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Objectives: How dementia affects lesbian, gay, bisexual, trans, queer people or those with other minoritised sexual/gender identities (LGBTQ+) is not well understood. Furthermore, existing research often excludes the voices of LGBTQ+ people living with dementia and focuses instead on their care partners. This study addresses this evidence gap by drawing on the ESRC/NIHR funded DETERMIND cohort, consisting of 940 newly diagnosed people with dementia, to explore the peri‐diagnostic experiences of people living with dementia who identify as LGBTQ+. Methods: We recruited five people (who identified as lesbian, gay or bisexual [LGB]) and completed semi‐structured interviews with them and their partner caregivers (n = 3) discussing their experiences of (1) engaging with dementia health care services, (2) receiving a dementia diagnosis, and (3) the support they were offered after diagnosis. Interviews were shaped by the Candidacy Framework, a theoretical model for understanding accessibility of health services, and an inductive thematic analysis was employed to develop common themes. Findings: Participants did not routinely disclose their LGBTQ+ identities to health service professionals, despite feeling this was an essential aspect of who they are. They relied on their resilience of overcoming previous experiences of lifetime discrimination to navigate complicated dementia care systems. The importance of 'chosen families' as informal support networks for LGBTQ+ people living with dementia was highlighted, particularly given the lack of formal care services they felt comfortable accessing. All participants were concerned about their future care needs and whether they would receive home‐based or community‐based support that respected their LGBTQ+ identities. Conclusions: This study adds to the limited evidence base that can be used to inform future research, policy and practice seeking to address inequalities across the dementia care pathway. We only interviewed people who identified as LGB so generalizability to the whole LGBTQ+ population is limited, however our data suggest dementia health care professionals should encourage and support disclosures of LGBTQ+ identities so that inclusive care and support planning can be provided to LGBTQ+ people at every stage of dementia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Intraneuronal inclusions composed of tau protein are found in Alzheimer's disease (AD) and other tauopathies. Tau normally binds microtubules (MTs), and its disengagement from MTs and misfolding in AD is thought to result in MT abnormalities. We previously identified triazolopyrimidine‐containing MT‐stabilizing compounds that provided benefit in AD mouse models and herein describe the characterization and efficacy testing of an optimized candidate, CNDR‐51997. METHODS: CNDR‐51997 underwent pharmacokinetic, pharmacodynamic, safety pharmacology, and mouse tolerability testing. In addition, the compound was examined for efficacy in 5XFAD amyloid beta (Aβ) plaque mice and PS19 tauopathy mice. RESULTS: CNDR‐51997 significantly reduced Aβ plaques in 5XFAD mice and tau pathology in PS19 mice, with the latter also showing attenuated axonal dystrophy and gliosis. CNDR‐51997 was well tolerated at doses that exceeded efficacy doses, with a good safety pharmacology profile. DISCUSSION: CNDR‐51997 may be a candidate for advancement as a potential therapeutic agent for AD and/or other tauopathies. Highlights: There is evidence of microtubule alterations (MT) in Alzheimer's disease (AD) brain and in mouse models of AD pathology.Intermittent dosing with an optimized, brain‐penetrant MT‐stabilizing small‐molecule, CNDR‐51997, reduced both Aβ plaque and tau inclusion pathology in established mouse models of AD.CNDR‐51997 attenuated axonal dystrophy and gliosis in a tauopathy mouse model, with a strong trend toward reduced hippocampal neuron loss.CNDR‐51997 is well tolerated in mice at doses that are meaningfully greater than required for efficacy in AD mouse models, and the compound has a good safety pharmacology profile. [ABSTRACT FROM AUTHOR]

The role of Aβ plaques and neurofibrillary tangles in Alzheimer's disease (AD) pathogenesis have recently come into question due to failure of many pharmaceutical agents targeting these deposits and detection of these misfolded proteins in normal human brains. Therefore, we investigated correlations between microglial activation and toll like receptor 4 (TLR4) and Lck/Yes novel tyrosine (LYN) kinase signaling in an AD mouse model. In this study, we used 5–6‐month‐old 5XFAD and wild type (WT) male and female mice. Immunohistochemistry (IHC) and flow cytometry (FC) were performed on their brains. Cognitive performance was assessed with the Barnes‐Maze. IHC showed more Ab aggregation in microglia of female 5XFAD mice compared to their male counterparts. Increased co‐localization of microglial TLR4 and LYN was also observed in AD more than WT and females more than males. IHC also suggests microglial phagocytosis of neurons in AD mice, which is supported by FC data. Our FC data also support the involvement of disease associated microglia (DAMs) in this process based on cytokine secretion. Cognitive assessment by the Barnes maze showed 5XFAD females performed worse than males. In this study, we investigated the relationship between microglial TLR4 and LYN kinase in 5XFAD male and females. Our data reveals a correlation between microglial TLR4 and LYN co‐localization and AD pathogenesis, more in females than males. Targeting microglial TLR4 and Lyn in DAMs may offer new therapeutic opportunities in the treatment of AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease that is responsible for about one‐third of dementia cases worldwide. It is believed that AD is initiated with the deposition of Ab plaques in the brain. Genetic studies have shown that a high number of AD risk genes are expressed by microglia, the resident macrophages of brain. Common mode of action by microglia cells is neuroinflammation and phagocytosis. Moreover, it has been discovered that inflammatory marker levels are increased in AD patients. Recent studies advocate that neuroinflammation plays a major role in AD progression. Microglia have different activation profiles depending on the region of brain and stimuli. In different activation, profile microglia can generate either pro‐inflammatory or anti‐inflammatory responses. Microglia defend brain cells from pathogens and respond to injuries; also, microglia can lead to neuronal death along the way. In this review, we will bring the different roles played by microglia and microglia‐related genes in the progression of AD. [ABSTRACT FROM AUTHOR]

Purpose: The US Food and Drug Administration authorized lecanemab for the therapeutic use of Alzheimer's disease (AD) in January 2023. To assess the effectiveness and safety of lecanemab in treating AD, we thoroughly examined the studies that are currently accessible. Method: Preferred Reporting Items for Systematic Reviews and Meta‐Analysis recommendations were followed. In order to find relevant studies on lecanemab, we carried out a thorough literature search utilizing the electronic databases MEDLINE via PubMed, Cochrane, Web of Science, EBSCOhost, and Scopus. Excluding any research using experimental animals, we looked at lecanemab's effectiveness and side effects in treating AD in human clinical trials. Three randomized controlled studies were included. Findings: According to studies, lecanemab lessens clinical deterioration and reduces brain amyloid‐beta plaques (difference,.45; 95% confidence interval,.67 to.23; p <.001). Participants who received lecanemab saw a greater frequency of amyloid‐related imaging abnormalities (ARIA)‐H (17.3% vs. 9.0%) and ARIA‐E (12.6% vs. 1.7%), which is a significant adverse outcome. Conclusion: Lecanemab has been shown to have an impact on the two primary pathophysiologic indicators of AD (Aβ and tau). There are still a lot of unresolved issues related to lecanemab. Future research on the effectiveness and safety of lecanemab is advised in order to determine that the advantages of this medication exceed the disadvantages. [ABSTRACT FROM AUTHOR]

