Hippocampal subfield plasticity is associated with improved spatial memory.

Physical exercise studies are generally underrepresented in young adulthood. Seventeen subjects were randomized into an intervention group (24.2 ± 3.9 years; 3 trainings/week) and 10 subjects into a passive control group (23.7 ± 4.2 years), over a duration of 6 months. Every two months, performance diagnostics, computerized spatial memory tests, and 3 Tesla magnetic resonance imaging were conducted. Here we find that the intervention group, compared to controls, showed increased cardiorespiratory fitness, spatial memory performance and subregional hippocampal volumes over time. Time-by-condition interactions occurred in right cornu ammonis 4 body and (trend only) dentate gyrus, left hippocampal tail and left subiculum. Increases in spatial memory performance correlated with hippocampal body volume changes and, subregionally, with left subicular volume changes. In conclusion, findings support earlier reports of exercise-induced subregional hippocampal volume changes. Such exercise-related plasticity may not only be of interest for young adults with clinical disorders of hippocampal function, but also for sedentary normal cohorts.

High-copy transposons from a pathogen give rise to a conserved sRNA family with a novel host immunity target.

Small RNAs (sRNAs) are involved in gene silencing in multiple ways including through cross-kingdom transfers from parasites to their hosts. Little is known about the evolutionary mechanisms enabling eukaryotic microbes to evolve functional mimics of host small regulatory RNAs. Here, we describe the identification and functional characterization of SINE_sRNA1, a sRNA family derived from highly abundant SINE retrotransposons in the genome of the wheat powdery mildew pathogen. SINE_sRNA1 is encoded by a sequence motif that is conserved in multiple SINE families and corresponds to a functional plant miRNA mimic targeting Tae_AP1, a wheat gene encoding an aspartic protease only found in monocots. Tae_AP1 has a novel function enhancing both pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) thus contributing to the cross activation of plant defenses. We conclude that SINE_sRNA1 and Tae_AP1 are functional innovations suggesting the contribution of transposons to the evolutionary arms race between a parasite and its host.

Ripple-locked coactivity of stimulus-specific neurons and human associative memory.

Associative memory enables the encoding and retrieval of relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves temporally correlated spiking of medial temporal lobe (MTL) neurons that exhibit stimulus-specific tuning. Using single-neuron recordings from patients with epilepsy performing an associative object-location memory task, we identified the object-specific and place-specific neurons that represented the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object-specific and place-specific neurons activated together during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients' associative learning progressed. Between encoding and retrieval, the ripple-locked timing of coactivity shifted, suggesting flexibility in the interaction between MTL neurons and hippocampal ripples according to behavioral demands. Our results are consistent with a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Dissociating effects of aging and genetic risk of sporadic Alzheimer's disease on path integration.

Path integration is a spatial navigation ability that requires the integration of information derived from self-motion cues and stable landmarks, when available, to return to a previous location. Path integration declines with age and Alzheimer's disease (AD). Here, we sought to separate the effects of age and AD risk on path integration, with and without a landmark. Overall, 279 people participated, aged between 18 and 80 years old. Advanced age impaired the appropriate use of a landmark. Older participants furthermore remembered the location of the goal relative to their starting location and reproduced this initial view without considering that they had moved in the environment. This lack of adaptative behavior was not associated with AD risk. In contrast, participants at genetic risk of AD (apolipoprotein E ε4 carriers) exhibited a pure path integration deficit, corresponding to difficulty in performing path integration in the absence of a landmark. Our results show that advanced-age impacts landmark-supported path integration, and that this age effect is dissociable from the effects of AD risk impacting pure path integration.

Multi-scale goal distance representations in human hippocampus during virtual spatial navigation.

Goal-directed navigation relies on both coarse and fine-grained coding of spatial distance between the current position of a navigating subject and a goal destination. However, the neural signatures underlying goal distance coding remain poorly understood. Using intracranial EEG recordings from the hippocampus of drug-resistant epilepsy patients who performed a virtual spatial navigation task, we found that the right hippocampal theta power was significantly modulated by goal distance and decreased with goal proximity. This modulation varied along the hippocampal longitudinal axis such that theta power in the posterior hippocampus decreased more strongly with goal proximity. Similarly, neural timescale, reflecting the duration across which information can be maintained, increased gradually from the posterior to anterior hippocampus. Taken together, this study provides empirical evidence for multi-scale spatial representations of goal distance in the human hippocampus and links the hippocampal processing of spatial information to its intrinsic temporal dynamics.

