Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

In the years preceding a diagnosis of Alzheimer’s disease (AD), hyperexcitability of the hippocampus is a commonly observed phenomenon in those at risk for AD. Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for ALS that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved memory performance that was associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus (DG), cornu ammonis 3(CA3), and cornu ammonis 1(CA1) regions of the hippocampus. Riluzole treatment also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter (vGLUT1), and the TauP301L-mediated decrease in hippocampal glutamate transporter 1 (GLT-1) and PSD-95 expression. Riluzole treatment also reduced tau pathology. These findings further elucidate the changes in glutamate regulation associated with tau pathology and open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD.

Objectives Projections from the United States Census Bureau suggest that the African American population may be the fastest growing race over the next 30 years and that they may be at the highest risk for developing dementia later in life. Various social factors have been shown to be associated with cognitive function and health outcomes. The present study aims to evaluate the relationship between social engagement and cognitive decline in a cohort of older African American adults. Methods We utilized multilevel modeling to examine the association between cognitive decline and social engagement in a sample of 617 older African American adults. Results Social activity was associated with global cognition, perceptual speed, perceptual orientation, and episodic memory over time. Loneliness was associated with better semantic memory performance over time. Perceived discrimination was associated with better semantic memory performance over time. Larger social network was associated with worse perceptual speed scores over time. Conclusions Although our findings on loneliness and perceived discrimination over time were inconsistent with prior research, our findings on social activity and social network size over time were consistent with past literature and are thought to be due to positive social interactions providing a catalyst for cognitively stimulating activities. These results suggest that interventions designed to preserve cognition in African American older adults should incorporate adequate social activity. Furthermore, to maximize effectiveness, interventions should not necessarily focus on just expanding one's social network.

The Morris water maze (MWM) is a commonly used task to assess hippocampal-dependent spatial learning and memory in transgenic mouse models of disease, including neurocognitive disorders such as Alzheimer's disease. However, the background strain of the mouse model used can have a substantial effect on the observed behavioral phenotype, with some strains exhibiting superior learning ability relative to others. To ensure differences between transgene negative and transgene positive mice can be detected, identification of a training procedure sensitive to the background strain is essential. Failure to tailor the MWM protocol to the background strain of the mouse model may lead to under-or over-training, thereby masking group differences in probe trials. Here, a MWM protocol tailored for use with the F1 FVB/N x 129S6 background is described. This is a frequently used background strain to study the age-dependent effects of mutant P301L tau (rTg(TauP301L)4510 mice) on the memory deficits associated with Alzheimer's disease. Also described is a strategy to re-optimize, as dictated by the particular testing environment utilized. Video LinkThe video component of this article can be found at

Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer’s disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer’s disease.

Objective: Serial position effects (SPEs) on list learning tasks refer to the relationship between a word’s placement on the list and its likelihood of being recalled. Typically, adults recall more words from the beginning (primacy) and end (recency) of the list compared to the middle of the list. These effects can be affected by neurological disease such that SPEs have been shown to be related to both current and future cognitive decline. This review aimed to summarize existing research on SPEs in individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Method: A systematic review of SPEs in MCI and AD was conducted. Results: Despite inconsistencies in the number of items included on word list tasks analyzing SPEs and inconsistencies in how researchers have defined and analyzed SPEs, SPEs have demonstrated the ability to predict future cognitive decline, at times above and beyond traditional memory score performance. In addition, individuals with MCI and AD show similar SPE patterns of reduced primacy and intact recency, with primacy being more reduced in AD, whereas individuals with vascular dementia demonstrate a reversed SPE pattern. Conclusion: The analysis of SPEs has demonstrated some utility as a marker of cognitive impairment associated with MCI, AD, and other dementias; however, research is limited by the multiple ways in which SPEs are defined and analyzed. Future research is discussed, including the need for increased data accessibility in order to quantitatively summarize previous research on SPEs in relation to MCI and AD.

The coronavirus disease pandemic has brought a new urgency for the development and deployment of web-based applications which complement, and offer alternatives to, traditional one-on-one consultations and pencil-and-paper (PaP) based assessments that currently dominate clinical research. We have recently developed a web-based application that can be used for the self-administered collection of patient demographics, self-rated health, depression and anxiety, and cognition as part of a single platform. In this study we report the findings from a study with 155 cognitively healthy older adults who received established PaP versions, as well as our novel computerized measures of self-rated health, depression and anxiety, and cognition. Moderate to high correlations were observed between PaP and web- based measures of self-rated health (r = 0.77), depression and anxiety (r = 0.72), and preclinical Alzheimer’s disease cognitive composite (PACC) (r = .61). Test-retest correlations were variable with high correlations for a measure of processing speed and a measure of delayed episodic memory. Taken together, these data support the feasibility and validity of utilization of this novel web-based platform as a new alternative for collecting patient demographics and the assessment of self-rated health, depression and anxiety, and cognition in the elderly.

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