A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease.

Background: Amyloid beta protein (Aß) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aß. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aß metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aß40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aß and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results: From June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aß40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups. Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. Trial registration: NCT02925650 on clinicaltrials.gov.

Cerebrovascular reactivity in Alzheimer's disease signature regions is associated with mild cognitive impairment in adults with hypertension.

INTRODUCTION: Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could reduce dementia risk. The objective of this study is to evaluate the association of cerebrovascular reactivity (CVR), a measure of brain blood vessel elasticity, with mild cognitive impairment (MCI) and dementia. METHODS: Participants were enrolled in the Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT-MIND) magnetic resonance imaging substudy. Baseline CVR in Alzheimer's disease (AD) signature regions were primary variables of interest. The occipital pole and postcentral gyrus were included as control regions. RESULTS: Higher AD composite CVR was associated with lower MCI risk. No significant associations between inferior temporal gyrus, occipital pole, or postcentral gyrus CVR and MCI risk, or any regional CVR-combined risk associations were observed. DISCUSSION: CVR in AD signature regions is negatively associated with occurrence of MCI, implicating CVR in AD signature regions as a potential mechanism leading to cognitive impairment.

Protective effects of sleep duration and physical activity on cognitive performance are influenced by ß-amyloid and brain volume but not tau burden among cognitively unimpaired older adults.

BACKGROUND AND OBJECTIVES: Sleep and physical activity have gained traction as modifiable risk factors for Alzheimer's disease. Sleep duration is linked to amyloid-ß clearance while physical activity is associated with brain volume maintenance. We investigate how sleep duration and physical activity are associated with cognition by testing if the associations between sleep duration or physical activity to cognition are explained by amyloid-ß burden and brain volume, respectively. Additionally, we explore the mediating role of tau deposition in sleep duration-cognition and physical activity-cognition relationships. METHODS: This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, a randomized clinical trial. In trial screening, cognitively unimpaired participants (age 65-85 years) underwent amyloid PET and brain MRI; APOE genotype and lifestyle questionnaire data were obtained. Cognitive performance was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Self-reported nightly sleep duration and weekly physical activity were the primary predictors. Regional Aß and tau pathologies and volumes were the proposed variables influencing relationships between sleep duration or physical activity and cognition. RESULTS: Aß data were obtained from 4322 participants (1208 with MRI, 59% female, 29% amyloid positive). Sleep duration was associated with a Aß composite score (ß = -0.005, CI: (-0.01, -0.001)) and Aß burden in the anterior cingulate (ACC) (ß = -0.012, CI: (-0.017, -0.006)) and medial orbitofrontal cortices (MOC) (ß = -0.009, CI: (-0.014, -0.005)). Composite (ß = -1.54, 95% CI:(-1.93, -1.15)), ACC (ß = -1.22, CI:(-1.54, -0.90)) and MOC (ß = -1.44, CI:(-1.86, -1.02)) Aß deposition was associated with PACC. Sleep duration-PACC association was explained by Aß burden in path analyses. Physical activity was associated with hippocampal (ß = 10.57, CI: (1.06, 20.08)), parahippocampal (ß = 9.3, CI: (1.69, 16.91)), entorhinal (ß = 14.68, CI: (1.75, 27.61), and fusiform gyral (ß = 38.38, CI: (5.57, 71.18)) volumes, which were positively associated with PACC (p < 0.02 for hippocampus, entorhinal cortex and fusiform gyrus). Physical activity-cognition relationship was explained by regional volumes. PET tau imaging was available for 443 participants. No direct sleep duration-tau burden, physical activity by tau burden, or mediation by regional tau was observed in sleep duration-cognition or physical activity-cognition relationships. DISCUSSION: Sleep duration and physical activity are associated with cognition through independent paths of brain Aß and brain volume, respectively. These findings implicate neural and pathological mechanisms for the relationships between sleep duration and physical activity on cognition. Dementia risk reduction approaches that emphasize the adequate sleep duration and a physically active lifestyle may benefit those with risk for Alzheimer's disease.

Generalizability of cognitive results from clinical trial participants to an older adult population: Addressing external validity.

Introduction: Study inclusion criteria and recruitment practices limit the generalizability of randomized-controlled trial (RCT) results. Statistical modeling could enhance generalizability of outcomes. To illustrate this, the cognition-depression relationship was assessed with and without adjustment relative to the target population of older women. Methods: Randomized participants from four RCTs and non-randomized participants from two cohorts were included in this study. Prediction models estimated probability of being randomized into trials from target populations. These probabilities were used for inverse odds weighting relative to target populations. Weighted linear regression was used to assess the depression-cognition relationship. Results: There was no depression-cognition relationship in the combined randomized sample. After applying weights relative to a representative cohort, negative relationships were observed. After applying weights relative to a non-representative cohort, bias of estimates increased. Discussion: Quantitative approaches to transportability using representative samples may explain the absence of a-priori established relationships in RCTs.

