Profiles of Lifestyle Health Behaviors and Postmortem Dementia-Related Neuropathology.

High engagement in lifestyle health behaviors appears to be protective against cognitive decline in aging. We investigated the association between patterns of modifiable lifestyle health behaviors and common brain neuropathologies of dementia as a possible mechanism. We examined 555 decedents from the Rush Memory and Aging Project, free of dementia at their initial concurrent report of lifestyle health behaviors of interest (physical, social, and cognitive activities, and healthy diet), and who underwent a postmortem neuropathology evaluation. First, we used latent profile analysis to group participants based on baseline behavior patterns. Second, we assessed the associations of profile membership with each neurodegenerative (global Alzheimer's disease [AD] pathology, amyloid-beta load, density of neurofibrillary tangles, and presence of cortical Lewy bodies and TAR DNA-binding protein 43 cytoplasmic inclusions) and neurovascular pathologies (presence of chronic gross or microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), using separate linear or logistic regression models, adjusted for age at death, sex (core model), vascular disease risk factors, and vascular conditions (fully adjusted model). Participants had either consistently lower (N = 224) or consistently higher (N = 331) engagement across 4 lifestyle health behaviors. We generally found no differences in neuropathologies between higher and lower engagement groups in core or fully adjusted models; for example, higher engagement in lifestyle health behaviors was not associated with global AD pathology after core or full adjustment (both p > .8). In conclusion, we found no evidence of associations between patterns of lifestyle health behaviors and neuropathology. Other mechanisms may underlie protective effects of health behaviors against dementia.

Associations of Serum Insulin and Related Measures With Neuropathology and Cognition in Older Persons With and Without Diabetes.

OBJECTIVE: To examine associations of serum insulin and related measures with neuropathology and cognition in older persons. METHODS: We studied 192 older persons (96 with diabetes and 96 without, matched by sex and balanced by age-at-death, education, and postmortem interval) from a community-based, clinical-pathologic study of aging, with annual evaluations including neuropsychological testing (summarized into global cognition and 5 cognitive domains) and postmortem autopsy. We assessed serum insulin, glucose, leptin, adiponectin, hemoglobin A1C, advanced glycation-end products (AGEs), and receptors for advanced glycation-end products, and calculated the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and adiponectin-to-leptin ratio. Using adjusted regression analyses, we examined the associations of serum measures with neuropathology of cerebrovascular disease and Alzheimer's disease, and with the level of cognition proximate-to-death. RESULTS: Higher HOMA-IR was associated with the presence of brain infarcts and specifically microinfarcts, and higher HOMA-IR and leptin were each associated with subcortical infarcts. Further, higher leptin levels and lower adiponectin-to-leptin ratios were associated with the presence of moderate-to-severe atherosclerosis. Serum insulin and related measures were not associated with the level of Alzheimer's disease pathology, as assessed by global, as well as amyloid burden or tau tangle density scores. Regarding cognitive outcomes, higher insulin and leptin levels, and lower adiponectin and receptors for advanced glycation-end products levels, respectively, were each associated with lower levels of global cognition. INTERPRETATION: Peripheral insulin resistance indicated by HOMA-IR and related serum measures was associated with a greater burden of cerebrovascular neuropathology and lower cognition. ANN NEUROL 2024;95:665-676.

Profiles of lifestyle health behaviors and cognitive decline in older adults.