Beta amyloid PET scans are a minimally invasive biomarker that may inform Alzheimer's disease (AD) diagnosis. The Caregiver's Reactions and Experience (CARE) study, an IDEAS supplement, aimed to understand experiences of PET scan recipients and their care partners regarding motivations for scans, reporting and interpreting results, and impact of results. Patients with mild cognitive impairment or dementia who agreed to join the CARE‐IDEAS study and their care partners participated in a baseline survey and follow‐up survey approximately 18 months later, supplemented by in‐depth qualitative interviews with subsets of participants. Patients who received scans and volunteered for follow‐up research were more likely to be male, better educated, and have higher income than the general population. Survey information was merged with Medicare data. This article integrates findings from several CARE‐IDEAS publications and provides implications for practice and research. Although most participants accurately reported scan results, they were often confused about their meaning for prognosis. Some participants reported distress with results, but there were no significant changes in measured depression, burden, or economic strain over time. Many respondents desired more information about prognosis and supportive resources. Scan results were not differentially associated with changes in service use over time. Findings suggest a need for carefully designed and tested tools for clinicians to discuss risks and benefits of scans and their results, and resources to support patients and care partners in subsequent planning. Learning of scan results provides a point‐of‐contact that should be leveraged to facilitate shared decision‐making and person‐centered longitudinal AD care. [ABSTRACT FROM AUTHOR]

Background: We investigated the association between atrial fibrillation (AF) and dementia, and its subtypes (vascular‐VaD, Alzheimer, mixed and rare dementia), and identified predictors for dementia in AF patients. Methods: The analysis was based on 183,610 patients with new‐onset AF and 367,220 non‐AF controls in the United Kingdom between 1998 and 2016, identified in three prospectively collected, linked electronic health records sources. Time‐to‐event (dementia or subtypes) analyses were performed using Cox proportional hazards and weighted Cox. Sub‐analyses performed: including & censoring stroke and age (median used as cut‐off). Results: Over a median follow‐up of 2.67 years (IQR.65–6.02) for AF patients and 5.84 years for non‐AF patients (IQR 2.26–11.80), incidence of dementia in the AF cohort was 2.65 per 100 person‐years, compared to 2.02 in the non‐AF cohort. After adjustment, a significant association was observed between AF and all‐cause dementia (HR = 1.38, 95% CI: 1.31–1.45), driven by a strong association with VaD (HR = 1.55, 95% CI: 1.41–1.70). AF was also associated with mixed dementia (HR = 1.26, 95% CI: 1.01–1.56), but we could not confirm an association with Alzheimer (HR = 1.05, 95% CI:.94–1.16) and rare dementia forms (HR = 1.19, 95% CI:.90–1.56). Ischemic stroke (HR = 1.40, 95% CI: 1.26–1.56), subarachnoid haemorrhage (HR = 2.08, 95% CI: 1.47–2.96), intracerebral haemorrhage (HR = 1.95, 95% CI: 1.54–2.48) and diabetes (HR = 1.32, 95% CI: 1.24–1.41) were identified as the strongest predictors of dementia in AF patients. Conclusions: AF patients have an increased risk of dementia, independent of stroke, with highest risk of VaD. Management and prevention of the identified risk factors could be crucial to reduce the increasing burden of dementia. [ABSTRACT FROM AUTHOR]

This Preface introduces the Special Issue entitled, “Energy Substrates and Microbiome Govern Brain Bioenergetics and Cognitive Function with Aging”, which is comprised of manuscripts contributed by invited speakers and program/organizing committee members who participated in the 14th International Conference on Brain Energy Metabolism (ICBEM) held on October 24–27, 2022 in Santa Fe, New Mexico, USA. The conference covered the latest developments in research related to neuronal energetics, emerging roles for glycogen in higher brain functions, the impact of dietary intervention on aging, memory, and Alzheimer's disease, roles of the microbiome in gut-brain signaling, astrocyte-neuron interactions related to cognition and memory, novel roles for mitochondria and their metabolites, and metabolic neuroimaging in aging and neurodegeneration. The special issue contains 25 manuscripts on these topics plus three tributes to outstanding scientists who have made important contributions to brain energy metabolism and participated in numerous ICBEM conferences. In addition, two of the manuscripts describe important directions and the rationale for future research in many thematic areas covered by the conference. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not latelife obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission. [ABSTRACT FROM AUTHOR]

Background and purpose: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at‐risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU‐ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. Methods: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU‐ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU‐ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU‐ADRI, and the potential impact of baseline ANU‐ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. Results: A higher ANU‐ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was −0.028 [−0.032 to −0.025]) and over the 2‐year study (e.g., estimate for 2‐year changes in ANU‐ADRI and per‐year changes in global cognition [95% confidence interval] was −0.068 [−0.026 to −0.108]). No significant beneficial intervention effect was reported for ANU‐ADRI, and baseline ANU‐ADRI did not significantly affect the response to the intervention on changes in cognition. Conclusions: The ANU‐ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context. [ABSTRACT FROM AUTHOR]

Introduction: The combination of apolipoprotein E ε4 (ApoE ε4) status, odor identification, and odor familiarity predicts conversion to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: To further understand olfactory disturbances and AD risk, ApoE ε4 carrier (mean age 76.38 ± 5.21) and ε4 non‐carrier (mean age 76.8 ± 3.35) adults were given odor familiarity and identification tests and performed an odor identification task during fMRI scanning. Five task‐related functional networks were detected using independent components analysis. Main and interaction effects of mean odor familiarity ratings, odor identification scores, and ε4 status on network activation and task‐modulation of network functional connectivity (FC) during correct and incorrect odor identification (hits and misses), controlling for age and sex, were explored using multiple linear regression. Results: Findings suggested that sensory‐olfactory network activation was positively associated with odor identification scores in ε4 carriers with intact odor familiarity. The FC of sensory‐olfactory, multisensory‐semantic integration, and occipitoparietal networks was altered in ε4 carriers with poorer odor familiarity and identification. In ε4 carriers with poorer familiarity, connectivity between superior frontal areas and the sensory‐olfactory network was negatively associated with odor identification scores. Conclusions: The results contribute to the clarification of the neurocognitive structure of odor identification processing and suggest that poorer odor familiarity and identification in ε4 carriers may signal multi‐network dysfunction. Odor familiarity and identification assessment in ε4 carriers may contribute to the predictive value of risk for MCI and AD due to the breakdown of sensory‐cognitive network integration. Additional research on olfactory processing in those at risk for AD is warranted. [ABSTRACT FROM AUTHOR]

