The role of APOE in transgenic mouse models of AD.

Identified in 1993, APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold compared to the common variant APOE3. Since the mid 1990's, transgenic (Tg) mice have been developed to model AD pathology and progression, primarily via expression of the familial AD (FAD) mutations in the presence of mouse-APOE (m-APOE). APOE4, associated with enhanced amyloid-ß (Aß) accumulation, has rarely been the focus in designing FAD-Tg mouse models. Initially, FAD-Tg mice were crossed with human (h)-APOE driven by heterologous promoters to identify an APOE genotype-specific AD phenotype. These models were later supplemented with FAD-Tg mice crossed with APOE-knockouts (APOE-/- or APOE-KO) and h-APOE-targeted replacement (h-APOE-TR) mice, originally generated to study the role of APOE genotype in peripheral lipid metabolism and atherosclerotic lesion development. Herein, we compare the m- and h-APOE multi-gene clusters, and then critically review the relevant history and approaches to developing a Tg mouse model to characterize APOE-dependent AD pathology, in combination with genetic (sex, age) and modifiable (e.g., inflammation, obesity) risk factors. Finally, we present recent data from the EFAD mice, which express 5xFAD mutations with the expression of the human apoE isoforms (E2FAD, E3FAD and E4FAD). This includes a study of 6- and 18-month-old male and female E3FAD and E4FAD, a comparison that enables examination of the interaction among the main AD risk factors: age, APOE genotype and sex. While no single transgenic mouse can capture the effects of all modifiable and genetic risk factors, going forward, a conscious effort needs to be made to include the factors that most significantly modulate AD pathology.

Examining HPA-axis functioning as a mediator of the relationship between depression and cognition across the adult lifespan.

Altered HPA-axis functioning is a hypothesized mechanism for worsened cognition in depression. The current study examines the indirect effects of depression on processing speed, executive functioning, and memory as a function of the HPA-axis. 38 individuals with a depression diagnosis and 50 healthy controls (HCs) aged 18-86 underwent neuropsychological testing and at-home diurnal salivary cortisol collection. Depression was assessed via structured clinical interviews and rating scales. Cognitive composite scores were derived from factor analysis. Daytime cortisol exposure was estimated using area under the curve (AUC). Depression was associated with higher cortisol levels and slower processing speed . A significant suppression effect of AUC was present on the relationship between depression and processing speed. Limitations include the cross-sectional design and limited sample heterogeneity. Though poorly modulated HPA-axis is one proposed mechanism of cognitive alterations in depression, our results did not support this conclusion for processing speed. Alternative mechanisms should be considered to inform interventions to target cognitive alterations in depression.

The Titrated Monetary Incentive Delay Task: Sensitivity, convergent and divergent validity, and neural correlates in an RDoC sample.

INTRODUCTION: Neuropsychological tests are designed to assay brain function via performance measurements. Many tests corresponding to visual and motor cortex function have been validated. Tests probing reward circuitry, including the ventral striatum (VS), could benefit assessment of numerous neurological and psychiatric disorders in which reward or VS function is disturbed. The present study sought to examine convergent and divergent validity of our modified, titrated version of the Monetary Incentive Delay Task, such that it may in the future stand as a validated neuropsychological test for reward function. METHOD: Participants were 132 individuals with a history of mood disturbance (HMD) and 43 healthy comparisons, ages 18-30 years. In addition to a standard neuropsychological battery and symptom measures, participants completed a modified version of the Monetary Incentive Delay Task (T-MIDT) during functional magnetic resonance imaging (fMRI), which involved a multistage titration procedure to incrementally increase or decrease the response window time per each participant's psychomotor speed and optimize individual performance. RESULTS: Across groups after titration, performance on the T-MIDT diverged from measures of processing speed, attention, and spatial working memory, but not inhibitory control. Performance in the HMD group was differentially correlated with executive function measures before and after titration. The reward circuit (e.g., subcortical, insular, medial prefrontal) was activated during reward anticipation. CONCLUSION: The present findings provide preliminary evidence that the T-MIDT measures a construct distinct from many executive functions and that individualized titration of the task parameters is critical in parsing reward from executive function. The T-MIDT correlated with residual mood symptoms in individuals with remitted depression or bipolar disorder, implying that behavioral or brain activation group differences are only to be observed in the active state of illness.

Investigating the separate and interactive associations of trauma and depression on neurocognition in urban dwelling adults.

BACKGROUND: Trauma and depression have each been associated with neurocognitive alterations, but their combined effect on neurocognition is unclear. We investigated the separate and interactive associations of trauma and depression on neurocognition in a sample of ethnically diverse urban dwellers, and explored the impact of age on these effects. METHODS: 284 adults aged 30-89 were divided into groups based on their current depression and trauma history. Individuals meeting DSM-IV criteria for depression were considered Depressed (D+) and individuals rated through diagnostic interview as having trauma history were considered positive for Trauma (T+). Resulting Ns were 73 D+T+, 56 D+T-, 68 D-T+, and 87 D-T-. A principal component analysis of neuropsychological scores resulted in a 3-factor solution representing verbal learning/memory/recognition (VERBAL-LMR), visual learning/memory/recognition, and speeded attention/cognitive flexibility accounting for 70.21% of the variance. RESULTS: Multivariable linear regressions adjusting for age revealed that Trauma, regardless of Depression, is associated with worse VERBAL-LMR performance. This Trauma association was driven by verbal list and prose passages learning and memory, but not recognition memory. Age-stratified (<60 versus ≥60 years) regressions revealed the Trauma association was only significant for older adults. No main or interactive effects for Depression were observed. CONCLUSIONS: Trauma, regardless of Depression, is associated with worse verbal learning and memory, but not recognition performance. These results suggest that trauma exposure may negatively impact neurocognition. Clinicians working with adults in urban settings should query for trauma in addition to depression when considering subjective and objective measures of neurocognitive functioning, particularly in older adults.