INTRODUCTION: We aimed to identify profiles of modifiable, late-life lifestyle health behaviors related to subsequent maintenance of cognition and explore sociodemographics and health characteristics as effect modifiers. METHODS: Analyses used data from 715 older adults without baseline dementia from the Rush Memory and Aging Project and with lifestyle health behaviors (physical activity, cognitive activity, healthy diet, social activity) at baseline and ≥ 2 annual assessments of cognition. We used latent profile analysis to group participants based on behavior patterns and assessed change in cognition by group. RESULTS: Three latent profiles were identified: high (n = 183), moderate (n = 441), and low (n = 91) engagement in health behaviors. Compared to high engagement, the moderate (mean difference [MD] = -0.02, 95% CI = [-0.03;-0.0002], p = 0.048) and low (MD = -0.06, 95% CI = [-0.08;-0.03], p < 0.0001) groups had faster annual rates of decline in global cognition, with no significant effects modifiers (vascular risk factors, apolipoprotein E [APOE] ε4, motor function). DISCUSSION: Avoiding low levels of lifestyle health behaviors may help maintain cognition. HIGHLIGHTS: Latent profile analysis (LPA) captures lifestyle health behaviors associated with cognitive function. Such behavior include physical activity, cognitive activity, healthy diet, social activity. We used LPA to examine associations of behaviors and cognitive function over time. Older adults with low lifestyle health behaviors showed more rapid decline. To a lesser degree, so did those with moderate lifestyle health behaviors. Vascular conditions and risks, APOEε4, or motor function did not modify the effect.

Metformin, age-related cognitive decline, and brain pathology.

The objective of this study was to evaluate the relation of metformin with change in cognition and brain pathology. During a mean of 8 years (SD = 5.5) of annual follow-up visits, 262/3029 participants were using metformin at any time during the study. Using a linear-mixed effect model adjusted for age, sex, and education, metformin users had slower decline on a score of global cognition compared to non-users (estimate = 0.017, SE = 0.007, p = 0.027). Analyses of cognitive domains showed a slower decline in episodic memory and semantic memory specifically. In sensitivity analysis, when examining any diabetes medication use vs none, no association was observed of any diabetes medication use with cognitive function. In the autopsy subset of 1584 participants, there was no difference in the level of Alzheimer's disease (AD) pathology or the presence of infarcts (of any size or location) between groups of metformin users vs non-users. However, in additional analyses, metformin users had higher odds of subcortical infarcts, and lower odds of atherosclerosis and arteriosclerosis.

Brain Insulin Signaling is Associated with Late-Life Cognitive Decline.

Type-2 diabetes is associated with an increased risk of dementia, and the underlying mechanism might involve abnormal insulin signaling in the brain. The objective of this study was to examine the association of postmortem brain insulin signaling with late-life cognitive decline. Among participants of Religious Orders Study, a community-based clinical-pathological cohort, 150 deceased and autopsied older individuals (75 with diabetes matched to 75 without by age at death, sex, and education) had postmortem brain insulin signaling measurements collected in the prefrontal cortex using ELISA and immunohistochemistry. By using adjusted linear mixed-effects models, we examined the association of postmortem brain insulin signaling with late-life cognitive function assessed longitudinally (mean follow-up duration = 9.4 years) using a battery of neuropsychological tests. We found that a higher level of serine/threonine-protein kinase (AKT) phosphorylation (pT308AKT1/total AKT1) was associated with a faster decline in global cognition (estimate = -0.023, p = 0.030), and three domains: episodic memory (estimate = -0.024, p = 0.032), working memory (estimate = -0.018, p = 0.012), and visuospatial abilities (estimate = -0.013, p = 0.027). The level of insulin receptor substrate-1 (IRS1) phosphorylation (pS307IRS1/total IRS1) was not associated with decline in global cognition or most cognitive domains, except for perceptual speed (estimate = 0.020, p = 0.020). The density of pS616IRS1-stained cells was not associated with decline in global cognition or any of the domains. In conclusion, these findings provide novel evidence for an association between brain insulin signaling and late-life cognitive decline. AKT phosphorylation is associated with a decline in global cognition and memory in particular, whereas IRS1 phosphorylation is associated with a decline in perceptual speed.

Applying Customer Discovery Method to a Chronic Disease Self-Management Mobile App: Qualitative Study.