This article presents research that explored the ways that systemic and family therapists might approach the support of families living with dementia. A constructivist grounded theory methodology was used to interpret interviews with four systemic family therapists working in the United Kingdom. All participants had professional and/or lived experience of dementia. Transcript analysis and theoretical sampling led to the development of five categories, each related to different aspects of considering systemic therapy in a dementia context. These categories were further developed into a 'systemically informed dementia orienteering' conceptual framework, which is presented in this paper as a learning resource. Findings are related to existing literature, and recommendations for future research are made. [ABSTRACT FROM AUTHOR]

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid‐β (Aβ) accumulation based on Centiloids (CL) in pre‐dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease–Prognostic and Natural History Study (AMYPAD‐PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid‐PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub‐populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision‐recall analyses. Accumulation rates were examined using linear mixed‐effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ‐accumulators. Rates of amyloid accumulation were tracer‐independent, lower for APOE ε4 non‐carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12–20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations. [ABSTRACT FROM AUTHOR]

BACKGROUND: With the availability of disease‐modifying therapies for Alzheimer's disease (AD), it is important for clinicians to have tests to aid in AD diagnosis, especially when the presence of amyloid pathology is a criterion for receiving treatment. METHODS: High‐throughput, mass spectrometry‐based assays were used to measure %p‐tau217 and amyloid beta (Aβ)42/40 ratio in blood samples from 583 individuals with suspected AD (53% positron emission tomography [PET] positive by Centiloid > 25). An algorithm (PrecivityAD2 test) was developed using these plasma biomarkers to identify brain amyloidosis by PET. RESULTS: The area under the receiver operating characteristic curve (AUC‐ROC) for %p‐tau217 (0.94) was statistically significantly higher than that for p‐tau217 concentration (0.91). The AUC‐ROC for the PrecivityAD2 test output, the Amyloid Probability Score 2, was 0.94, yielding 88% agreement with amyloid PET. Diagnostic performance of the APS2 was similar by ethnicity, sex, age, and apoE4 status. DISCUSSION: The PrecivityAD2 blood test showed strong clinical validity, with excellent agreement with brain amyloidosis by PET. [ABSTRACT FROM AUTHOR]

Many patients with dementia want the option of using medical aid in dying (MAID) to end their lives before losing decision‐making capacity and other abilities that impact their desired quality of life. But, for over two decades, it has been widely understood that these patients cannot (solely because of their dementia diagnosis) satisfy three statutory eligibility requirements in all U.S. MAID laws: (1) decisional capacity, (2) the ability to self‐administer the life‐ending medications, and (3) a terminal condition with 6 months or less to live. Now, because of recent statutory amendments together with the use of voluntarily stopping eating and drinking (VSED) to quickly advance to a terminal condition, this dementia exclusion from MAID might no longer apply. If combining VSED and MAID is now a possibility for patients with dementia, then clinicians need more guidance on whether and when to support patients seeking to take this path. In this article, we begin to provide this guidance. First, we describe the recent case of an Oregon patient with early‐stage Alzheimer's dementia who successfully used VSED to qualify for and use MAID. Second, we discuss prior barriers to using VSED as a bridge to MAID for people with dementia. Third, we describe recent legal changes that might make this path now possible. See related editorial by Briscoe and Widera in this issue. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia‐associated pathologies and is important in the context of anti‐amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology‐confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD‐LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD‐LBP. In AD‐LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD‐LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Highlights: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology.In the context of anti‐amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered. [ABSTRACT FROM AUTHOR]

BACKGROUND: Impairment of the ubiquitin‐proteasome system (UPS) has been implicated in abnormal protein accumulation in Alzheimer's disease. It remains unclear if genetic variation affects the intrinsic properties of neurons that render some individuals more vulnerable to UPS impairment. METHODS: Induced pluripotent stem cell (iPSC)‐derived neurons were generated from over 50 genetically variant and highly characterized participants of cohorts of aging. Proteomic profiling, proteasome activity assays, and Western blotting were employed to examine neurons at baseline and in response to UPS perturbation. RESULTS: Neurons with lower basal UPS activity were more vulnerable to tau accumulation following mild UPS inhibition. Chronic reduction in proteasome activity in human neurons induced compensatory elevation of regulatory proteins involved in proteostasis and several proteasome subunits. DISCUSSION: These findings reveal that genetic variation influences basal UPS activity in human neurons and differentially sensitizes them to external factors perturbing the UPS, leading to the accumulation of aggregation‐prone proteins such as tau. Highlights: Polygenic risk score for AD is associated with the ubiquitin‐proteasome system (UPS) in neurons.Basal proteasome activity correlates with aggregation‐prone protein levels in neurons.Genetic variation affects the response to proteasome inhibition in neurons.Neuronal proteasome perturbation induces an elevation in specific proteins involved in proteostasis.Low basal proteasome activity leads to enhanced tau accumulation with UPS challenge. [ABSTRACT FROM AUTHOR]

A series of novel styryl dye derivatives incorporating indolium and quinolinium core structures were successfully synthesized to explore their interacting and binding capabilities with tau aggregates in vitro and in cells. The synthesized dyes exhibited enhanced fluorescence emission in viscous environments due to the rotatable bond confinement in the core structure. Dye 4, containing a quinolinium moeity and featuring two cationic sites, demonstrated a 28‐fold increase in fluorescence emission upon binding to tau aggregates. This dye could also stain tau aggregates in living cells, confirmed by cell imaging using confocal fluorescence microscopy. A molecular docking study was conducted to provide additional visualization and support for binding interactions. This work offers novel and non‐cytotoxic fluorescent probes with desirable photophysical properties, which could potentially be used for studying tau aggregates in living cells, prompting further development of new fluorescent probes for early Alzheimer's disease detection. [ABSTRACT FROM AUTHOR]

