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.

Women with hearing loss show increased dementia risk and brain atrophy.

Hearing loss is a modifiable risk factor for dementia. However, it is unknown whether risk differs by sex. Study 1 used Cox proportional hazard models to examine sex differences in the association between hearing loss (measured by speech-reception thresholds) and dementia risk. Study 2 examined how 2-year changes in hearing is associated with changes in brain volume in auditory-limbic regions. Both studies used UK Biobank data. Women with poor hearing had the greatest risk of dementia, whereas women and men with insufficient hearing were at similar risk. Men with poor hearing did not have increased risk. Presence of social isolation/depressed mood minimally contributed to dementia risk in men and women. Women, but not men, with hearing loss had greater atrophy in auditory and limbic regions compared to normal hearing women and men. Women with hearing loss show greater risk of dementia and brain atrophy, highlighting the need to examine sex-specific mechanisms.

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.

Decreased functional connectivity is associated with increased levels of Cerebral Spinal Fluid soluble-PDGFRß, a marker of blood brain barrier breakdown, in older adults.

Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal fluid soluble platelet-derived growth factor receptor-ß (CSF sPDGFRß, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRß in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured significant associations between BOLD FC strength among seed-target regions and sPDGFRß values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRß as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC while the hippocampus exhibited an interaction effect using CDR score. We conclude that BBB breakdown as measured by CSF sPDGFRß affects neural networks resulting in decreased functional connections that leads to cognitive dysfunction.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

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.

The role of mitochondrial genome abundance in Alzheimer's disease.

Mitochondrial dysfunction is an early and prominent feature of Alzheimer's disease (AD), with impaired energy metabolism preceding the onset of clinical symptoms. Here we propose an update to the mitochondrial dysfunction hypothesis of AD based on recent results examining the role of mitochondrial genome abundance in AD. In a large post mortem study, we show that lower brain mitochondrial genome abundance is associated with a greater odds of AD neuropathological change and worse cognitive performance. We hypothesize that lower mitochondrial genome abundance impairs mitochondrial function by reducing mitochondrial bioenergetics, thereby impacting neuronal and glial cell function. However, it remains to be determined if mitochondrial dysfunction causes, mediates, or is a by-product of AD pathogenesis. Additional support for this hypothesis will be generated by linking peripheral blood mitochondrial genome abundance to AD and establishing clinical trials of compounds that upregulate total mitochondrial genome abundance or boost mitochondrial mass.

AD and non-AD mediators of the pathway between the APOE genotype and cognition.

INTRODUCTION: The apolipoprotein E (APOE) genotype is a driver of cognitive decline and dementia. We used causal mediation methods to characterize pathways linking the APOE genotype to late-life cognition through Alzheimer's disease (AD) and non-AD neuropathologies. METHODS: We analyzed autopsy data from 1671 individuals from the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study (ROS/MAP/MARS) studies with cognitive assessment within 5 years of death and autopsy measures of AD (amyloid beta (Aß), neurofibrillary tangles), vascular (athero/arteriolo-sclerosis, micro-infarcts/macro-infarcts), and non-AD neurodegenerative neuropathologies (TAR DNA protein 43 [TDP-43], Lewy bodies, amyloid angiopathy, hippocampal sclerosis). RESULTS: The detrimental effect of APOE ε4 on cognition was mediated by summary measures of AD and non-AD neurodegenerative neuropathologies but not vascular neuropathologies; effects were strongest in individuals with dementia. The protective effect of APOE ε2 was partly mediated by AD neuropathology and stronger in women than in men. DISCUSSION: The APOE genotype influences cognition and dementia through multiple neuropathological pathways, with implications for different therapeutic strategies targeting people at increased risk for dementia. HIGHLIGHTS: Both apolipoprotein E (APOE) ε2 and APOE ε4 effects on late-life cognition are mediated by AD neuropathology. The estimated mediated effects of most measures of AD neuropathology were similar. Non-Alzheimer's disease (AD) neurodegenerative pathologies mediate the effect of ε4 independently from AD. Non-AD vascular pathologies did not mediate the effect of the APOE genotype on cognition. The protective effect of APOE ε2 on cognition was stronger in women.

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.

A Mitochondrial DNA Haplogroup Defines Patterns of Five-Year Cognitive Change.

