Risk Factor For Alzheimer's Disease Research Articles

Abstract TP395: Alzheimer's Disease model APP/PS1 mice exhibit motor deficits following 15-minute focal ischemia.

Introduction: Ischemic stroke is one of the leading causes of death in the United States and is a known risk factor for Alzheimer’s Disease (AD) development. One of the characterizations of AD is the accumulation of β-amyloid peptide due to the proteolysis of Amyloid Precursor Protein (APP) by the protein Presenilin 1 (PS1) among others. In APP/PS1 mice, which contain an additional human copy of APP and PS1, a 15-minute Middle Cerebral Artery Occlusion (MCAO) model was developed. Here we investigate the effects of increased β-amyloid peptide on motor coordination when subjected to local ischemia. Methods: APP/PS1or Wt male mice are initially subjected to either a 15-minute MCAO or Sham surgery. Injury volume using MRI is assessed at 3-days using T2 imaging. To test motor coordination the mice went through a tapered beam analysis at the 7-day time point. Following the tapered beam test, Cresyl Violet was used to stain brain slices. All mice were 8-12 weeks old at the time of surgery. Differences between groups were determined by Welch’s T-Test. Significance was determined as p < 0.05. Results: No significant difference in infarct volume was observed between the APP/PS1-MCAO and Wt-MCAO groups. In the hind legs, it was observed that there is a significant difference in the number of slips off the tapered beam in the APP/PS1-MCAO group when compared to the Wt-MCAO group (9.4 ± 3.356, n=7, p < 0.05 and 2.5 ± 0.289, n=4, p < 0.05 respectively). No significant difference was found in the Cresyl Violet staining. Conclusions: Our study shows motor deficit in the APP/PS1-MCAO experimental group when compared to the Wt-MCAO group as measured on hind-limb coordination. Therefore, further studies are warranted to assess the interaction between ischemia and β-amyloid peptide on histological injury and functional recovery.

APOE4 and sedentary lifestyle synergistically impair neurovascular function in the visual cortex of awake mice

Reduced cerebral blood flow occurs early in the development of Alzheimer’s disease (AD), but the factors producing this reduction are unknown. Here, we ask whether genetic and lifestyle risk factors for AD—the ε4 allele of the Apolipoprotein (APOE) gene, and physical activity—can together produce this reduction in cerebral blood flow which leads eventually to AD. Using in vivo two-photon microscopy and haemodynamic measures, we record neurovascular function from the visual cortex of physically active or sedentary mice expressing APOE3 and APOE4 in place of murine APOE. Energy supply and demand are mismatched in APOE4 mice, with smaller increases in cerebral blood flow, blood volume and blood oxygenation occurring during neuronal activation as blood vessels frequently fail to dilate. Exercise dose-dependently overall improves neurovascular function, with an increased impact of exercise apparent after longer exposure times. Several haemodynamic measures show a larger beneficial effect of exercise in APOE4 vs. APOE3 mice. Thus, APOE4 genotype in conjunction with sedentary behaviour produces the worst neurovascular function. Promotion of physical activity may therefore be particularly important to improve cerebrovascular function and reduce dementia risk in APOE4 carriers.

HELICOBACTER PYLORI ERADICATION TREATMENTS AND RISK OF ALZHEIMER DISEASE: A CASE-CONTROL STUDY NESTED IN THE FINNISH POPULATION.

Helicobacter pylori (H. pylori) has been inconsistently associated with risk of Alzheimer disease. The exposure assessment period has often overlapped with the prodromal time of Alzheimer disease. Cognitive disorders might increase vulnerability to infectious pathogens, complicating the ascertainment of temporal relationship between H. pylori infection and Alzheimer disease. This Finnish nested case-control study included 70,520 persons with incident Alzheimer disease diagnosed between 2005-2011 and 281,233 age-, sex-, and region of residence-matched controls. We obtained information on comorbidities and drug use from the national healthcare registers. We identified dispensed H. pylori eradication treatments from the Prescription register. We considered exposure at least 5 years before Alzheimer disease diagnosis in the main analysis. We compared risk of Alzheimer disease between H. pylori eradication treatment users and nonusers using confounder-adjusted (comorbidities and other drug use) conditional logistic regression. We assessed cumulative exposure by calculating the number of eradication treatments. The prevalence of exposure to H. pylori eradication treatment at least 5 years before the outcome was 4.1% in cases and 3.9% in controls. The odds ratio (95% confidence interval) was 1.06 (1.02-1.11) in the crude and 1.03 (0.99-1.07) in the confounder-adjusted model. We observed no association between cumulative exposure and risk of Alzheimer disease. Our results, reflecting diagnosed and treated H. pylori infection late in life, do not support the hypothesis of H. pylori as an independent risk factor for Alzheimer disease. The previously reported association may be explained by reverse association and confounding.