Liver transplant (LT) recipients have a high burden of cognitive impairment risk factors identified in other populations, yet little work has explored cognition in the United States LT population. We characterized prevalence of cognitive impairment (CI) in LT recipients pre‐LT and ≥3 months post‐LT. Adult LT recipients with cirrhosis but without active pre‐LT hepatic encephalopathy (HE) were screened for CI using the Montreal Cognitive Assessment (MoCA) for CI (MoCA <24) both pre‐LT and ≥3 months post‐LT. The association between cognitive performance and recipient characteristics was assessed using logistic regression. Of 107 LT recipients, 36% had pre‐LT CI and 27% had post‐LT CI [median (Q1–Q3) MoCA 26 (23–28)]. Each 1‐point increase in pre‐LT MoCA was associated with 26% lower odds of post‐LT cognitive impairment (aOR.74, 95% CI.63–.87, p <.001), after adjusting for recipient age, history of HE, and time since LT. In this study of cirrhosis recipients without active pre‐LT HE, cognitive impairment was prevalent before LT and remained prevalent ≥3 months after LT (27%), long after effects of portal hypertension on cognition would be expected to have resolved. Our data expose an urgent need for more comprehensive neurologic examination of LT recipients to better identify, characterize, and address predictors of post‐LT cognitive impairment. [ABSTRACT FROM AUTHOR]

Swertia species are common ingredients in numerous herbal remedies. It is also used to treat a wide range of illnesses and possess diverse therapeutic activities. The aim of the study is to elucidate the comprehensive metabolomics profile of Swertia chirayita and the role of various extraction methods in the phytochemical compositions of the extracts of S. chirayita, and their antioxidant and enzyme inhibitory activities. Extraction of the stems, leaves, and flowering tops of S. chirayita was performed by maceration, infusion, and soxhlation using methanol and water as solvent. Extracts were subjected to phytochemical profiling by a liquid‐chromatographic system. Antioxidant and enzyme inhibitory activity was carried out. The metabolomics profiling showed that a diverse range of specialized metabolites were present in the stems and leaves & flowering tops of the plant. All the extracts showed substantial antioxidant and enzyme inhibitory activities further confirmed by molecular docking studies. This study appraised the use of S. chirayita aerial parts as a potential antioxidant and its therapeutic application in various chronic illnesses including Alzheimer's disease, diabetes, and other skin‐related disorders. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights: Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults.Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden.AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity.Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Down syndrome (DS) is a genetic cause of early‐onset Alzheimer's disease (AD). The National Institute on Aging–Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium–Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11C]Pittsburgh compound B) and tau (10 mCi of [18F]AV‐1451) were used to classify amyloid (A) –/+ and tau (T) +/–. Hippocampal volume classified neurodegeneration (N) –/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A–/T–/(N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A–T–(N)– and A+T–(N)–. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. Highlights: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)–/tau (T)–/neurodegeneration (N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+.The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology.Findings inform models for predicting the transition to the prodromal stage of AD in DS. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) and AD‐related dementias (ADRD) are leading causes of death among older adults in the United States. Efforts to understand risk factors for prevention are needed. METHODS: Participants (n = 146,166) enrolled in the Women's Health Initiative without AD at baseline were included. Diabetes status was ascertained from self‐reported questionnaires and deaths attributed to AD/ADRD from hospital, autopsy, and death records. Competing risk regression models were used to estimate the cause‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of type 2 diabetes mellitus (T2DM) with AD/ADRD and non‐AD/ADRD mortality. RESULTS: There were 29,393 treated T2DM cases and 8628 AD/ADRD deaths during 21.6 (14.0–23.5) median (IQR) years of follow‐up. Fully adjusted HRs (95% CIs) of the association with T2DM were 2.94 (2.76–3.12) for AD/ADRD and 2.65 (2.60–2.71) for the competing risk of non‐AD/ADRD mortality. DISCUSSION: T2DM is associated with AD/ADRD and non‐AD/ADRD mortality. Highlights: Type 2 diabetes mellitus is more strongly associated with Alzheimer's disease (AD)/AD and related dementias (ADRD) mortality compared to the competing risk of non‐AD/ADRD mortality among postmenopausal women.This relationship was consistent for AD and ADRD, respectively.This association is strongest among participants without obesity or hypertension and with younger age at baseline, higher diet quality, higher physical activity, higher alcohol consumption, and older age at the time of diagnosis of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Introduction: The exclusion of affected populations from Alzheimer's disease (AD) clinical research limits our understanding of disease heterogeneity and its impact on clinical care. While micro sampling with dried plasma spots (DPS) can promote inclusivity by enabling sample collection in remote areas, current techniques lack the sensitivity required for the quantification of phosphorylated tau at Thr181 (pTau‐181) in DPS extracts. Methods: We developed an assay for pTau‐181 with reduced bead count and improved bead read efficiency (BRE) using a prototype Simoa instrument. This novel assay's performance was evaluated against standard pTau‐181 assays on two Simoa platforms, and DPS extracts were tested for pTau‐181 quantification feasibility. Results: The novel assay quantifies pTau‐181 at concentrations up to 16x lower than traditional pTau‐181 assays on HD‐X and SR‐X platforms. DPS extracts tested with our low‐bead assay were quantified considerably above the lower limit of quantification (LLOQ), indicating the suitability of this assay for future DPS extract measurements. Discussion: Implementing DPS sampling and pTau‐181 quantification could increase participation from underrepresented groups in AD research. However, additional assay optimization and an in‐depth study of preanalytical sample stability are essential for the transition to clinical applicability. [ABSTRACT FROM AUTHOR]