Variability in objective sleep is associated with Alzheimer's pathology and cognition.

Both sleep duration and sleep efficiency have been associated with risk of Alzheimer's disease, suggesting that interventions to promote optimal sleep may be a way to reduce Alzheimer's disease risk. However, studies often focus on average sleep measures, usually from self-report questionnaires, ignoring the role of intra-individual variability in sleep across nights quantified from objective sleep measures. The current cross-sectional study sought to investigate the role of intra-individual variability in accelerometer-based objective sleep duration and sleep efficiency in relation to in vivo Alzheimer's disease pathology (ß-amyloid and tau) using positron emission tomography imaging and cognition (working memory, inhibitory control, verbal memory, visual memory and global cognition). To examine these relationships, we evaluated 52 older adults (age = 66.4 ± 6.89, 67% female, 27% apolipoprotein E4 carriers) with objective early mild cognitive impairment. Modifying effects of apolipoprotein E4 status were also explored. Less intra-individual variability in sleep duration was associated with lower ß-amyloid burden, higher global cognition and better inhibitory control, with a trend for lower tau burden. Less intra-individual variability in sleep efficiency was associated with lower ß-amyloid burden, higher global cognition and better inhibitory control, but not with tau burden. Longer sleep duration was associated with better visual memory and inhibitory control. Apolipoprotein E4 status significantly modified the association between intra-individual variability in sleep efficiency and ß-amyloid burden, such that less sleep efficiency variability was associated with lower ß-amyloid burden in apolipoprotein E4 carriers only. There was a significant interaction between sleep duration and apolipoprotein E4 status, suggesting that longer sleep duration is more strongly associated with lower ß-amyloid burden in apolipoprotein E4 carriers relative to non-carriers. These results provide evidence that lower intra-individual variability in both sleep duration and sleep efficiency and longer mean sleep duration are associated with lower levels of ß-amyloid pathology and better cognition. The relationships between sleep duration and intra-individual variability in sleep efficiency with ß-amyloid burden differ by apolipoprotein E4 status, indicating that longer sleep duration and more consistent sleep efficiency may be protective against ß-amyloid burden in apolipoprotein E4 carriers. Longitudinal and causal studies are needed to better understand these relationships. Future work should investigate factors contributing to intra-individual variability in sleep duration and sleep efficiency in order to inform intervention studies.

Higher baseline levels of CSF inflammation increase risk of incident mild cognitive impairment and Alzheimer's disease dementia.

Introduction: Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods: Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E (APOE) ε4 were also examined. Results: Elevated levels of tumor necrosis factor α (TNF-α), interleukin (IL)-9, and IL-12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF-α and all APOE ε4 carriers with elevated IL-9 levels had shorter times to conversion. In addition, TNF-α mediated the relationship between elevated IL-12p40 and IL-9. Discussion: Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.

Sex-specific effects of microglial activation on Alzheimer's disease proteinopathy in older adults.

Females show a disproportionate burden of Alzheimer's disease pathology and higher Alzheimer's disease dementia prevalences compared to males, yet the mechanisms driving these vulnerabilities are unknown. There is sexual dimorphism in immunological functioning, and neuroimmune processes are implicated in Alzheimer's disease genesis. Using neuropathology indicators from human brain tissue, we examined the mediational role of microglial activation on the relationship between amyloid and tau and how it differs by sex. 187 decedents (64% female; 89 mean age at death; 62% non-demented) from the Rush Memory and Aging Project completed neuropathological evaluations with brain tissue quantified for microglial activation, amyloid-ß and tau. Proportion of morphologically activated microglia was determined via immunohistochemistry (HLA-DP-DQ-DR) and morphological staging (stage I, II or III). Amyloid-ß and tau burden were quantified via immunohistochemistry (M00872 or AT8, respectively). Using causal counterfactual modelling, we estimated the mediational effect of microglial activation on the amyloid-ß to tau relationship in the whole sample and stratified by sex (amyloid-ß â†’ microglial activation → tau). Alternative models tested the role of microglia activation as the precipitating event (microglial activation → amyloid-ß â†’ tau). Microglial activation significantly mediated 33% [95% confidence interval (CI) 10-67] of the relationship between amyloid-ß and tau in the whole sample; stratified analyses suggested this effect was stronger and only statistically significant in females. 57% (95% CI 22-100) of the effect of amyloid-ß on tau was mediated through microglial activation in females, compared to 19% (95% CI 0-64) in males. Regional analyses suggested that mediational effects were driven by greater cortical versus subcortical microglial activation. Relationships were independent of cerebrovascular disease indices. Alternative models suggested that in females, microglial activation was a significant exposure both preceding the amyloid-ß to tau relationship (mediational effect: 50%, 95% CI 23-90) and directly related to tau burden (microglia direct effect: 50%, 95% CI 10-77). By contrast, in males, only the direct effect of microglial activation to tau reached significance (74%, 95% CI 32-100) (mediational effect: 26%, 95% CI 0-68). Our models suggest a reciprocal, bidirectional relationship between amyloid-ß and microglial activation that significantly accounts for tau burden in females. By contrast, in males, direct independent (non-mediational) relationships between microglial activation or amyloid-ß with tau were observed. Microglial activation may be disproportionately important for Alzheimer's disease pathogenesis in females. Determining sex-specific vulnerabilities to Alzheimer's disease development both inform fundamental pathophysiology and support precision health approaches for this heterogeneous disease.