BACKGROUND: Mitochondrial DNA (mtDNA) may play a role in Alzheimer's disease (AD) and cognitive decline. A particular haplogroup of mtDNA, haplogroup J, has been observed more commonly in patients with AD than in cognitively normal controls. OBJECTIVE: We used two mtDNA haplogroups, H and J, to predict change in cognitive performance over five years. We hypothesized that haplogroup J carriers would show less cognitive resilience. METHODS: We analyzed data from 140 cognitively normal older adults who participated in the University of Kansas Alzheimer's Disease Research Center clinical cohort between 2011 and 2020. We used factor analysis to create three composite scores (verbal memory, attention, and executive function) from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change adjusting for age, sex, years of education, and APOE ɛ4 allele carrier status. We compared haplogroup H, the most common group, to haplogroup J, the potential risk group. RESULTS: Haplogroup J carriers had significantly lower baseline performance and slower rates of improvement on tests of verbal memory compared to haplogroup H carriers. We did not observe differences in executive function or attention. CONCLUSION: Our results reinforce the role of mtDNA in changes to cognitive function in a domain associated with risk for dementia, verbal memory, but not with other cognitive domains. Future research should investigate the distinct mechanisms by which mtDNA might affect performance on verbal memory as compared to other cognitive domains across haplogroups.

Effects of a 12-Week Periodized Resistance Training Program on Resting Brain Activity and Cerebrovascular Function: A Nonrandomized Pilot Trial.

Resistance training is a promising strategy to promote healthy cognitive aging; however, the brain mechanisms by which resistance training benefits cognition have yet to be determined. Here, we examined the effects of a 12-week resistance training program on resting brain activity and cerebrovascular function in 20 healthy older adults (14 females, mean age 69.1 years). In this single group clinical trial, multimodal 3 T magnetic resonance imaging was performed at 3 time points: baseline (preceding a 12-week control period), pre-intervention, and post-intervention. Along with significant improvements in fluid cognition (d = 1.27), 4 significant voxelwise clusters were identified for decreases in resting brain activity after the intervention (Cerebellum, Right Middle Temporal Gyrus, Left Inferior Parietal Lobule, and Right Inferior Parietal Lobule), but none were identified for changes in resting cerebral blood flow. Using a separate region of interest approach, we provide estimates for improved cerebral blood flow, compared with declines over the initial control period, in regions associated with cognitive impairment, such as hippocampal blood flow (d = 0.40), and posterior cingulate blood flow (d = 0.61). Finally, resistance training had a small countermeasure effect on the age-related progression of white matter lesion volume (rank-biserial = -0.22), a biomarker of cerebrovascular disease. These proof-of-concept data support larger trials to determine whether resistance training can attenuate or even reverse salient neurodegenerative processes.

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.

Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of ß-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal ß-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic ß-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal ß-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Subclinical carotid artery atherosclerosis and cognitive function in older adults.

BACKGROUND: The combined effects of increased life expectancy and the considerable number of persons reaching old age will magnify the dementia epidemic in the USA. Demonstration that subclinical atherosclerosis precedes and is associated with cognitive impairment suggests a modifiable risk factor for age-associated cognitive impairment and dementia. The purpose of this study is to determine whether subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) is associated with changes in cognitive function over time in older adults. METHODS: This study combined longitudinal data from three clinical trials conducted between 2000 and 2013: the B-Vitamin Atherosclerosis Intervention Trial (BVAIT), the Women's Isoflavone Soy Health (WISH) trial, and the Early versus Late Intervention Trial with Estradiol (ELITE). Participants were recruited from the general population in the Greater Los Angeles area and were free of cardiovascular disease and diabetes; no cognitive or psychiatric exclusion criteria were specified. The same standardized protocol for ultrasound image acquisition and measurement of CIMT was used in all trials. CIMT measurements performed at baseline and 2.5 years were used in these analyses. Cognitive function was assessed at baseline and 2.5 years using a battery of 14 standardized cognitive tests. All clinical trials were conducted at the University of Southern California Atherosclerosis Research Unit, Los Angeles, and had at least 2.5 years of cognitive follow-up. RESULTS: A total of 308 men and 1187 women, mean age of 61 years, were included in the combined longitudinal dataset for the primary analysis. No associations were found between CIMT and cognitive function at baseline or at 2.5 years. There was a weak inverse association between CIMT measured at baseline and change in global cognition assessed over 2.5 years (ß (SE) = - 0.056 (0.028) units per 0.1 mm CIMT, 95% CI - 0.110, - 0.001, p = 0.046). No associations between CIMT at baseline and changes in executive function, verbal memory, or visual memory were found. CONCLUSIONS: In this sample of healthy older adults, our findings suggest an association between subclinical atherosclerosis and change in global cognitive function over 2.5 years. Stronger associations were observed longitudinally over 2.5 years than cross-sectionally. When analysis was stratified by age group (<65 and ≥65 years old), the inverse association remained statistically significant for participants in the older age group. Subclinical atherosclerosis of the carotid artery may be a modifiable correlate of cognitive decline in middle and older age. TRIAL REGISTRATION: BVAIT, NCT00114400 . WISH, NCT00118846 . ELITE, NCT00114517 .