Harmony in Motion: The Role of Exercise in Orchestrating Neuroprotection for Individuals with Alzheimer's Disease and Diabetes Examined from a Psychological Perspective.

According to epidemiological studies, diabetes is more common in patients with AD, which suggests that diabetes is a significant risk factor for AD. Accelerating brain cell degeneration, worsening cognitive decline, and increasing susceptibility to AD can be attributed to pathogenic mechanisms linked to diabetes, such as impaired insulin signaling in the brain, neuroinflammation, oxidative stress, mitochondrial dysfunction, and vascular impairment. These factors can also lead to the accumulation of β-amyloid and tau protein phosphorylation. New research suggests that certain drugs used to manage diabetes have different levels of effectiveness in treating or preventing Alzheimer's disease. Exercise has numerous advantages, including the reduction of neuroinflammation, alleviation of oxidative stress and mitochondrial dysfunction, improvement of endothelial and cerebrovascular function, stimulation of neurogenesis, and prevention of pathological changes associated with diabetes-related Alzheimer's disease through various internal mechanisms. This study examined the development of Alzheimer's disease (AD) in relation to diabetes, evaluated the ability of specific antidiabetic drugs to prevent and treat AD, and investigated the impacts and underlying processes of exercise interventions in improving AD treatment for individuals with diabetes.

The biological intersection between chemotherapy-related cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with AD patients, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment (CRCI). This Review discusses biologically plausible pathways underlying both disorders, with the goal of understanding why a proportion of chemotherapy patients may be at higher risk of developing AD. Highlighted are the E4 allele of the apolipoprotein E gene, neuroinflammation, oxidative stress, DNA damage, mitochondrial dysfunction, neuronal and synaptic loss, cellular senescence, brain-derived neurotrophic factor signaling, white matter damage, blood-brain barrier/vascular dysfunction, tau pathology, and transposable element reactivation.

ALZHEIMER'S DISEASE: COMPREHENSIVE INSIGHTS INTO RISK FACTORS, BIOMARKERS, AND ADVANCED TREATMENT APPROACHES

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder primarily affecting individuals over 60. It is a multifactorial disease driven by both modifiable factors, such as lifestyle, diet, and prior health conditions, as well as non-modifiable factors, like age, genetics, and family history. The key pathological features of AD include the buildup of amyloid β plaques and neurofibrillary tangles resulting from hyperphosphorylated tau proteins in the brain. Biomarkers like amyloid β and tau protein levels in cerebrospinal fluid (CSF) and blood are essential for diagnosing and tracking AD progression. Current research focuses on developing drugs targeting multiple aspects of AD pathology, including inflammation, oxidative stress, synaptic dysfunction, and protein accumulation. These treatments aim to slow cognitive decline and neuronal damage. Given the complexity of AD, multi-targeted therapeutic approaches are being explored to enhance treatment efficacy. This review provides an overview of AD risk factors, key biomarkers used for diagnosis, and the latest advances in clinical drug development.

Lower slow wave sleep and rapid eye-movement sleep are associated with brain atrophy of AD-vulnerable regions.

Sleep deficiency is associated with Alzheimer's disease (AD) pathogenesis. We examined the association of sleep architecture with anatomical features observed in AD: (1) atrophy of hippocampus, entorhinal, inferior parietal, parahippocampal, precuneus, and cuneus regions ("AD-vulnerable regions") and (2) cerebral microbleeds. In 271 participants of the Atherosclerosis Risk in the Communities Study, we examined the association of baseline sleep architecture with anatomical features identified on brain MRI 13~17 years later. Sleep architecture was quantified as the proportion of slow wave sleep (SWS), proportion of rapid eye-movement sleep (REM), and arousals index using polysomnography. Outcomes included (1) volumetric measurements of each AD-vulnerable region and (2) the presence of any cerebral microbleeds (CMBs) and that of lobar CMBs, which are more specifically associated with AD. We analyzed the association of each sleep predictor with each MRI outcome, adjusting for covariates. Having less SWS was associated with smaller inferior parietal region (β=-44.19 mm3 [95%CI=76.63, -11.76]) and cuneus (β=-11.99 mm3 [-20.93, -3.04]) after covariate adjustment. Having less REM was associated with smaller inferior parietal region (β=-75.52 mm3 [-129.34, -21.70]) and precuneus (β=-31.93 mm3 [-63.79, -0.07]). After FDR adjustments, lower SWS and REM, respectively, were associated with smaller inferior parietal region. Arousal index was not associated with the volumes of AD-vulnerable regions. None of the sleep architecture variables were associated with CMBs or lobar CMBs. Sleep deficiency is associated with the atrophy of the inferior parietal region, which is observed in early AD. Sleep architecture may be a modifiable risk factor for AD.