Effects of Sex, APOE4, and Lifestyle Activities on Cognitive Reserve in Older Adults.

BACKGROUND AND OBJECTIVES: Lifestyle activities, such as physical activity and cognitive stimulation, may mitigate age-associated cognitive decline, delay dementia onset, and increase cognitive reserve. Whether the association between lifestyle activities and cognitive reserve differs by sex and APOE4 status is an understudied yet critical component for informing targeted prevention strategies. The current study examined interactions between sex and physical or cognitive activities on cognitive reserve for speed and memory in older adults. METHODS: Research participants with unimpaired cognition, mild cognitive impairment, or dementia from the Washington Heights-Inwood Columbia Aging Cohort were included in this study. Cognitive reserve scores for speed and memory were calculated by regressing out hippocampal volume, total gray matter volume, and white matter hyperintensity volume from composite cognitive scores for speed and memory, respectively. Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire, converted to metabolic equivalents (METS). Self-reported cognitive activity (COGACT) was calculated as the sum of 3 yes/no questions. Sex by activity interactions and sex-stratified analyses were conducted using multivariable linear regression models, including a secondary analysis with APOE4 as a moderating factor. RESULTS: Seven hundred fifty-eight participants (mean age = 76.11 ± 6.31 years, 62% women) were included in this study. Higher METS was associated with greater speed reserve in women (ß = 0.04, CI 0.0-08) but not in men (ß = 0.004, CI -0.04 to 0.05). METS was not associated with memory reserve in women or men. More COGACT was associated with greater speed reserve in the cohort (ß = 0.13, CI 0.05-0.21). More COGACT had a trend for greater memory reserve in women (ß = 0.06, CI -0.02 to 0.14) but not in men (ß = -0.04, CI -0.16 to 0.08). Only among women, APOE4 carrier status attenuated relationships between METS and speed reserve (ß = -0.09, CI -0.22 to 0.04) and between COGACT and both speed (ß = -0.26, CI -0.63 to 0.11) and memory reserves (ß = -0.20, CI -0.50.0 to 093). DISCUSSION: The associations of self-reported physical and cognitive activities with cognitive reserve are more pronounced in women, although APOE4 attenuates these associations. Future studies are needed to understand the causal relationship among sex, lifestyle activities, and genetic factors on cognitive reserve in older adults to best understand which lifestyle activities may be most beneficial and for whom.

Functional connectivity among brain regions affected in Alzheimer's disease is associated with CSF TNF-α in APOE4 carriers.

It is now recognized that understanding how neuroinflammation affects brain function may provide new insights into Alzheimer's pathophysiology. Tumor necrosis factor (TNF)-α, an inflammatory cytokine marker, has been implicated in Alzheimer's disease (AD), as it can impair neuronal function through suppression of long-term potentiation. Our study investigated the relationship between cerebrospinal fluid TNF-α and functional connectivity (FC) in a cohort of 64 older adults (µ age = 69.76 years; 30 cognitively normal, 34 mild AD). Higher cerebrospinal fluid TNF-α levels were associated with lower FC among brain regions important for high-level decision-making, inhibitory control, and memory. This effect was moderated by apolipoprotein E-ε4 (APOE4) status. Graph theory metrics revealed there were significant differences between APOE4 carriers at the node level, and by diagnosis at the network level suggesting global brain network dysfunction in participants with AD. These findings suggest proinflammatory mechanisms may contribute to reduced FC in regions important for high-level cognition. Future studies are needed to understand the role of inflammation on brain function and clinical progression, especially in APOE4 carriers.