Using multi-task experiments to test principles of hippocampal function.

Investigations of hippocampal functions have revealed a dizzying array of findings, from lesion-based behavioral deficits, to a diverse range of characterized neural activations, to computational models of putative functionality. Across these findings, there remains an ongoing debate about the core function of the hippocampus and the generality of its representation. Researchers have debated whether the hippocampus's primary role relates to the representation of space, the neural basis of (episodic) memory, or some more general computation that generalizes across various cognitive domains. Within these different perspectives, there is much debate about the nature of feature encodings. Here, we suggest that in order to evaluate hippocampal responses-investigating, for example, whether neuronal representations are narrowly targeted to particular tasks or if they subserve domain-general purposes-a promising research strategy may be the use of multi-task experiments, or more generally switching between multiple task contexts while recording from the same neurons in a given session. We argue that this strategy-when combined with explicitly defined theoretical motivations that guide experiment design-could be a fruitful approach to better understand how hippocampal representations support different behaviors. In doing so, we briefly review key open questions in the field, as exemplified by articles in this special issue, as well as previous work using multi-task experiments, and extrapolate to consider how this strategy could be further applied to probe fundamental questions about hippocampal function.

A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.

The broad use of the Pm8 resistance gene in wheat resulted in hypermutation of the AvrPm8 gene in the powdery mildew pathogen.

BACKGROUND: Worldwide wheat production is under constant threat by fast-evolving fungal pathogens. In the last decades, wheat breeding for disease resistance heavily relied on the introgression of chromosomal segments from related species as genetic sources of new resistance. The Pm8 resistance gene against the powdery mildew disease has been introgressed from rye into wheat as part of a large 1BL.1RS chromosomal translocation encompassing multiple disease resistance genes and yield components. Due to its high agronomic value, this translocation has seen continuous global use since the 1960s on large growth areas, even after Pm8 resistance was overcome by the powdery mildew pathogen. The long-term use of Pm8 at a global scale provided the unique opportunity to study the consequences of such extensive resistance gene application on pathogen evolution. RESULTS: Using genome-wide association studies in a population of wheat mildew isolates, we identified the avirulence effector AvrPm8 specifically recognized by Pm8. Haplovariant mining in a global mildew population covering all major wheat growing areas of the world revealed 17 virulent haplotypes of the AvrPm8 gene that grouped into two functional categories. The first one comprised amino acid polymorphisms at a single position along the AvrPm8 protein, which we confirmed to be crucial for the recognition by Pm8. The second category consisted of numerous destructive mutations to the AvrPm8 open reading frame such as disruptions of the start codon, gene truncations, gene deletions, and interference with mRNA splicing. With the exception of a single, likely ancient, gain-of-virulence mutation found in mildew isolates around the world, all AvrPm8 virulence haplotypes were found in geographically restricted regions, indicating that they occurred recently as a consequence of the frequent Pm8 use. CONCLUSIONS: In this study, we show that the broad and prolonged use of the Pm8 gene in wheat production worldwide resulted in a multitude of gain-of-virulence mechanisms affecting the AvrPm8 gene in the wheat powdery mildew pathogen. Based on our findings, we conclude that both standing genetic variation as well as locally occurring new mutations contributed to the global breakdown of the Pm8 resistance gene introgression.

Chronic stress is associated with specific path integration deficits.