MHC class I molecules regulate brain development and plasticity in mice and HLA class I molecules are associated with brain disorders in humans. We investigated the relationship between plasma‐derived soluble human HLA class I molecules (sHLA class I), HLA class I serotypes and dementia. A cohort of HLA class I serotyped elderly subjects with no dementia/pre‐dementia (NpD, n = 28), or with dementia (D, n = 28) was studied. Multivariate analysis was used to examine the influence of dementia and HLA class I serotype on sHLA class I levels, and to compare sHLA class I within four groups according to the presence or absence of HLA‐A23/A24 and dementia. HLA‐A23/A24 and dementia, but not age, significantly influenced the level of sHLA class I. Importantly, the concurrent presence of HLA‐A23/A24 and dementia was associated with higher levels of sHLA class I (p < 0.001). This study has shown that the simultaneous presence of HLA‐A23/HLA‐A24 and dementia is associated with high levels of serum sHLA class I molecules. Thus, sHLA class I could be considered a biomarker of neurodegeneration in certain HLA class I carriers. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's‐focused participant recruitment registries are tools for accelerating enrollment into studies, however, registry members are primarily White women. METHODS: We conducted a national online survey of 1501 adults ages 50–80, oversampling for Black and Hispanic/Latino respondents, assessing intention to join a generic "brain health" registry and to join a registry that required specific tasks. RESULTS: Intention to join a registry was low (M 3.48, SD 1.77), and lower than intention to join a registry requiring specific tasks. Intention was greatest for registries requiring completing surveys (M 4.70, SD 1.77). Differences in intention were primarily between White women and Black women; differences between other groups were limited to specific tasks required. DISCUSSION: The results indicate uncertainty about what a registry is, its purpose, and/or the concept of "brain health." Using the Reasoned Action Approach (RAA) to develop evidence‐based outreach messages describing a registry and required tasks may increase diversity. [ABSTRACT FROM AUTHOR]

Decision‐making capacity describes the ability to make a particular decision at a given time. People with Mild Cognitive Impairment (MCI) and mild stage dementia typically experience an associated erosion of their decisional abilities. Many could be said to have marginal capacity. These individuals are in a liminal space between adequate and inadequate capacity. Too often, marginal capacity is overlooked as a category: individuals are classified either as having capacity and being able to make decisions independently or as lacking capacity and needing a surrogate to make decisions for them. These approaches can, respectively, result in under‐ or overprotection of individuals with marginal capacity. A promising alternative approach is supported decision making. In supported decision making, a person with marginal capacity identifies a trusted person or network of persons to aid them in making their own decisions. Supported decision making is recognized by law in a growing number of states; it is important for geriatricians to be familiar with the concept, as they are increasingly likely to encounter it in their practice. Even in states where supported decision making is not formally recognized, it can be practiced informally, helping patients, care partners, and clinicians strike an appropriate balance between respecting autonomy and recognizing vulnerability. In this article, we describe supported decision making, discuss its ethical and legal foundations, and identify steps by which geriatricians can incorporate it into their practice. [ABSTRACT FROM AUTHOR]

Fatty acids are metabolized by β‐oxidation within the "mitochondrial ketogenic pathway" (MKP) to generate β‐hydroxybutyrate (BHB), a ketone body. BHB can be generated by most cells but largely by hepatocytes following exercise, fasting, or ketogenic diet consumption. BHB has been shown to modulate systemic and brain inflammation; however, its direct effects on microglia have been little studied. We investigated the impact of BHB on Aβ oligomer (AβO)‐stimulated human iPS‐derived microglia (hiMG), a model relevant to the pathogenesis of Alzheimer's disease (AD). HiMG responded to AβO with proinflammatory activation, which was mitigated by BHB at physiological concentrations of 0.1–2 mM. AβO stimulated glycolytic transcripts, suppressed genes in the β‐oxidation pathway, and induced over‐expression of AD‐relevant p46Shc, an endogenous inhibitor of thiolase, actions that are expected to suppress MKP. AβO also triggered mitochondrial Ca2+ increase, mitochondrial reactive oxygen species production, and activation of the mitochondrial permeability transition pore. BHB potently ameliorated all the above mitochondrial changes and rectified the MKP, resulting in reduced inflammasome activation and recovery of the phagocytotic function impaired by AβO. These results indicate that microglia MKP can be induced to modulate microglia immunometabolism, and that BHB can remedy "keto‐deficiency" resulting from MKP suppression and shift microglia away from proinflammatory mitochondrial metabolism. These effects of BHB may contribute to the beneficial effects of ketogenic diet intervention in aged mice and in human subjects with mild AD. [ABSTRACT FROM AUTHOR]

The role of betaine in the liver and kidney has been well documented, even from the cellular and molecular point of view. Despite literature reporting positive effects of betaine supplementation in Alzheimer's, Parkinson's and schizophrenia, the role and function of betaine in the brain are little studied and reviewed. Beneficial effects of betaine in neurodegeneration, excitatory and inhibitory imbalance and against oxidative stress in the central nervous system (CNS) have been collected and analysed to understand the main role of betaine in the brain. There are many 'dark' aspects needed to complete the picture. The understanding of how this osmolyte is transported across neuron and glial cells is also controversial, as the expression levels and functioning of the known protein capable to transport betaine expressed in the brain, betaine‐GABA transporter 1 (BGT‐1), is itself not well clarified. The reported actions of betaine beyond BGT‐1 related to neuronal degeneration and memory impairment are the focus of this work. With this review, we underline the scarcity of detailed molecular and cellular information about betaine action. Consequently, the requirement of detailed focus on and study of the interaction of this molecule with CNS components to sustain the therapeutic use of betaine. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early‐onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. METHODS: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early‐Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J‐curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. RESULTS: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter‐syndromic differences were noted with raw score, primacy, recency, J‐curve, and stopping time. DISCUSSION: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. Highlights: RAVLT patterns characterize various presentations of EOAD and EOnonADAmyloid impacts raw score, primacy, recency, and stopping timeTiming‐based scores add value over traditional count‐based scores [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin‐converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. Methods: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two‐sample Mendelian randomization (MR) approach. Results: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04–1.10], P = 5 × 10−07) and frontotemporal dementia (1.16 [1.04–1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. Discussion: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin‐converting enzyme (ACE) inhibition association with dementias.The results suggest an association between ACE inhibition and Alzheimer's disease.The results suggest an association between ACE inhibition and frontotemporal dementia.Those associations can be interpreted as potentially causal. [ABSTRACT FROM AUTHOR]

Introduction: Mild cognitive impairment remains substantially underdiagnosed, especially in disadvantaged populations. Failure to diagnose deprives patients and families of the opportunity to treat reversible causes, make necessary life and lifestyle changes and receive disease‐modifying treatments if caused by Alzheimer's disease. Primary care, as the entry point for most, plays a critical role in improving detection rates. Methods: We convened a Work Group of national experts to develop consensus recommendations for policymakers and third‐party payers on ways to increase the use of brief cognitive assessments (BCAs) in primary care. Results: The group recommended three strategies to promote routine use of BCAs: providing primary care clinicians with suitable assessment tools; integrating BCAs into routine workflows; and crafting payment policies to encourage adoption of BCAs. Disscussion: Sweeping changes and actions of multiple stakeholders are necessary to improve detection rates of mild cognitive impairment so that patients and families may benefit from timely interventions. [ABSTRACT FROM AUTHOR]

An editorial is presented which explores the potential link between routine vaccinations (e.g., influenza vaccines) and reduced risk of dementia, based on emerging evidence of the role of the immune system and inflammation in dementia pathogenesis and various studies suggesting a protective link between some routinely used vaccines and dementia. The authors use the Bradford-Hill criteria, an epidemiological approach.