Effect of genetic and vascular risk factors on rates of cognitive decline in early-onset and late-onset Alzheimer's disease.

Although previous studies have shown that cognitive decline in Alzheimer's disease (AD) is associated with various risk factors, they primarily focused on late-onset AD (LOAD). We aim to evaluate the differential impact of risk factors on the cognitive decline between early-onset AD (EOAD, onset < 65 years) and LOAD (onset 65 years) and explore the longitudinal effect of Apolipoprotein E allele 4 (APOE ε4) on cortical atrophy in both cohorts. Using data from 212 EOAD and 1101 LOAD participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), we conducted multivariable mixed-effect models to evaluate the impact of APOE ε4, education, hypertension, diabetes, dyslipidemia, and body mass index on cognitive performance. Preprocessed MRI data were utilized for longitudinal parametric mapping. APOE ε4 carriers in both groups showed significantly accelerated declines in language, verbal memory, executive function, and general cognition. By controlling other significant risk factors, APOE ε4 carriers showed faster declines in language and verbal memory in both groups. Females exhibited accelerated declines in Language and verbal memory in the EOAD and LOAD cohorts respectively. LOAD individuals with hypertension showed faster declines while overweight and obese participants displayed slower declines in both cohorts across all domains except visuospatial. Notably, APOE ε4 status was associated with longitudinal cortical atrophy in the LOAD cohort but not in the EOAD cohort. Known risk factors for AD were associated with cognitive decline in both EOAD and LOAD cohorts.

Menopausal hormone therapy is associated with worse levels of Alzheimer's disease biomarkers in APOE ε4-carrying women: An observational study.

Menopausal hormone therapy (MHT), along with the apolipoprotein E (APOE) ε4 allele, has been suggested as a possible risk factor for Alzheimer's disease (AD). However, the relationship between MHT and cerebrospinal fluid (CSF) biomarkers is unknown: we investigated this association, and whether APOE ε4 carrier status moderates it. In an observational study of 136 cognitively unimpaired female participants (Mage=66.0; standard deviation=6.3), we examined whether MHT use alone or in interaction with APOE ε4 carrier status was associated with CSF levels of phosphorylated tau (p-tau), amyloid beta (Aβ)40, Aβ42, p-tau/Aβ42, and Aβ42/40 ratios. Significant interactions were found between APOE ε4 and MHT use for CSF biomarkers. APOE ε4 carriers who were MHT users showed worse levels of CSF p-tau/Aβ42 and Aβ42/40 ratios than all other users and non-users. The presence of both APOE ε4 and MHT may be associated with elevated amyloid deposition and AD pathology in this sample of participants who demonstrated high familial AD risk. Significant interactions were found between apolipoprotein E (APOE) ε4 and menopausal hormone therapy (MHT) use for cerebrospinal fluid (CSF) phosphorylated tau (p-tau)/amyloid beta (Aβ)42 and Aβ42/40 ratios. APOE ε4 carriers who were MHT users showed worse levels of CSF biomarkers than non-users and non-carriers, both users and non-users. Younger age at MHT initiation was associated with worse levels of the p-tau/Aβ42 and Aβ42/40 ratios in carriers only. The presence of both APOE ε4 carriage and MHT use may be associated with elevated amyloid deposition and AD pathology. Further studies with larger sample sizes are necessary to confirm the differences observed in the current study.

Identification of risk factors and development of a predictive nomogram for sarcopenia in Alzheimer's disease.