Longitudinal Changes in Resting-State Functional Connectivity and Gray Matter Volume Are Associated with Conversion to Hearing Impairment in Older Adults.

BACKGROUND: Hearing loss was recently identified as a modifiable risk factor for dementia although the potential mechanisms explaining this relationship are unknown. OBJECTIVE: The current study examined longitudinal change in resting-state fMRI functional connectivity and gray matter volume in individuals who developed a hearing impairment compared to those whose hearing remained normal. METHODS: This study included 440 participants from the UK Biobank: 163 who had normal hearing at baseline and impaired hearing at follow-up (i.e., converters, mean age = 63.11±6.33, 53% female) and 277 who had normal hearing at baseline and maintained normal hearing at follow-up (i.e., non-converters, age = 63.31±5.50, 50% female). Functional connectivity was computed between a priori selected auditory seed regions (left and right Heschl's gyrus and cytoarchitectonic subregions Te1.0, Te1.1, and Te1.2) and select higher-order cognitive brain networks. Gray matter volume within these same regions was also obtained. RESULTS: Converters had increased connectivity from left Heschl's gyrus to left anterior insula and from right Heschl's gyrus to right anterior insula, and decreased connectivity between right Heschl's gyrus and right hippocampus, compared to non-converters. Converters also had reduced gray matter volume in left hippocampus and left lateral visual cortex compared to non-converters. CONCLUSION: These findings suggest that conversion to a hearing impairment is associated with altered brain functional connectivity and gray matter volume in the attention, memory, and visual processing regions that were examined in this study.

Erratum: Simultaneous Exercise and Cognitive Training in Virtual Reality Phase 2 Pilot Study: Impact on Brain Health and Cognition in Older Adults.

[This corrects the article DOI: 10.3233/BPL210126.].

Longitudinal Relationship of Leisure Activity Engagement With Cognitive Performance Among Non-Demented, Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: Leisure activity engagement (LAE) may reduce the risk of incident dementia. However, cognitive performance may predict LAE change. We evaluated the temporal ordering of overall and subtypes of LAE (intellectual, physical, and social) and cognitive performance (global, language, memory, and visuospatial function) among non-demented older adults. RESEARCH DESIGN AND METHODS: The Washington Heights-Inwood Columbia Aging Project concurrently administered a survey measure of 13 leisure activities and a neuropsychological battery every 18-24 months for up to 14 years to 5,384 racially and ethnically diverse participants. We used parallel process conditional latent growth curve models to examine temporal ordering in the overall sample and within baseline diagnostic groups (mild cognitive impairment [MCI] vs. cognitively normal). RESULTS: Levels and changes of overall and subtypes of LAE were positively correlated with cognitive performance in the overall sample and within each diagnostic group. In the overall sample, higher initial memory was associated with slower declines in social LAE (estimate = 0.019, 95% confidence interval [95% CI]: 0.001-0.037). Among MCI, higher initial physical LAE was associated with slower declines in memory (estimate = 0.034, 95% CI: 0.001-0.067), but higher initial intellectual LAE was related to steeper declines in visuospatial function (estimate = -0.028, 95% CI: -0.052 to -0.004). Among cognitively normal, higher initial memory was associated with slower declines in intellectual LAE (estimate = 0.012, 95% CI: 0.002-0.022). DISCUSSION AND IMPLICATIONS: Dynamic interplay of LAE with cognitive performance was observed across diagnostic groups. Levels of LAE subtypes could be more predictive of change in certain cognitive domains within older adults with MCI.