Introduction: Traumatic brain injury (TBI) is a dementia risk factor, with Alzheimer's disease (AD) more common following injury. Patterns of neurodegeneration produced by TBI can be compared to AD and aging using volumetric MRI. Methods: A total of 55 patients after moderate to severe TBI (median age 40), 45 with AD (median age 69), and 61 healthy volunteers underwent magnetic resonance imaging over 2 years. Atrophy patterns were compared. Results: AD patients had markedly lower baseline volumes. TBI was associated with increased white matter (WM) atrophy, particularly involving corticospinal tracts and callosum, whereas AD rates were increased across white and gray matter (GM). Subcortical WM loss was shared in AD/TBI, but deep WM atrophy was TBI‐specific and cortical atrophy AD‐specific. Post‐TBI atrophy patterns were distinct from aging, which resembled AD. Discussion: Post‐traumatic neurodegeneration 1.9–4.0 years (median) following moderate‐severe TBI is distinct from aging/AD, predominantly involving central WM. This likely reflects distributions of axonal injury, a neurodegeneration trigger. Highlights: We compared patterns of brain atrophy longitudinally after moderate to severe TBI in late‐onset AD and healthy aging.Patients after TBI had abnormal brain atrophy involving the corpus callosum and other WM tracts, including corticospinal tracts, in a pattern that was specific and distinct from AD and aging.This pattern is reminiscent of axonal injury following TBI, and atrophy rates were predicted by the extent of axonal injury on diffusion tensor imaging, supporting a relationship between early axonal damage and chronic neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. Methods: This retrospective longitudinal, autopsy‐confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD‐LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) score. Results: Non‐amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD‐LBP. There was a similar trend for visuospatial symptoms in AD‐LBP. Discussion: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. Highlights: Initial non‐amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology.Given the relative size of CDR‐SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Increased availability of Alzheimer's disease (AD) biomarker tests provides older adults with opportunities to seek out and learn results. We evaluated the feasibility of virtually returning AD biomarker results. Methods: Trained study clinicians disclosed amyloid positron emission tomography (PET) results and provided dementia risk‐reduction counseling via televideo to cognitively unimpaired participants already enrolled in AD research (n = 99; mean age ± SD: 72.0 ± 4.8; 67% women; 95% White; 28% amyloid elevated). Results: Our study demonstrated acceptable levels of retention (93%), compliance (98%), adherence (98%), clinician competence (97%), education comprehension (quiz scores 14/15), and virtual visit functionality (rating 9.4/10). Depression, anxiety, and suicidality remained low and did not differ by amyloid result. Discussion: Virtual return of amyloid PET results to cognitively unimpaired research participants is feasible and does not result in increased psychological symptoms. Technological barriers for some participants highlight the need for flexibility. These findings support the use of televideo in AD biomarker disclosure, although our study sample and design have important limitations for generalizability. [ABSTRACT FROM AUTHOR]

Fluid biomarkers are currently measured in cerebrospinal fluid and blood for Alzheimer's disease diagnosis and are promising targets for drug development and for patients' follow‐up in clinical trials. These biomarkers have been grouped in an unbiased research framework, the amyloid (Aβ), tau, and neurodegeneration (AT[N]) biomarker system to aid patients' early diagnosis and stratification. Metrological approaches relying on mass spectrometry have been used for the development of reference materials and reference measurement procedures. Despite their excellent performances as clinical tools, fluid biomarkers often present an important between‐laboratory variation. Standardization efforts were carried out on the biomarkers currently included in the AT(N) classification system, involving the collaboration of national metrology institutes, clinicians, researchers, and in vitro diagnostic providers. This article provides an overview of current activities towards standardization. These reference methods and reference materials may be used for recalibration of immunoassays and the establishment of standardized cutoff values allowing a better stratification of Alzheimer's disease patients. Highlights: The AT(N) biomarker system allows stratifying AD patients on the basis of biomarker profiles.Fluid biomarker measurements often present an important between‐laboratory variation preventing the establishment of standardized cutoff values.Overview on the standardization initiatives involving the fluid biomarkers currently included in the AT(N) framework. [ABSTRACT FROM AUTHOR]

Introduction: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age‐related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. Methods: We examined post‐mortem brain tissue from people in mid‐life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell‐derived neurons were challenged with Alzheimer's brain homogenate. Results: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid‐life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline. Discussion: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing. [ABSTRACT FROM AUTHOR]

Introduction: This culturally tailored enrollment effort aims to determine the feasibility of enrolling 5000 older Latino adults from California into the Brain Health Registries (BHR) over 2.25 years. Methods: This paper describes (1) the development and deployment of culturally tailored BHR websites and digital ads, in collaboration with a Latino community science partnership board and a marketing company; (2) an interim feasibility analysis of the enrollment efforts and numbers, and participant characteristics (primary aim); as well as (3) an exploration of module completion and a preliminary efficacy evaluation of the culturally tailored digital efforts compared to BHR's standard non–culturally tailored efforts (secondary aim). Results: In 12.5 months, 3603 older Latino adults were enrolled (71% of the total California Latino BHR initiative enrollment goal). Completion of all BHR modules was low (6%). Discussion: Targeted ad placement, culturally tailored enrollment messaging, and culturally tailored BHR websites increased enrollment of Latino participants in BHR, but did not translate to increased module completion. Highlights: Culturally tailored social marketing and website improvements were implemented.The efforts enrolled 5662 Latino individuals in 12.5 months.The number of Latino Brain Health Registry (BHR) participants increased by 122.7%.We failed to adequately enroll female Latinos and Latinos with lower education.Future work will evaluate effects of a newly released Spanish‐language BHR website. [ABSTRACT FROM AUTHOR]