Sarcopenia, with its complex diagnostic process, is a likely independent predictor of poor prognosis in patients with Alzheimer's disease (AD). However, research on the clinical characteristics and biomarkers of AD patients with sarcopenia (ADSA) is limited. This study included 180 ADSA and 188 AD patients without sarcopenia (ADNSA), and evaluated demographics, cognitive function, motor capacity, emotional state, and daily living abilities. ADSA patients were older, with worse motor and cognitive functions, more severe depression, poorer social functioning, and lower daily living abilities compared to ADNSA patients. Multivariate regression identified age, low Frailty Rating Scale (FRS) scores, low serum albumin level, and low creatinine/cystatin C ratio (CCR) as risk factors for sarcopenia. A nomogram model based on these indicators demonstrated high discriminative power and clinical utility. Sarcopenia significantly affects AD patients' various functions. The nomogram model aids in the early detection of and personalized interventions for sarcopenia in AD. Sarcopenia is a risk factor for Alzheimer's disease (AD), and the coexistence of sarcopenia affects various functions and quality of life in patients with AD. Serum albumin and Frailty Rating Scale (FRS) scores are significantly associated with both sarcopenia and cognitive assessment indicators in AD patients with sarcopenia (ADSA). The combined sarcopenia nomogram model with indexes of age at diagnosis, creatinine/cystatin C ratio (CCR), FRS score, and albumin levels can aid in effectively identifying and personalizing interventions for sarcopenia in the AD population.

APOE4 and infectious diseases jointly contribute to brain glucose hypometabolism, a biomarker of Alzheimer's pathology: New findings from the ADNI.

Impaired brain glucose metabolism is a preclinical feature of neurodegenerative diseases such as Alzheimer's disease (AD). Infections may promote AD-related pathology. Therefore, we investigated the interplay between infections and APOE4, a strong genetic risk factor for AD. We analyzed data on 1,509 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database using multivariate linear regression models. The outcomes were rank-normalized hypometabolic convergence index (HCI), statistical regions of interest (SROI) for AD, and mild cognitive impairment (MCI). Marginal mean estimates for infections, stratified by APOE4 carrier status, were then computed. Prior infections were associated with greater HCI [β = 0.15, 95% CI: 0.03, 0.27, p = 0.01]. The combined effects of infections and APOE4 carriers on HCI levels were significantly greater than either variable alone. Among APOE4 carriers, the estimated marginal mean was 0.62, rising to 0.77, with infections (p<0.001), indicating an interaction effect. Carriers with multiple infections showed greater hypometabolism (higher HCI), with an estimate of 0.44 (p = 0.01) compared to 0.11 (p = 0.08) for those with a single infection, revealing a dose-response relationship. The estimates for the association of infections with SROI AD and SROI MCI were β = -0.01 (p = 0.02) and β = -0.01 (p = 0.04), respectively. Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development.

Cerebral perfusion alterations in healthy young adults due to two genetic risk factors of Alzheimer's disease: APOE and MAPT.

Functional brain changes such as altered cerebral blood flow occur long before the onset of clinical symptoms in Alzheimer's disease (AD) and other neurodegenerative disorders. While cerebral hypoperfusion occurs in established AD, middle-aged carriers of genetic risk factors for AD, including APOE ε4, display regional hyperperfusion due to hypothesised pleiotropic or compensatory effects, representing a possible early biomarker of AD and facilitating earlier AD diagnosis. However, it is not clear whether hyperperfusion already exists even earlier in life. Here, 160 young and cognitively healthy participants from the Chinese PREVENT cohort underwent 3 T arterial spin labelling and T1 MRI and genetic testing for APOE and MAPT rs242557 status. Using FSL, we performed a whole brain voxel-wise analysis and a global mean grey matter analysis comparing for the effects of both risk genes on cerebral perfusion. No significant alterations were seen for APOE genotype, but in MAPT rs242557 A carriers, we observed a significantly hyperperfusion in the left anterior cingulate cortex and left insular cortex. There were no effects of APOE or MAPT status on the global perfusion. These results are novel and may suggest that MAPT genotypes demonstrated a distinct hemodynamic profile in a very young age.

Exploring the Kidney-Brain Crosstalk: Biomarkers for Early Detection of Kidney Injury-Related Alzheimer's Disease.