BACKGROUND: A significant health challenge is evident in the United States, with 6 in 10 adults having a chronic disease and 4 in 10 adults having 2 or more. Chronic disease self-management aims to prevent or delay disease progression and disability and reduce mortality risk. The evidence to support the use of information technology tools, including mobile apps, web-based portals, and web-based educational interventions, that support disease self-management and improve clinical outcomes is growing. Customer discovery and value proposition design methodology is a form of stakeholder engagement and is based on marketing and lean start-up business methods. As applied in health care, customer discovery and value proposition methodology can be used to understand the clinical problem and articulate the product's hypothesized unique value proposition relative to alternative options that are available to end users. OBJECTIVE: This study aims to describe the experience and findings of academic researchers applying the customer discovery and value proposition methodology to identify stakeholders, needs, adaptability, and sustainability of a chronic disease self-management mobile app (CDapp). The motivation of the work is to make mobile health app interventions accessible and acceptable for all segments of patients' chronic diseases. METHODS: Data were obtained through key informant interviews and analyzed using rapid qualitative analysis techniques. The value proposition framework was used to build the interview guide. The aim was to identify the needs, challenges (pains), and potential benefits (gains) of the CDapp for our stakeholders. RESULTS: Our results showed that the primary consumers (end users) of a CDapp were the patients. The app adopters (decision makers) can be medical center leaders including population health department managers or insurance providers, while the consumer adoption influencers (influencers or saboteurs) are clinicians and patient caregivers. We developed an ecosystem map to visualize the clinical practice workflow and how an app for chronic disease management might integrate within an academic health care center or system. A value proposition for the identified customer segments was generated. Each stakeholder segment was working within a different framework to improve patient self-management. Patients needed help to adhere to self-care activities and they needed tailored health education. Health care leaders aim to improve the quality of care while reducing costs and workload. Clinicians wanted to improve patient education and care while reducing the time burden. Our results also showed that within academic medical centers, there were variations regarding patients' self-reported abilities to manage their diseases. CONCLUSIONS: Customer discovery is a useful form of stakeholder engagement when designing studies that seek to implement, adapt, and sustain an intervention. The customer discovery and value proposition methodology can be used as an alternative or complementary approach to formative research to generate valuable information in a brief period.

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer's disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.

The MIND diet, brain transcriptomic alterations, and dementia.

Identifying novel mechanisms underlying dementia is critical to improving prevention and treatment. As an approach to mechanistic discovery, we investigated whether MIND diet (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), a consistent risk factor for dementia, is correlated with a specific profile of cortical gene expression, and whether such a transcriptomic profile is associated with dementia, in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). RNA sequencing (RNA-Seq) was conducted in postmortem dorsolateral prefrontal cortex tissue from 1,204 deceased participants; neuropsychological assessments were performed annually prior to death. In a subset of 482 participants, diet was assessed ~6 years before death using a validated food-frequency questionnaire; in these participants, using elastic net regression, we identified a transcriptomic profile, consisting of 50 genes, significantly correlated with MIND diet score (P=0.001). In multivariable analysis of the remaining 722 individuals, higher transcriptomic score of MIND diet was associated with slower annual rate of decline in global cognition (ß=0.011 per standard deviation increment in transcriptomic profile score, P=0.003) and lower odds of dementia (odds ratio [OR] =0.76, P=0.0002). Cortical expression of several genes appeared to mediate the association between MIND diet and dementia, including TCIM, whose expression in inhibitory neurons and oligodendrocytes was associated with dementia in a subset of 424 individuals with single-nuclei RNA-seq data. In a secondary Mendelian randomization analysis, genetically predicted transcriptomic profile score was associated with dementia (OR=0.93, P=0.04). Our study suggests that associations between diet and cognitive health may involve brain molecular alterations at the transcriptomic level. Investigating brain molecular alterations related to diet may inform the identification of novel pathways underlying dementia.

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

Overcoming Pandemic-Related Challenges in Recruitment and Screening: Strategies and Representation of Older Women With Cardiovascular Disease for a Multidomain Lifestyle Trial to Prevent Cognitive Decline.