Objective: Memory and cognitive problems are central to the diagnosis of Alzheimer's disease (AD). Psychometric approaches to defining phenotypes can aid in identify genetic variants associated with AD. However, these approaches have mostly been limited to affected individuals. Defining phenotypes of both affected and unaffected individuals may help identify genetic variants associated with both AD and healthy aging. This study compares psychometric methods for developing cognitive phenotypes that are more granular than clinical classifications. Methods: 682 older Old Order Amish individuals were included in the analysis. Adjusted Z‐scores of cognitive tests were used to create four models including (1) global threshold scores or (2) memory threshold scores, and (3) global clusters and (4) memory clusters. An ordinal regression examined the coherence of the models with clinical classifications (cognitively impaired [CI], mildly impaired [MI], cognitively unimpaired), APOE‐e4, sex, and age. An ANOVA examined the best model phenotypes for differences in clinical classification, APOE‐e4, domain Z‐scores (memory, language, executive function, and processing speed), sex, and age. Results: The memory cluster identified four phenotypes and had the best fit (χ2 = 491.66). Individuals in the worse performing phenotypes were more likely to be classified as CI or MI and to have APOE‐e4. Additionally, all four phenotypes performed significantly differently from one another on the domains of memory, language, and executive functioning. Conclusions: Memory cluster stratification identified the cognitive phenotypes that best aligned with clinical classifications, APOE‐e4, and cognitive performance We predict these phenotypes will prove useful in searching for protective genetic variants. Key points: This study compares psychometric methods for developing cognitive phenotypes that are more granular than clinical classifications in individuals from the Old Order Amish.We found that the memory cluster model produced four distinct cognitive phenotypes had the best fit with clinical classification, presence of APOE‐e4, age, and sex in the Old Order Amish.This suggests that stratification of Old Order Amish individuals using cluster analysis based on memory performance performs better than memory threshold stratification, and stratification based on global cognition.Importantly, our memory cluster model stratified individuals into four distinct cognitive phenotypes with significant differences in cognitive performance across memory, executive functioning, and language, but similar prevalence rates of APOE‐e4 in top three performing phenotypes [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative disease. There is epidemiological evidence that heart failure (HF) patients are at higher risk of developing AD, and the impact of sacubitril/valsartan, the first angiotensin receptor‐neprilysin inhibitor (ARNI) approved for HF, on cognitive functions is still controversial. To investigate the effect of sacubitril/valsartan on cognitive functions in colchicine‐induced AD rat model. Forty adult male Wistar rats were equally allocated into four groups (each of 10 rats): Group I: normal control, Group II: intracerebroventricular injection of colchicine (15 μg/5 μl/bilaterally), Group III: colchicine (15 μg/5 μl/bilaterally, icv) + oral sacubitril/valsartan (100 mg/kg/day) for 25 days, and Group IV: colchicine (15 μg/5 μl/bilaterally, icv) + oral valsartan (50 mg/kg/day) for 25 days. Behavioral assessment was done using Morris water maze and passive avoidance tasks. Biochemically, β‐amyloid (1–40 and 1–42) peptides, oxidative stress (malondialdehyde and superoxide dismutase) and inflammatory (tumor necrosis factor‐alpha) parameters were measured in hippocampus and prefrontal cortex. Sacubitril/valsartan exaggerated colchicine‐induced cognitive impairment in both Morris water maze and passive avoidance tasks and was associated with significant increase in β‐amyloid accumulation, oxidative stress, and inflammation versus valsartan. Sacubitril/valsartan caused deleterious effect on cognitive impairment and biochemical alterations in colchicine‐induced AD rat model. Hence, special caution should be taken following long‐term intake of ARNI on cognitive functions. [ABSTRACT FROM AUTHOR]

Introduction: To determine the role of vitamin D intake on cognitive decline among Blacks and Whites. Methods: Using data from the population‐based Chicago Health and Aging Project, we studied 2061 Blacks and 1329 Whites with dietary vitamin D data and cognitive testing over 12 years of follow‐up. Multivariable linear mixed‐effects models were used to determine the association of vitamin D intake with cognitive decline. Results: Vitamin D intake, particularly dietary vitamin D, was associated with a slower rate of decline in cognitive function among Blacks. In Blacks, comparing individuals in the lowest tertile of dietary intake, those in the highest tertile had a slower cognitive decline of 0.017 units/year (95% confidence interval 0.006, 0.027), independently of supplementation use. In Whites, vitamin D intake was not associated with cognitive decline. Discussion: Dietary vitamin D may help to slow the decline in cognitive abilities among Blacks as they age. [ABSTRACT FROM AUTHOR]

Cerebral clearance of amyloid β‐protein (Aβ) is decreased in early‐onset and late‐onset Alzheimer's disease (AD). Aβ is cleared from the brain by enzymatic degradation and by transport out of the brain. More than 20 Aβ‐degrading enzymes have been described. Increasing the degradation of Aβ offers an opportunity to decrease brain Aβ levels in AD patients. This review discusses the direct and indirect approaches which have been used in experimental systems to alter the expression and/or activity of Aβ‐degrading enzymes. Also discussed are the enzymes' regulatory mechanisms, the conformations of Aβ they degrade, where in the scheme of Aβ production, extracellular release, cellular uptake, and intracellular degradation they exert their activities, and changes in their expression and/or activity in AD and its animal models. Most of the experimental approaches require further confirmation. Based upon each enzyme's effects on Aβ (some of the enzymes also possess β‐secretase activity and may therefore promote Aβ production), its direction of change in AD and/or its animal models, and the Aβ conformation(s) it degrades, investigating the effects of increasing the expression of neprilysin in AD patients would be of particular interest. Increasing the expression of insulin‐degrading enzyme, endothelin‐converting enzyme‐1, endothelin‐converting enzyme‐2, tissue plasminogen activator, angiotensin‐converting enzyme, and presequence peptidase would also be of interest. Increasing matrix metalloproteinase‐2, matrix metalloproteinase‐9, cathepsin‐B, and cathepsin‐D expression would be problematic because of possible damage by the metalloproteinases to the blood brain barrier and the cathepsins' β‐secretase activity. Many interventions which increase the enzymatic degradation of Aβ have been shown to decrease AD‐type pathology in experimental models. If a safe approach can be found to increase the expression or activity of selected Aβ‐degrading enzymes in human subjects, then the possibility that this approach could slow the AD progression should be examined in clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost‐effectiveness of amyloid‐PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. Methods: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid‐PET; ARM2, late amyloid‐PET; and ARM3, free‐choice. Results: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. Discussion: The features of AMYPAD‐DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results. [ABSTRACT FROM AUTHOR]