The phenomenon of "kidney-brain crosstalk" has stimulated scholarly inquiry into the correlations between kidney injury (KI) and Alzheimer's disease (AD). Nonetheless, the precise interactions and shared mechanisms between KI and AD have yet to be fully investigated. The primary goal of this study was to investigate the link between KI and AD, with a specific focus on identifying diagnostic biomarkers for KI-related AD. The first step of the present study was to use Mendelian randomization (MR) analysis to investigate the link between KI and AD, followed by verification of in vivo and in vitro experiments. Subsequently, bioinformatics and machine learning techniques were used to identify biomarkers for KI-associated ferroptosis-related genes (FRGs) in AD, which were validated in following experiments. Moreover, the relationship between hub biomarkers and immune infiltration was assessed using CIBERSORT, and the potential drugs or small molecules associated with the core biomarkers were identified via the DGIdb database. MR analysis showed that KI may be a risk factor for AD. Experiments showed that the combination of D-galactose and aluminum chloride was found to induce both KI and AD, with ferroptosis emerging as a bridge to facilitate crosstalk between KI and AD. Besides, we identified EGFR and RELA have significant diagnostic value. These biomarkers are associated with NK_cells_resting and B_cells_memory and could be targeted for intervention in KI-related AD by treating gefitinib and plumbagin. Our study elucidates that ferroptosis may be an important pathway for kidney-brain crosstalk. Notably, gefitinib and plumbagin may be therapeutic candidates for intervening in KI-associated AD by targeting EGFR and RELA.

Association of mid-life cardiovascular risk with biomarkers of Alzheimer's disease, neurodegeneration, and white matter hyperintensities: Heart SCORE brain study

Background Atherosclerotic cardiovascular disease (ASCVD) risk factors in mid-life are associated with cognitive decline and late-life dementia. However, the role of these risk factors in Alzheimer's disease (AD) pathology remains elusive. Objective We investigated the association of mid-life 10-year ASCVD risk with late-life amyloid, tau, neurodegeneration [AT(N)] measures and white matter hyperintensities (WMHs). Methods Participants enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study between 2003–2005 (mid-life) and underwent brain MRI and PET scans in 2018–2022 (age &gt;65 years, late-life) to detect and quantify amyloid (A, PiB-PET) and tau (T, Flortaucipir (FTP) PET) deposition, cortical thickness (N) and WMHs. Mid-life ASCVD risk was categorized as; borderline (5%–7.4%), intermediate (7.5%-&lt;15%), or high (≥15%). Association of mid-life ASCVD risk HR (95% CI) was assessed using logistic and linear regressions with A, T, or N and chi square beta coefficients for WMH in late life. Results Over a ∼16 years follow up, in 135 participants (mean age 73 years), mid-life ASCVD risk categories had a graded association with neurodegeneration (ORASCVD high vs low risk% 6.98 [2.44–19.95]; p &lt; 0.05) driven primarily by self-identified Black race and age, while none with A and T. ASCVD risk score was also associated with WMHs ((β=0.42 ± 0.22; p = 0.05). Conclusions In this asymptomatic, diverse cohort, 10-year ASCVD risk was predictive of late-life neurodegeneration and WMHs but not amyloid or tau. Further mechanistic studies can elucidate whether midlife ASCVD risk factors associated neurodegeneration initiates brain vulnerability leading to AD in late life.

Transcriptomic analysis reveals suppression of steroidogenic acute regulatory protein in gender-specific differences in Alzheimer's disease.

Alzheimer's disease (AD)-related dementia preferentially impacts two-thirds of women and one-third of men. The steroidogenic acute regulatory (StAR) protein mediates the biosynthesis of neurosteroids that sustain diverse neuronal activities. Aging, involving neurosteroidal imbalance, is the predominant risk factor for AD causing dementia. Transcriptomic analysis, including clinical cognitive diagnosis (cogdx) stages, displays marked attenuation of StAR in brains of AD women than those of AD men, compared with cognitively normal (Non-AD) subjects. The present data provide the first evidence and new insights into the underly mechanisms exemplifying the suppression of StAR in gender-specific differences in AD.