BACKGROUND: Recruiting participants with cardiovascular disease into research during the COVID-19 pandemic was challenging, particularly those at risk of health disparities. OBJECTIVE: During the pandemic, 12 cohorts of older women with cardiovascular disease were recruited from cardiology clinics into a lifestyle intervention trial to prevent cognitive decline. Objectives were to (a) describe the results of modified recruitment/screening strategies to overcome pandemic-related challenges and (b) evaluate differences in age, race, and ethnicity between patients recruited/randomized, recruited/not randomized (entered recruitment but not randomized because of being ineligible or not interested), and not recruited (clinic patients who met preliminary criteria but did not enter recruitment). METHODS: This was a cross-sectional descriptive analysis. In-person study strategies proposed before the COVID-19 pandemic were modified before study onset (September 2020). Women 65 years or older with cardiovascular disease were recruited from cardiology clinics by clinicians, posted flyers, and letters mailed to patients randomly selected from electronic health record data extractions. Patients were classified as recruited/randomized, recruited/not randomized, and not recruited. RESULTS: Of 5719 patients potentially eligible, 1689 patients entered recruitment via referral (49.1%), posted flyers (0.5%), or mailed letters (50.3%), and 253 patients were successfully recruited/randomized. Recruited/randomized participants were, on average, 72.4 years old (range, 65-90 years old), non-Hispanic White (54.2%), non-Hispanic Black (38.3%), Hispanic/Latinx (1.6%), and other/not reported (5.1%). The recruited/randomized group was significantly younger with fewer patients of Hispanic/Latinx ethnicity compared with those not recruited. CONCLUSIONS: During the pandemic, all recruitment/screening goals were met using modified strategies. Differences in sociodemographic representation indicate a need for tailored strategies.

Genome-Wide Mapping Implicates 5-Hydroxymethylcytosines in Diabetes Mellitus and Alzheimer's Disease.

BACKGROUND: Diabetes mellitus (DM) is a recognized risk factor for dementia. Because DM is a potentially modifiable condition, greater understanding of the mechanisms linking DM to the clinical expression of Alzheimer's disease dementia may provide insights into much needed dementia therapeutics. OBJECTIVE: In this feasibility study, we investigated DM as a dementia risk factor by examining genome-wide distributions of the epigenetic DNA modification 5-hydroxymethylcytosine (5hmC). METHODS: We obtained biologic samples from the Rush Memory and Aging Project and used the highly sensitive 5hmC-Seal technique to perform genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) from antemortem serum samples and in genomic DNA from postmortem prefrontal cortex brain tissue from 80 individuals across four groups: Alzheimer's disease neuropathologically defined (AD), DM clinically defined, AD with DM, and individuals with neither disease (controls). RESULTS: Distinct 5hmC signatures and biological pathways were enriched in persons with both AD and DM versus AD alone, DM alone, or controls, including genes inhibited by EGFR signaling in oligodendroglia and those activated by constitutive RHOA. We also demonstrate the potential diagnostic value of 5hmC profiling in circulating cfDNA. Specifically, an 11-gene weighted model distinguished AD from non-AD/non-DM controls (AUC = 91.8%; 95% CI, 82.9-100.0%), while a 4-gene model distinguished DM-associated AD from AD alone (AUC = 87.9%; 95% CI, 77.5-98.3%). CONCLUSION: We demonstrate in this small sample, the feasibility of detecting and characterizing 5hmC in DM-associated AD and of using 5hmC information contained in circulating cfDNA to detect AD in high-risk individuals, such as those with diabetes.

Insulin resistance, cognition, and Alzheimer disease.

Chronic diseases of aging are increasingly common. Dementia, often due to multiple etiologies including Alzheimer disease (AD), is at the forefront. Previous studies have reported higher rates of dementia among persons with diabetes, yet less is known about how insulin resistance relates to cognition. This article reviews recently published data on the relationship of insulin resistance to cognition and AD, and remaining knowledge gaps in the field are discussed. A structured review of studies was conducted over a 5-year period, investigating insulin and cognitive function in adults with a baseline mean age of ≥65 years. This search yielded 146 articles, of which 26 met the predetermined inclusion and exclusion criteria. Among the nine studies that specifically examined insulin resistance and cognitive dysfunction and/or decline, eight studies suggest an association, but some only in subanalyses. Results are mixed in studies relating insulin to structural and functional changes on brain imaging, and data on intranasal insulin for cognition remain unclear. Future avenues are proposed to elucidate the impact of insulin resistance on brain structure and function, including cognition, in persons with and without AD.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.