Repeated exposure to stress (chronic stress) can cause excess levels of circulating cortisol and has detrimental influences on various cognitive functions including long-term memory and navigation. However, it remains an open question whether chronic stress affects path integration, a navigational strategy that presumably relies on the functioning of grid cells in the medial entorhinal cortex. The entorhinal cortex is a brain region in the medial temporal lobe, which contains multiple cell types involved in spatial navigation (and episodic memory), and a high number of corticosteroid receptors, predisposing it as a potential target of cortisol effects. Here, our goal was to investigate the association between chronic stress and path integration performance. We assessed chronic stress via hair cortisol concentration (physiological measure) and the Perceived Stress Questionnaire (subjective measure) in 52 female participants aged 22-65 years. Path integration was measured using a virtual homing task. Linear mixed models revealed selective impairments associated with chronic stress that depended on error type and environmental features. When focusing on distance estimations in the path integration task, we observed a significant relationship to hair cortisol concentrations indicating impaired path integration particularly during trials with higher difficulty in participants with high hair cortisol concentrations. This relationship especially emerged in the absence of spatial cues (a boundary or a landmark), and particularly in participants who reported high levels of subjectively experienced chronic stress. The findings are in line with the hypothesis that chronic stress compromises path integration, possibly via an effect on the entorhinal grid cell system.

Aversive memory formation in humans involves an amygdala-hippocampus phase code.

Memory for aversive events is central to survival but can become maladaptive in psychiatric disorders. Memory enhancement for emotional events is thought to depend on amygdala modulation of hippocampal activity. However, the neural dynamics of amygdala-hippocampal communication during emotional memory encoding remain unknown. Using simultaneous intracranial recordings from both structures in human patients, here we show that successful emotional memory encoding depends on the amygdala theta phase to which hippocampal gamma activity and neuronal firing couple. The phase difference between subsequently remembered vs. not-remembered emotional stimuli translates to a time period that enables lagged coherence between amygdala and downstream hippocampal gamma. These results reveal a mechanism whereby amygdala theta phase coordinates transient amygdala -hippocampal gamma coherence to facilitate aversive memory encoding. Pacing of lagged gamma coherence via amygdala theta phase may represent a general mechanism through which the amygdala relays emotional content to distant brain regions to modulate other aspects of cognition, such as attention and decision-making.

Ancient variation of the AvrPm17 gene in powdery mildew limits the effectiveness of the introgressed rye Pm17 resistance gene in wheat.

Introgressions of chromosomal segments from related species into wheat are important sources of resistance against fungal diseases. The durability and effectiveness of introgressed resistance genes upon agricultural deployment is highly variable-a phenomenon that remains poorly understood, as the corresponding fungal avirulence genes are largely unknown. Until its breakdown, the Pm17 resistance gene introgressed from rye to wheat provided broad resistance against powdery mildew (Blumeria graminis). Here, we used quantitative trait locus (QTL) mapping to identify the corresponding wheat mildew avirulence effector AvrPm17. It is encoded by two paralogous genes that exhibit signatures of reoccurring gene conversion events and are members of a mildew sublineage specific effector cluster. Extensive haplovariant mining in wheat mildew and related sublineages identified several ancient virulent AvrPm17 variants that were present as standing genetic variation in wheat powdery mildew prior to the Pm17 introgression, thereby paving the way for the rapid breakdown of the Pm17 resistance. QTL mapping in mildew identified a second genetic component likely corresponding to an additional resistance gene present on the 1AL.1RS translocation carrying Pm17. This gene remained previously undetected due to suppressed recombination within the introgressed rye chromosomal segment. We conclude that the initial effectiveness of 1AL.1RS was based on simultaneous introgression of two genetically linked resistance genes. Our results demonstrate the relevance of pathogen-based genetic approaches to disentangling complex resistance loci in wheat. We propose that identification and monitoring of avirulence gene diversity in pathogen populations become an integral part of introgression breeding to ensure effective and durable resistance in wheat.

Theta oscillations coordinate grid-like representations between ventromedial prefrontal and entorhinal cortex.

Grid cells and theta oscillations are fundamental constituents of the brain's navigation system and have been described in the entorhinal cortex (EC). Recent fMRI studies reveal that the ventromedial prefrontal cortex (vmPFC) contains grid-like representations. However, the neural mechanisms underlying human vmPFC grid-like representations and their interactions with EC grid activity have remained unknown. We conducted intracranial electroencephalography (iEEG) recordings from epilepsy patients during a virtual spatial navigation task. Oscillatory theta power in the vmPFC exhibited a sixfold rotational symmetry that was coordinated with grid-like representations in the EC. We found that synchronous theta oscillations occurred between these regions that predicted navigational performance. Analysis of information transfer revealed a unidirectional signal from vmPFC to EC during memory retrieval. Together, this study provides insights into the previously unknown neural signature and functional role of grid-like representations outside the EC and their synchronization with the entorhinal grid during human spatial navigation.