TRAFFIC-RELATED AIR POLLUTION AND INFECTIONS JOINTLY INCREASE THE RISK OF ALZHEIMER’S DISEASE IN OLDER ADULTS

Abstract Accumulating evidence points to a potentially major role of vulnerability to infections in Alzheimer’s disease (AD) development, although the exact mechanism is not clear. AD is a multifactorial disorder, and the presence of other risk factors may exacerbate the impact of infections on AD. Here we investigated how the interplay between a history of infections and exposure to traffic-related air pollution (TRAP), another risk factor for AD that may influence the brain’s vulnerability to infections, affects the risks of AD and other dementias in UKB participants aged 60-75. Infectious diseases, AD, and other dementia diagnoses were based on ICD9/ICD10 codes. Chronic exposure to TRAP was approximated by closeness (50 meters or less) of participant’s primary residence to a major road. Chi-square, Wilson score interval, Wald interval, Wald risk ratio, and Welch tests, and regression were used to assess statistical significance. We found that the presence of both, a history of infections and exposure to TRAP in UKB participants aged 60-75, was associated with 177% higher risk of AD onset after the age of 75 (risk ratio, RR=2.77, 95% CI [1.86, 4.11]), compared to individuals of the same age who had no history of either of these factors. One mechanism could involve TRAP compromising the integrity of the blood-brain barrier (BBB), potentially increasing the brain’s vulnerability to infections and related damage. This, in turn, might contribute to the promotion of AD pathology.

EVALUATION OF AN ALZHEIMER’S DISEASE TRAINING FOR LATINX COMMUNITY HEALTH WORKERS

Abstract Despite an anticipated 800% increase in Alzheimer’s disease (AD) prevalence among U.S. Hispanic/Latinx by 2060, Hispanic/Latinx are persistently underrepresented in AD research, which is partly due to low participation in Alzheimer’s Disease Research Centers (ADRC). Community Health Workers (CHWs) are trusted community members and can serve as educators of AD and ADRC. This study evaluated changes in pre and post knowledge about AD and ADRC among CHWs serving Hispanic/Latinx after delivery of a culturally and linguistically appropriate AD training. The training covered AD prevalence and risk factors, AD preventive behaviors, knowledge about ADRC, and the importance of AD research. Pre/post assessment was conducted using non-matched, anonymous surveys; differences in pre/post measures (mean+SD) were estimated and analyzed using Wilcoxon-Mann-Whitney U tests. Participants (N=68) had a mean (SD) age of 40 (10.7) years, were majority female (87%), identified as Latinx (91%), born outside the U.S. (55%) and represented 21 Washington counties. There was a significant increase in knowledge of AD (pre: 2.16 + 1.25; post: 3.51 + 1.09; p&amp;lt; 0.001), AD signs and symptoms (pre: 2.04 + 1.25, post: 3.38 + 1.13; p&amp;lt; 0.001), and AD prevention (pre: 1.84 + 1.16, post: 3.46 + 1.19; p&amp;lt; 0.001) pre/post training. Similarly, there was significant increase in knowledge of the local ADRC (pre: 1.38 + 0.92, post: 3.27 + 1.48; p&amp;lt; 0.001), ADRC studies (pre: 1.63 + 1.11, post: 3.31 + 1.22; p&amp;lt; 0.001) and what ADRC participation entails (pre: 2.59 + 1.74, post: 4 + 1.17; p&amp;lt; 0.001) pre/post training. Culturally and linguistically concordant training for CHWs showed promise for increasing knowledge about AD and ADRC. Future research should explore how CHWs use training information to educate Hispanic/Latinx individuals about AD and ADRC.

SLEEP AND CORTISOL IMPACT COGNITIVE OUTCOMES IN MIDLIFE HISPANIC/LATINE ADULTS AT RISK FOR ALZHEIMER’S DISEASE

Abstract Sleep disturbance has been associated with an increased risk of Alzheimer’s disease (AD). Repeated stressors, including ongoing sleep disturbance, trigger persistent increases in glucocorticoid levels, which affect brain function. Various cognitive domains appear to be significantly impacted by sleep. This study examined the effect of sleep and cortisol levels on cognitive test outcomes. Hispanic/Latine adults (n=39; mean age 53 yrs (SD: 5.12)) with first-degree relatives with AD were recruited from Miami-Dade and Broward counties, FL. Cortisol was measured from saliva obtained three times in one day (waking, 30 minutes post-waking, and bedtime). Cognition was measured using the NACC Neuropsychological Battery (UDS3). Sleep was measured using wrist-worn actigraphy (ActiGraph wGT3X-BT). Multiple linear regression was performed to examine correlations between sleep, cognition, and cortisol. Average sleep duration was 6.40 (SD = 1.37) hours. Average efficiency was 92% (SD = 3%). Average sleep fragmentation was 27.79 (SD = 9.59) minutes post-sleep onset. Sleep efficiency was significantly associated with executive attention after adjusting for education and income (β = -18.73, p =.046). Sleep fragmentation was significantly associated with immediate memory (β = -.045, p =.0181). The effect of cortisol at waking on episodic memory delayed was dependent on sleep efficiency (β = 211.004, p =.031). The interaction between sleep duration and cortisol at bedtime was significantly associated with nonverbal memory (β =10.37, p =.023). The identification of modifiable risk factors for AD, including poor sleep and increased stress, will inform the development of intervention efforts to prevent or delay AD onset.