BACKGROUND: The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD. METHODS: L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS). FINDINGS: Relative to total blood acylcarnitines, levels of short chain acylcarnitines (SCAs) were higher whereas long chain acylcarnitines (LCAs) were lower in AD, which was observed pre-clinically in APOE ε4s. Plasma medium chain acylcarnitines (MCAs) were higher amongst cognitively healthy APOE ε2 carriers relative to other genotypes. Compared to their respective controls, elevated TMAO and lower L-carnitine and GBB were associated with AD clinical diagnosis and these differences were detected preclinically among APOE ε4 carriers. Plasma and brain GBB, TMAO, and acylcarnitines were also associated with post-mortem brain amyloid, tau, and cerebrovascular pathologies. INTERPRETATION: Alterations in blood L-carnitine, GBB, TMAO, and acylcarnitines occur early in clinical AD progression and are influenced by APOE genotype. These changes correlate with post-mortem brain AD and cerebrovascular pathologies. Additional studies are required to better understand the role of the FAO disturbances in AD.

Early incident and subsyndromal delirium in older patients undergoing elective surgical procedures: a randomized clinical trial of an avoid delirium protocol.

Background: Pharmacological avoidance guidelines for preventing delirium have been suggested; however, there are limited pragmatic studies of these strategies. Early (<24 h) delirium can be observed in the postoperative care unit and is associated with an increased risk of subsequent delirium. We examined the effectiveness of an avoid delirium protocol (ADP) in older (>65 years) patients undergoing elective surgeries. Methods: The randomized controlled trial assessed an ADP developed using the American Geriatric Society's Clinical Practice Guidelines for Postoperative Delirium in Older Adults, on early (<24 h) incident or subsyndromal delirium. Delirium was assessed using the confusion assessment method before surgery, in the post-anesthesia care unit, and on postoperative day 1. The primary outcome of early delirium was the combined incidence of incident or subsyndromal delirium. Results: Early delirium was identified in 24/235 patients (10.2%) with a risk ratio of 1.27 (95% CI 0.59-2.73, P = 0.667) for patients randomized to the ADP. In cases with protocol adherence and no benzodiazepine use, early delirium was present in 10/ 73 (13.7%) compared to 14/148 (9.5%) in non-adherent cases [risk ratio 1.45 (95% CI 0.57-3.10, P = 0.362)]. Lower American Society of Anesthesiologists physical class [odds ratio 3.31 (95% CI 1.35-8.92, P = 0.008)] and an inpatient admission [odds ratio 2.67 (95% CI 1.55-4.87, P = 0.0002)] were associated with early delirium. Conclusions: Our findings suggest that pharmacological avoidance protocols limiting or avoiding the use of specific classes of medications are not effective in reducing early incident or subsyndromal delirium in older patients undergoing elective surgery.

Eicosanoid lipidome activation in post-mortem brain tissues of individuals with APOE4 and Alzheimer's dementia.

BACKGROUND: Chronic neuroinflammation is one of the hallmarks of late-onset Alzheimer's disease (AD) dementia pathogenesis. Carrying the apolipoprotein ε4 (APOE4) allele has been associated with an accentuated response to brain inflammation and increases the risk of AD dementia progression. Among inflammation signaling pathways, aberrant eicosanoid activation plays a prominent role in neurodegeneration. METHODS: Using brains from the Religious Order Study (ROS), this study compared measures of brain eicosanoid lipidome in older persons with AD dementia to age-matched controls with no cognitive impairment (NCI), stratified by APOE genotype. RESULTS: Lipidomic analysis of the dorsolateral prefrontal cortex demonstrated lower levels of omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and DHA-derived neuroprotectin D1 (NPD-1) in persons with AD dementia, all of which associated with lower measures of cognitive function. A significant interaction was observed between carrying the APOE4 allele and higher levels of both pro-inflammatory lipids and pro-resolving eicosanoid lipids on measures of cognitive performance and on neuritic plaque burden. Furthermore, analysis of lipid metabolism pathways implicated activation of calcium-dependent phospholipase A2 (cPLA2), 5-lipoxygenase (5-LOX), and soluble epoxide hydrolase (sEH) enzymes. CONCLUSION: These findings implicate activation of the eicosanoid lipidome in the chronic unresolved state of inflammation in AD dementia, which is increased in carriers of the APOE4 allele, and identify potential therapeutic targets for resolving this chronic inflammatory state.

Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. The relation between APOE4 genotype and cPLA2 activity is not known. METHODS: Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation, and activity in relation to measures of inflammation and oxidative stress. RESULTS: Greater cPLA2 phosphorylation, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of persons with AD dementia carrying APOE3/4 compared to APOE3/3. Higher phosphorylated p38 MAPK but not ERK1/2 was found in ApoE4 primary astrocytes and mouse brains than that in ApoE3. Greater cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

Regulation and Role of Neuron-Derived Hemoglobin in the Mouse Hippocampus.

Hemoglobin (Hb) is the oxygen transport protein in erythrocytes. In blood, Hb is a tetramer consisting of two Hb-alpha (Hb-α) chains and two Hb-beta (Hb-ß) chains. A number of studies have also shown that Hb-α is also expressed in neurons in both the rodent and human brain. In the current study, we examined for age-related regulation of neuronal Hb-α and hypoxia in the hippocampus and cerebral cortex of intact male and female mice. In addition, to confirm the role and functions of neuronal Hb-α, we also utilized lentivirus CRISPR interference-based Hb-α knockdown (Hb-α CRISPRi KD) in the non-ischemic and ischemic mouse hippocampus and examined the effect on neuronal oxygenation, as well as induction of hypoxia-inducible factor-1α (HIF-1α) and its downstream pro-apoptotic factors, PUMA and NOXA, and on neuronal survival and neurodegeneration. The results of the study revealed an age-related decrease in neuronal Hb-α levels and correlated increase in hypoxia in the hippocampus and cortex of intact male and female mice. Sex differences were observed with males having higher neuronal Hb-α levels than females in all brain regions at all ages. In vivo Hb-α CRISPRi KD in the mouse hippocampus resulted in increased hypoxia and elevated levels of HIF-1α, PUMA and NOXA in the non-ischemic and ischemic mouse hippocampus, effects that were correlated with a significant decrease in neuronal survival and increased neurodegeneration. As a whole, these findings indicate that neuronal Hb-α decreases with age in mice and has an important role in regulating neuronal oxygenation and neuroprotection.

Derivation and validation of the Rapid Assessment of Dementia Risk (RADaR) for older adults.

BACKGROUND: There is no practical dementia risk score in the clinical setting. OBJECTIVE: To derive and validate a score obtained by a rapid and simple assessment, which guides primary care providers in predicting the risk of dementia among older adults. DESIGN: A total of 4178 participants from three longitudinal cohorts (mean age at baseline = 76.8 [SD = 7.6] years), without baseline dementia, followed annually for a median of 10 years (IQR: 5 to16 years, Reverse Kaplan-Meier). PARTICIPANTS: To derive the score, we used data from 1,780 participants from the Rush Memory and Aging Project (93% White). To validate the score, we used data from 1,299 participants from the Religious Order Study (92% White), and to assess generalizability, 679 participants from the Minority Aging Research Study (100% Black). MEASUREMENTS: Clinician-based dementia diagnosis at any time after baseline and predictive variables associated with dementia risk that can be collected in a primary care setting: demographics, clinical indicators, medical history, memory complaints, cognitive and motor tests, and questions to assess functional disability, depressive symptoms, sleep, social isolation, and genetics (APOE e4 and AD polygenic risk score). RESULTS: At baseline, age, memory complaint, the ability to handle finances, the recall of the month, recall of the room, and recall of three words, were associated with the cumulative incidence of dementia, in the derivation cohort. The discrimination of the RADaR (Rapid Risk Assessment of Dementia) was good for the derivation and external-validation cohorts (AUC3 years = 0.82-0.86), compared to the overall discrimination of age alone (AUC3 years = 0.73), a major risk factor for dementia. Adding genetic data did not increase discrimination. LIMITATIONS: Participants were volunteers, may not represent the general population. CONCLUSIONS: The RADaR, derived from community-dwelling older persons, is a brief and valid tool to predict dementia risk at 3 years in older White and Black persons.