Host Adaptation Through Hybridization: Genome Analysis of Triticale Powdery Mildew Reveals Unique Combination of Lineage-Specific Effectors.

The emergence of new fungal pathogens through hybridization represents a serious challenge for agriculture. Hybridization between the wheat mildew (Blumeria graminis f. sp. tritici) and rye mildew (B. graminis f. sp. secalis) pathogens has led to the emergence of a new mildew form (B. graminis f. sp. triticale) growing on triticale, a man-made amphiploid crop derived from crossing rye and wheat, which was originally resistant to the powdery mildew disease. The identification of the genetic basis of host adaptation in triticale mildew has been hampered by the lack of a reference genome. Here, we report the 141.4-Mb reference assembly of triticale mildew isolate THUN-12 derived from long-read sequencing and genetic map-based scaffolding. All 11 triticale mildew chromosomes were assembled from telomere-to-telomere and revealed that 19.7% of the hybrid genome was inherited from the rye mildew parental lineage. We identified lineage-specific regions in the hybrid, inherited from the rye or wheat mildew parental lineages, that harbor numerous bona fide candidate effectors. We propose that the combination of lineage-specific effectors in the hybrid genome is crucial for host adaptation, allowing the fungus to simultaneously circumvent the immune systems contributed by wheat and rye in the triticale crop. In line with this, we demonstrate the functional transfer of the SvrPm3 effector from wheat to triticale mildew, a virulence effector that specifically suppresses resistance of the wheat Pm3 allelic series. This transfer is the likely underlying cause for the observed poor effectiveness of several Pm3 alleles against triticale mildew and exemplifies the negative implications of pathogen hybridizations on resistance breeding.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Interictal spikes with and without high-frequency oscillation have different single-neuron correlates.

Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these 'HFO-IEDs' at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from 'non-HFO-IEDs'. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit's firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit's firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.

Low-frequency electrical stimulation reduces cortical excitability in the human brain.

Effective seizure control remains challenging for about 30% of epilepsy patients who are resistant to present-day pharmacotherapy. Novel approaches that not only reduce the severity and frequency of seizures, but also have limited side effects are therefore desirable. Accordingly, various neuromodulation approaches such as cortical electrical stimulation have been implemented to reduce seizure burden; however, the underlying mechanisms are not completely understood. Given that the initiation and spread of epileptic seizures critically depend on cortical excitability, understanding the neuromodulatory effects of cortical electrical stimulation on cortical excitability levels is paramount. Based on observations that synchronization in the electrocorticogram closely tracks brain excitability level, the effects of low-frequency (1 Hz) intracranial brain stimulation on the levels of cortical phase synchronization before, during, and after 1 Hz electrical stimulation were assessed in twelve patients. Analysis of phase synchronization levels across three broad frequency bands (1-45 Hz, 55-95 Hz, and 105-195 Hz) revealed that in patients with stimulation sites in the neocortex, phase synchronization levels were significantly reduced within the 55-95 Hz and 105-195 Hz bands during post-stimulation intervals compared to baseline; this effect persisted for at least 30 min post-stimulation. Similar effects were observed when phase synchronization levels were examined in the classic frequency bands, whereby a significant reduction was found during the post-stimulation intervals in the alpha, beta, and gamma bands. The anatomical extent of these effects was then assessed. Analysis of the results from six patients with intracranial electrodes in both hemispheres indicated that reductions in phase synchronization in the 1-45 Hz and 55-95 Hz frequency ranges were more prominent in the stimulated hemisphere. Overall, these findings demonstrate that low-frequency electrical stimulation reduces phase synchronization and hence cortical excitability in the human brain. Low-frequency stimulation of the epileptic focus may therefore contribute to the prevention of impending epileptic seizures.