Unraveling APOE4's Role in Alzheimer's Disease: Pathologies and Therapeutic Strategies.

Alzheimer's disease (AD), the most common kind of dementia worldwide, is characterized by elevated levels of the amyloid-β (Aβ) peptide and hyperphosphorylated tau protein in the neurons. The complexity of AD makes the development of treatments infamously challenging. Apolipoprotein E (APOE) genes's ɛ4 allele is one of the main genetic risk factors for AD. While the APOE gene's ɛ4 allele considerably increases the chance of developing AD, the ɛ2 allele is protective compared to the prevalent ɛ3 variant. It is fiercely discussed how APOE affects the development and course of disease since it has a variety of activities that influence both neuronal and non-neuronal cells. ApoE4 contributes to the formation of tau tangles, deposition of Aβ, neuroinflammation, and other processes. Four decades of research have provided a significant understanding of the structure of APOE and how this may affect the neuropathology and pathogenesis of AD. APOE is a crucial lipid transporter essential for the growth of the central nervous system (CNS), upkeep, and repair. The mechanisms by which APOE contributes to the pathophysiology of AD are still up for discussion, though. Evidence suggests that APOE affects the brain's clearance and deposition of Aβ. Additionally, APOE has Aβ-independent pathways in AD, which has led to the identification of new functions for APOE, including mitochondrial dysfunction. This study summarizes important studies that describe how APOE4 affects well-known AD pathologies, including tau pathology, Aβ, neuroinflammation, and dysfunction of neural networks. This study also envisions some of the therapeutic approaches being used to target APOE4 in the hopes of preventing or treating AD.

Effects of Probucol on plasma amyloid-β transport in patients with hyperlipidemia: a 12-week randomized, double-blind, placebo-controlled trial

BackgroundAlthough dyslipidemia has been acknowledged as a risk factor for Alzheimer’s disease (AD), the effects of lipid-lowering drugs on AD have not been determined. The primary pathophysiological hallmark of AD is the deposition of amyloid-β (Aβ) plaques in the brain. Plasma Aβ levels are influenced by the transport of Aβ from the central nervous system to the peripheral blood. This study investigates the effects of Probucol, a lipid-lowering and antioxidant drug, on plasma Aβ transport.MethodsA total of 120 hyperlipidemic patients with normal cognition were randomly assigned (1:1 ratio) to receive either Probucol (1000 mg daily for 12 weeks) or a placebo. Plasma Aβ, soluble receptor of advanced glycation end products (sRAGE), and fasting lipid profiles were measured at baseline and every 6 weeks.ResultsA total of 108 participants completed the study, with 55 in the Probucol group. The cohort consisted of 58 (53.7%) women, with a mean age of 58.4 ± 8.0 (range, 45–80) years. After 12 weeks of treatment, the changes in plasma Aβ42 and sRAGE levels significantly differed between the Probucol and placebo groups (ΔAβ42: β = 6.827, P = 0.030; ΔsRAGE: β = 98.668, P = 0.004). Furthermore, ΔsRAGE was positively correlated with the change in Aβ42 (β = 0.018, P = 0.048). When adjusted for ΔsRAGE, the effect of Probucol on plasma Aβ42 levels was attenuated (β = 5.065, P = 0.116). In the Probucol group only, ΔsRAGE was significantly correlated with oxidized low-density lipoproteins (β = 4.27, P = 0.011), total cholesterol (β = 67.50, P = 0.046), and low-density lipoproteins (β = − 91.01, P = 0.011).ConclusionsDaily oral administration of Probucol (1000 mg) for 12 weeks significantly increased plasma Aβ42 levels, likely through modulation of sRAGE. This effect may be attributed to the antioxidant and lipid-lowering properties of Probucol. These findings suggest that Probucol could potentially serve as a protective agent against the pathological processes of AD.Trial registrationThis study was registered on the Chinese Clinical Trial Registry platform in June 2019 (Trial registration number: ChiCTR-1900023542).