A chronic state of unresolved inflammation in Alzheimer's disease (AD) is intrinsically involved with the remodeling of brain lipids. This review highlights the effect of carrying the apolipoprotein E ε4 allele (APOE4) on various brain cell types in promoting an unresolved inflammatory state. Among its pleotropic effects on brain lipids, we focus on APOE4's activation of Ca2+‐dependent phospholipase A2 (cPLA2) and its effects on arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid signaling cascades in the brain. During the process of neurodegeneration, various brain cell types, such as astrocytes, microglia, and neurons, together with the neurovascular unit, develop distinct inflammatory phenotypes that impact their functions and have characteristic lipidomic fingerprints. We propose that lipidomic phenotyping of single cell‐types harvested from brains differing by age, sex, disease severity stage, and dietary and genetic backgrounds can be employed to probe mechanisms of neurodegeneration. A better understanding of the brain cellular inflammatory/lipidomic response promises to guide the development of nutritional and drug interventions for AD dementia. [ABSTRACT FROM AUTHOR]

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. Highlights: The burden of dementia is unevenly distributed geographically and by sex and gender.Scientific advances in genetics and biomarkers challenge beliefs that sex is binary.Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline.Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the most frequent form of dementia in elderly people. The triple transgenic (3xTg‐AD) mouse model of Alzheimer's Disease is important in biomedical research as these mice develop both neuropathological and behavioural phenotypes. However, their behavioural phenotype is variable, with findings depending on the specific task, as well as the age and sex of the mice. Whisker movements show motor, sensory and cognitive deficits in mouse models of neurodegenerative disease. Therefore, we examined whisker movements in 3, 12.5 and 17‐month‐old female 3xTg‐AD mice and their B6129S/F2 wildtype controls. Mice were filmed using a high‐speed video camera (500 fps) in an open arena during a novel object exploration task. Genotype and age differences were found in mice exploring the arena prior to object contact. Prior to whisker contact, the 3‐month‐old 3xTg‐AD mice had smaller whisker angles compared with the wildtype controls, suggesting an early motor phenotype in these mice. Pre‐contact mean angular position at 3 months and whisking amplitude at 17 months of age differed between the 3xTg‐AD and wildtype mice. During object contact 3xTg‐AD mice did not reduce whisker spread as frequently as the wildtype mice at 12.5 and 17 months, which may suggest sensory or attentional deficits. We show that whisker movements are a powerful behavioural measurement tool for capturing behavioural deficits in mouse models that show complex phenotypes, such as the 3xTg‐AD mouse model. [ABSTRACT FROM AUTHOR]

Issue addressed: Memory Cafés are a psychosocial intervention that aims to provide socialisation and interpersonal support for those living with dementia and their carers. This study explores the Memory Café model and determines the impact of the peer‐to‐peer Memory Café model on the psychosocial well‐being of those living with dementia and their carers. Methods: Participants were informal carers of those living with dementia, recruited from four Memory Café's located in metropolitan Perth, Western Australia. Demographic information was collected from participants. Eleven semi‐structured interviews were conducted. The data were transcribed and analysed thematically. Results: The benefits of participation are described under four themes; sharing experiences and reduction of stigma, a place to feel joy and be yourself, a time to socialise and build friendships and improvements in life outside the Memory Café. The positive attributes of the Memory Cafés that contributed to the benefits were also identified. Concerns about Memory Cafés were limited to it becoming a carers‐only group. Conclusions: Memory Cafés contribute significantly to the psychosocial well‐being of carers of those living with dementia and provide a positive outlet for carers to build social networks and become active in their community. The effect on the psychosocial well‐being of those living with dementia may be more limited but is still described positively. So what?: Dementia is a condition with significant impacts on carers and families. Successful peer‐based social interventions such as Memory Cafés can lead to further development of dementia‐friendly communities aimed at providing joy as well as support. [ABSTRACT FROM AUTHOR]

Objectives: Aducanumab is a monoclonal antibody which has recently been licenced for use by the food and drug administration for treatment of patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia. Appropriate use criteria (AUC) for Aducanumab in clinical practice are available. We look to review patients in our specialist interdisciplinary cognitive service with positive cerebrospinal fluid (CSF) biomarkers for AD for their hypothetical eligibility for Aducanumab, or a similar anti-amyloid agent.Methods: Retrospective analysis was undertaken of patients with positive AD-biomarker CSF analysis. Data available at time of CSF analysis was reviewed to determine hypothetical eligibility for Aducanumab.Results: Seventy patients had positive AD-CSF biomarkers. Forty nine of these were seen in the Gerontology-led service, with 21 in the neurology cohort. Average patient age was 70 years old. Forty patients (57%) met eligibility criteria for Aducanumab therapy by AUC guidelines.Conclusion: We highlight the patients within our service who would be appropriate for Aducanumab or similar anti-amyloid agents should licencing be granted in the European Union, and the need to develop the resources and capacity to deliver this or other emerging disease modifying AD therapies.Clinical Trial Registration: All patients in the combined cognitive clinic provide consent re willingness to be contacted re research. [ABSTRACT FROM AUTHOR]

Background: The Medicare Advantage (MA) program is rapidly growing. Limited evidence exists about the care experiences of MA beneficiaries with Alzheimer's Disease and Related Dementia (ADRD). Our objective was to compare care experiences for MA beneficiaries with and without ADRD. Methods: We examined MA beneficiaries who completed the Medicare Advantage Consumer Assessment of Healthcare Providers and Systems (CAHPS) and used inpatient, nursing home, or home health services in the past 3 years. We classified beneficiaries with ADRD using the presence of diagnosis codes in hospitals, nursing homes, and home health records. Our key measures included overall ratings of care and health plan, and indices of receiving timely care, care coordination, receiving needed care, and customer service. We compared differences between beneficiaries with and without ADRD using regression analysis adjusting for demographic, health, and plan characteristics, and stratifying by proxy response status. Results: Among beneficiaries sampled by CAHPS, 22.2% with ADRD completed the survey compared to 38.5% without ADRD. Among proxy responses, beneficiaries with ADRD were 4.2 (95% CI: 0.1–8.4) percentage points less likely to report a high score for receiving needed care, and 3.5 percentage points (95% CI: 0.2–6.9) less likely to report a high score for customer service. Among non‐proxy responses, those with ADRD were 9.0 (95% CI: 5.5–12.5) percentage points less likely to report a high score for needed care, and 8.5 (95% CI: 5.4–11.5) percentage points less likely to report a high score for customer service. Conclusions: ADRD respondents to the CAHPS were more likely to be excluded from CAHPS performance measures because they did not meet eligibility requirements and rates of non‐response were higher. Among responders with or without a proxy, MA enrollees with an ADRD diagnosis reported worse care experiences in receiving needed care and in customer service than those without an ADRD diagnosis. [ABSTRACT FROM AUTHOR]