A neural code for egocentric spatial maps in the human medial temporal lobe.

Spatial navigation and memory rely on neural systems that encode places, distances, and directions in relation to the external world or relative to the navigating organism. Place, grid, and head-direction cells form key units of world-referenced, allocentric cognitive maps, but the neural basis of self-centered, egocentric representations remains poorly understood. Here, we used human single-neuron recordings during virtual spatial navigation tasks to identify neurons providing a neural code for egocentric spatial maps in the human brain. Consistent with previous observations in rodents, these neurons represented egocentric bearings toward reference points positioned throughout the environment. Egocentric bearing cells were abundant in the parahippocampal cortex and supported vectorial representations of egocentric space by also encoding distances toward reference points. Beyond navigation, the observed neurons showed activity increases during spatial and episodic memory recall, suggesting that egocentric bearing cells are not only relevant for navigation but also play a role in human memory.

Effects of Spatial Memory Processing on Hippocampal Ripples.

Human High-Frequency-Oscillations (HFO) in the ripple band are oscillatory brain activity in the frequency range between 80 and 250 Hz. HFOs may comprise different subgroups that either play a role in physiologic or pathologic brain functions. An exact differentiation between physiologic and pathologic HFOs would help elucidate their relevance for cognitive and epileptogenic brain mechanisms, but the criteria for differentiating between physiologic and pathologic HFOs remain controversial. In particular, the separation of pathologic HFOs from physiologic HFOs could improve the identification of epileptogenic brain regions during the pre-surgical evaluation of epilepsy patients. In this study, we performed intracranial electroencephalography recordings from the hippocampus of epilepsy patients before, during, and after the patients completed a spatial navigation task. We isolated hippocampal ripples from the recordings and categorized the ripples into the putative pathologic group iesRipples, when they coincided with interictal spikes, and the putative physiologic group isolRipples, when they did not coincide with interictal spikes. We found that the occurrence of isolRipples significantly decreased during the task as compared to periods before and after the task. The rate of iesRipples was not modulated by the task. In patients who completed the spatial navigation task on two consecutive days, we furthermore examined the occurrence of ripples in the intervening night. We found that the rate of ripples that coincided with sleep spindles and were therefore putatively physiologic correlated with the performance improvement on the spatial navigation task, whereas the rate of all ripples did not show this relationship. Together, our results suggest that the differentiation of HFOs into putative physiologic and pathologic subgroups may help identify their role for spatial memory and memory consolidation processes. Conversely, excluding putative physiologic HFOs from putative pathologic HFOs may improve the HFO-based identification of epileptogenic brain regions in future studies.

A highly differentiated region of wheat chromosome 7AL encodes a Pm1a immune receptor that recognizes its corresponding AvrPm1a effector from Blumeria graminis.

Pm1a, the first powdery mildew resistance gene described in wheat, is part of a complex resistance (R) gene cluster located in a distal region of chromosome 7AL that has suppressed genetic recombination. A nucleotide-binding, leucine-rich repeat (NLR) immune receptor gene was isolated using mutagenesis and R gene enrichment sequencing (MutRenSeq). Stable transformation confirmed Pm1a identity which induced a strong resistance phenotype in transgenic plants upon challenge with avirulent Blumeria graminis (wheat powdery mildew) pathogens. A high-density genetic map of a B. graminis family segregating for Pm1a avirulence combined with pathogen genome resequencing and RNA sequencing (RNAseq) identified AvrPm1a effector gene candidates. In planta expression identified an effector, with an N terminal Y/FxC motif, that induced a strong hypersensitive response when co-expressed with Pm1a in Nicotiana benthamiana. Single chromosome enrichment sequencing (ChromSeq) and assembly of chromosome 7A suggested that suppressed recombination around the Pm1a region was due to a rearrangement involving chromosomes 7A, 7B and 7D. The cloning of Pm1a and its identification in a highly rearranged region of chromosome 7A provides insight into the role of chromosomal rearrangements in the evolution of this complex resistance cluster.

Unmasking selective path integration deficits in Alzheimer's disease risk carriers.

Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.