Prominent models of human long-term memory distinguish between memory systems on the basis of whether learning and retrieval occur consciously or unconsciously. Episodic memory formation requires the rapid encoding of associations between different aspects of an event which, according to these models, depends on the hippocampus and on consciousness. However, recent evidence indicates that the hippocampus mediates rapid associative learning with and without consciousness in humans and animals, for long-term and short-term retention. Consciousness seems to be a poor criterion for differentiating between declarative (or explicit) and non declarative (or implicit) types of memory. A new model is therefore required in which memory systems are distinguished based on the processing operations involved rather than by consciousness.

To test whether antibodies against beta-amyloid are effective in slowing progression of Alzheimer's disease, we assessed cognitive functions in 30 patients who received a prime and a booster immunization of aggregated Abeta(42) over a 1 year period in a placebo-controlled, randomized trial. Twenty patients generated antibodies against beta-amyloid, as determined by tissue amyloid plaque immunoreactivity assay. Patients who generated such antibodies showed significantly slower rates of decline of cognitive functions and activities of daily living, as indicated by the Mini Mental State Examination, the Disability Assessment for Dementia, and the Visual Paired Associates Test of delayed recall from the Wechsler Memory Scale, as compared to patients without such antibodies. These beneficial clinical effects were also present in two of three patients who had experienced transient episodes of immunization-related aseptic meningoencephalitis. Our results establish that antibodies against beta-amyloid plaques can slow cognitive decline in patients with Alzheimer's disease.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele–dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

Previous work indicates that stress levels of circulating glucocorticoids can impair retrieval of declarative memory in human subjects. Several studies have reported that declarative memory retrieval relies on the medial temporal lobe. The present study used H(2)(15)O-positron emission tomography to investigate whether acutely elevated glucocorticoid levels affect regional cerebral blood flow in the medial temporal lobe, as well as in other brain regions, during declarative memory retrieval in healthy male human subjects. When measured over four different declarative memory retrieval tasks, a single, stress-level dose of cortisone (25 mg) administered orally 1 h before retention testing, induced a large decrease in regional cerebral blood flow in the right posterior medial temporal lobe, the left visual cortex and the cerebellum. The decrease in the right posterior medial temporal lobe was maximal in the parahippocampal gyrus, a region associated with successful verbal memory retrieval. Cortisone administration also significantly impaired cued recall of word pairs learned 24 h earlier, while drug effects on performance in the other tasks (verbal recognition, semantic generation and categorization) were not significant. The present results provide further evidence that acutely elevated glucocorticoid levels can impair declarative memory retrieval processes and suggest that such impairments may be related to a disturbance of medial temporal lobe function.

The apolipoprotein E (APOE) e4 allele is the major genetic risk factor for Alzheimer's disease, but an APOE effect on memory performance and memory-related neurophysiology in young, healthy subjects is unknown. We found an association of APOE e4 with better episodic memory compared with APOE e2 and e3 in 340 young, healthy persons. Neuroimaging was performed in a subset of 34 memory-matched individuals to study genetic effects on memory-related brain activity independently of differential performance. E4 carriers decreased brain activity over 3 learning runs, whereas e2 and e3 carriers increased activity. This smaller neural investment of e4 carriers into learning reappeared during retrieval: e4 carriers exhibited reduced retrieval-related activity with equal retrieval performance. APOE isoforms had no differential effects on cognitive measures other than memory, brain volumes, and brain activity related to working memory. We suggest that APOE e4 is associated with good episodic memory and an economic use of memory-related neural resources in young, healthy humans.

The hippocampal formation, one of the most complex and vulnerable brain structures, is recognized as a crucial brain area subserving human long-term memory. Yet, its specific functions in memory are controversial. Recent experimental results suggest that the hippocampal contribution to human memory is limited to episodic memory, novelty detection, semantic (deep) processing of information, and spatial memory. We measured the regional cerebral blood f low by positron-emission tomography while healthy volunteers learned pairs of words with different learning strategies. These led to different forms of learning, allowing us to test the degree to which they challenge hippocampal function. Neither novelty detection nor depth of processing activated the hippocampal formation as much as semantically associating the primarily unrelated words in memory. This is compelling evidence for another function of the human hippocampal formation in memory: establishing semantic associations.The discovery that the mediotemporal brain regions, particularly the hippocampal formations, are essential for human memory (1, 2) set the ground for neuroscientific theories and experimental practice during the past 40 years. In the years following this discovery, research with amnesic patients led to the finding that memory is not a unitary system but is divided into subsystems, each supported by a different but partially overlapping neuronal network. The function of the human hippocampal formation was pinned down to declarative memory alone and became specified even further to declarative learning͞consolidation (3, 4), episodic memory (5), novelty detection (6-9), the retrieval of deeply encoded items (10), and spatial learning (11-13). At the same time, learning experiments with rats (14-17) indicated that the hippocampal formation is important for the establishment of associations between components of episodes in memory. The experience of an episode typically involves the simultaneous processing of diverse sensory inputs, bodily sensations, thoughts, and emotions in distributed cortical regions, creating patterns of coactivations in the cortex. The composition of these coactivations needs to be stored in memory for the later recovery of some or all aspects of that episode. The anatomy and physiology of the hippocampal formation (dentate gyrus, Ammon's horn͞hippocampus proper, presubiculum) lends itself to store such patterns of neuronal coactivations temporarily (3,4,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). The less complex a scene is, the fewer associations are required to memorize it, and, thus, the less hippocampal activation can be expected. We tested this hypothesis in the human, reducing the complexity of a natural scene to the sensorily restricted environment of a word-learning experiment in the positron-emission tomography (PET) scanner. Visually presented pairs of semantically unrelated nouns had to be learned by one of three strategies inducing a (i) deep or (ii) shallow encoding of the words in isolation of each ot...

Studies of amnesia have demonstrated that the hippocampus is necessary for long-term memory, but its precise role in memory is unknown. We designed a positron emission tomography experiment with tailored encoding and retrieval tasks that permitted the isolation of different mnemonic functions theorized to be mediated by the hippocampus. These functions included encoding single items, establishing interitem associations, novelty detection, and retrieving recently formed associations. Of these, we found hippocampal and parahippocampal activation only during associative learning. Our results indicate that the hippocampal formation may be particularly involved in the establishment of associations among components of an episode in memory.

The hippocampus is crucial for conscious, explicit memory, but whether it is also involved in nonconscious, implicit memory is uncertain. We investigated with functional magnetic resonance imaging whether implicit learning engages the hippocampus and interacts with subsequent explicit learning. The presentation of subliminal faces-written profession pairs for implicit learning was followed by the explicit learning of supraliminal pairs composed of the same faces combined with written professions semantically incongruous to those presented subliminally (experiment 1), semantically congruous professions (experiment 2), or identical professions (experiment 3). We found that implicit face-profession learning interacted with explicit face-profession learning in all experiments, impairing the explicit retrieval of the associations. Hippocampal activity increased during the subliminal presentation of face-profession pairs versus face-nonword pairs and correlated with the later impairment of explicit retrieval. These findings suggest that implicit semantic associative learning engages the hippocampus and influences explicit memory.