Studies of individuals with amnestic mild cognitive impairment (aMCI) have detected hyperactivity in the hippocampus during task-related functional magnetic resonance imaging (fMRI). Such elevated activation has been localized to the hippocampal dentate gyrus/CA3 (DG/CA3) during performance of a task designed to detect the computational contributions of those hippocampal circuits to episodic memory. The current investigation was conducted to test the hypothesis that greater hippocampal activation in aMCI represents a dysfunctional shift in the normal computational balance of the DG/CA3 regions, augmenting CA3-driven pattern completion at the expense of pattern separation mediated by the dentate gyrus. We tested this hypothesis using an intervention based on animal research demonstrating a beneficial effect on cognition by reducing excess hippocampal neural activity with low doses of the atypical anti-epileptic levetiracetam. In a within-subject design we assessed the effects of levetiracetam in three cohorts of aMCI participants, each receiving a different dose of levetiracetam. Elevated activation in the DG/CA3 region, together with impaired task performance, was detected in each aMCI cohort relative to an aged control group. We observed significant improvement in memory task performance under drug treatment relative to placebo in the aMCI cohorts at the 62.5 and 125 mg BID doses of levetiracetam. Drug treatment in those cohorts increased accuracy dependent on pattern separation processes and reduced errors attributable to an over-riding effect of pattern completion while normalizing fMRI activation in the DG/CA3 and entorhinal cortex. Similar to findings in animal studies, higher dosing at 250 mg BID had no significant benefit on either task performance or fMRI activation. Consistent with predictions based on the computational functions of the DG/CA3 elucidated in basic animal research, these data support a dysfunctional encoding mechanism detected by fMRI in individuals with aMCI and therapeutic intervention using fMRI to detect target engagement in response to treatment.

Increased fMRI activation in the hippocampus is recognized as a signature characteristic of the amnestic mild cognitive impairment (aMCI) stage of Alzheimer's disease (AD). Previous work has localized this increased activation to the dentate gyrus/CA3 subregion of the hippocampus and showed a correlation with memory impairments in those patients. Increased hippocampal activation has also been reported in carriers of the ApoE-4 allelic variation independently of mild cognitive impairment although these findings were not localized to a hippocampal subregion. To assess the ApoE-4 contribution to increased hippocampal fMRI activation, patients with aMCI genotyped for ApoE-4 status and healthy age-matched control participants completed a high-resolution fMRI scan while performing a memory task designed to tax hippocampal subregion specific functions. Consistent with previous reports, patients with aMCI showed increased hippocampal activation in the left dentate gyrus/CA3 region of the hippocampus as well as memory task errors attributable to this subregion. However, this increased fMRI activation in the hippocampus did not differ between ApoE-4 carriers and ApoE-4 non-carriers and the proportion of memory errors attributable to dentate gyrus/CA3 function did not differ between ApoE-4 carriers and ApoE-4 non-carriers. These results indicate that increased fMRI activation of the hippocampus observed in patients with aMCI is independent of ApoE-4 status and that ApoE-4 does not contribute to the dysfunctional hippocampal activation or the memory errors attributable to this subregion in these patients.

Recently, the field of Alzheimer’s disease (AD) research has adopted a new framework that places the progression of AD along a continuum consisting of a preclinical stage, followed by conversion to mild cognitive impairment, and ultimately dementia. Important neuropathological changes occur in the preclinical phase, necessitating the identification of metrics that can detect such early changes. While cerebrospinal fluid (CSF) measures of amyloid and tau are generally accepted as biomarkers of AD pathology, neuroimaging measures used to index white matter alterations throughout the brain remain less widely endorsed as candidate biomarkers. To explore the relationship between white matter alterations and AD pathology, we review the literature on multimodal studies that assessed both CSF markers and white matter indices, derived from diffusion tensor imaging (DTI) methods, across cohorts primarily in the early phases of AD. Our review indicates that abnormal CSF measures of Aβ ₄₂ and tau are associated with widespread alterations in white matter microstructure throughout the brain. Furthermore, white matter variability is related to individual differences in behavior and can aid in tracking longitudinal changes in cognition. Our review advocates for the utilization of DTI metrics in investigations of early AD and suggests that the combined use of DTI and CSF markers may better explain individual differences in cognition and disease progression. However, further research is needed to resolve certain mixed findings.

INTRODUCTION: In addition to the accumulation of amyloid plaques and neurofibrillary tangles, the presence of excess neural activity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for progression of AD pathology and clinical/cognitive worsening in mild cognitive impairment due to Alzheimer's disease (MCI due to AD). The HOPE4MCI clinical study tested the efficacy of a therapeutic with demonstrated ability to normalize heightened neural activity in the hippocampus in a randomized controlled trial of 78 weeks duration in patients with MCI due to AD. METHODS: One hundred and sixty‐four participants were randomized to placebo ( n = 83) or AGB101 ( n = 81), an extended‐release formulation of low dose (220 mg) levetiracetam. The primary endpoint was the change in Clinical Dementia Rating Scale Sum of Boxes score (CDR‐SB) comparing follow up at 18 months to baseline. The goal of the primary efficacy analysis was to estimate the difference between the AGB101 and placebo arms in the mean change of the primary endpoint. RESULTS: The mean change in CDR‐SB was estimated to be 1.12 (95% confidence interval [CI]: 0.66, 1.69) for the AGB101 arm and 1.22 (95% CI: 0.75, 1.78) for the placebo arm. The estimated difference between arms is ‐0.10 (95% CI: ‐0.85, 0.58), which was not statistically significant. In a prespecified analysis, the difference was ‐0.45 (95% CI: ‐1.43, 0.53) for ApoE‐4 noncarriers and ‐0.10 (95% CI: ‐0.92, 0.72) for apolipoprotein E (ApoE)‐4 carriers. DISCUSSION: The possibility that ApoE‐4 carriers and noncarriers will respond differently to therapeutic intervention is consistent with recently reported findings from biologics and the present results show further testing of AGB101 in patients with MCI due to AD who are noncarriers of the ApoeE‐4 allele is warranted. Conclusions from the HOPE4MCI study are limited primarily due to the small sample size and results can only be regarded as a guide to future research.

Stress is a potent modulator of brain function and particularly mnemonic processes. While chronic stress is associated with long-term deficits in memory, the effects of acute stress on mnemonic functions are less clear as previous reports have been inconsistent. Some studies suggest that cortisol, a stress hormone that modulates biological changes in response to stress, may enhance memory consolidation and impair memory retrieval. However, other studies report no effect of cortisol on either memory consolidation or retrieval. These discrepancies could be due to differences in the timing and sequencing of the experimental procedures or individual differences in participants’ stress response. In the present study, we examined the effect of increased cortisol levels due to acute stress, induced by the Trier Social Stress Test (TSST), on a pattern separation memory task while differentiating the distinct stages of memory processing and controlling for the effects of diurnal variation. Sixty-nine young adults completed a 2-d study in which subjects either underwent the TSST immediately following the encoding part of the memory task, targeting memory consolidation, or immediately prior to the recognition part of the memory task on the second day, targeting memory retrieval. Control subjects completed the same study procedures but underwent a control version of the TSST that did not induce a stress response. Mnemonic discrimination of highly similar stimuli was enhanced by stress induced during consolidation with better discrimination showing a significant correlation with increased cortisol responses. Stress induced during memory retrieval showed no significant effect on memory performance. These findings suggest that stress induced changes in cortisol differentially affect the consolidation and retrieval stages of memory function.