) and inhibitory abilities are causally linked. To probe this possible causal link in aging, we compared in a second experiment parietal alpha-transcranial alternating current stimulation (tACS) with either no stimulation (Sham) or with two control stimulation frequencies (theta- and gamma-tACS) in the elderly group while performing the same WM paradigm. Alpha- (but not theta- or gamma-) tACS selectively and significantly improved performance (now comparable to younger adults' performance in the first experiment), particularly for invalid cues where initially elderly showed the highest costs. Alpha oscillations are therefore causally linked to inhibitory abilities and frequency-tuned alpha-tACS interventions can selectively change these abilities in the elderly.SIGNIFICANCE STATEMENT Ignoring task-irrelevant information, an ability associated to rhythmic brain activity in the alpha frequency band, is fundamental for optimal performance. Indeed, impoverished inhibitory abilities contribute to age-related decline in cognitive functions like working memory (WM), the capacity to briefly hold information in mind. Whether in aging adults alpha oscillations and inhibitory abilities are causally linked is yet unknown. We experimentally manipulated frequency-tuned brain activity using transcranial alternating current stimulation (tACS), combined with a retro-cue paradigm assessing WM and inhibition. We found that alpha-tACS induced a significant improvement in target responses and misbinding errors, two indexes of inhibition. We concluded that in aging alpha oscillations are causally linked to inhibitory abilities, and that despite being impoverished, these abilities are still malleable.

Sex and APOE: A memory advantage in male APOE ε4 carriers in midlife.

Short-term memory in middle-aged individuals with different APOE alleles was examined using a recently developed task which is sensitive to medial temporal lobe (MTL) damage. Individuals (age-range: 40-51 years) with ε3/ε3, ε3/ε4 and ε4/ε4 APOE genotypes (N = 60) performed a delayed estimation task with a sensitive continuous measure of report. The paradigm allowed us to measure memory for items and their locations, as well as maintenance of identity-location feature binding in memory. There was a significant gene-dosage dependent effect of the ε4 allele on performance: memory decay or forgetting was slower in ε4 carriers, as measured by localization error and after controlling for misbinding errors. Furthermore ε4 carriers made less misbinding errors. These findings were specific to male carriers only. Thus, male ε4 carriers are at a behavioral advantage in midlife on a sensitive task of short-term memory. The results would be consistent with an antagonistic pleiotropy hypothesis and hightight the interaction of gender on the influence of APOE in cognition.