ApoE Research Articles

Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: βMMSE = -0.055, 95% CI -0.067 to -0.043, βFCSRT = -0.034, 95% CI -0.043 to -0.025, βfluency = -0.029, 95% CI -0.038 to -0.020, βSPPB = -0.040, 95% CI -0.057 to -0.022, and β4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: βMMSE = -0.039, 95% CI -0.053 to -0.025, βFCSRT = -0.022, 95% CI -0.032 to -0.012, βfluency = -0.014, 95% CI -0.024 to -0.004, and β4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002-0.020, and β = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Single-value brain activity scores reflect both severity and risk across the Alzheimer's continuum.

Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD). To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype. Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel. Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.

Updated safety results from phase 3 lecanemab study in early Alzheimer’s disease

BackgroundAlzheimer disease (AD) is a major health problem of aging, with tremendous burden on healthcare systems, patients, and families globally. Lecanemab, an FDA-approved amyloid beta (Aβ)-directed antibody indicated for the treatment of early AD, binds with high affinity to soluble Aβ protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. Lecanemab has been shown to be well tolerated in multiple clinical trials, although risks include an increased rate of amyloid-related imaging abnormalities (ARIA) and infusion reactions relative to placebo.MethodsClarity AD was an 18-month treatment (Core study), multicenter, double-blind, placebo-controlled, parallel-group study with open-label extension (OLE) in participants with early AD. Eligible participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly). Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by magnetic resonance imaging, read both locally and centrally.ResultsOverall, 1795 participants from Core and 1612 participants with at least one dose of lecanemab (Core + OLE) were included. Lecanemab was generally well-tolerated in Clarity AD, with no deaths related to lecanemab in the Core study. There were 9 deaths during the OLE, with 4 deemed possibly related to study treatment. Of the 24 deaths in Core + OLE, 3 were due to intracerebral hemorrhage (ICH): 1 placebo in the Core due to ICH, and 2 lecanemab in OLE with concurrent ICH (1 on tissue plasminogen activator and 1 on anticoagulant therapy). In the Core + OLE, the most common adverse events in the lecanemab group (> 10%) were infusion-related reactions (24.5%), ARIA with hemosiderin deposits (ARIA-H) microhemorrhages (16.0%), COVID-19 (14.7%), ARIA with edema (ARIA-E; 13.6%), and headache (10.3%). ARIA-E and ARIA-H were largely radiographically mild-to-moderate. ARIA-E generally occurred within 3–6 months of treatment, was more common in ApoE e4 carriers (16.8%) and most common in ApoE ε4 homozygous participants (34.5%).ConclusionsLecanemab was generally well-tolerated, with the most common adverse events being infusion-related reactions, ARIA-H, ARIA-E. Clinicians, participants, and caregivers should understand the incidence, monitoring, and management of these events for optimal patient care.Trial registrationClinicalTrials.gov numbers: Clarity AD NCT03887455)

Consumption of Olive Oil and Diet Quality and Risk of Dementia-Related Death

Age-standardized dementia mortality rates are on the rise. Whether long-term consumption of olive oil and diet quality are associated with dementia-related death is unknown. To examine the association of olive oil intake with the subsequent risk of dementia-related death and assess the joint association with diet quality and substitution for other fats. This prospective cohort study examined data from the Nurses' Health Study (NHS; 1990-2018) and Health Professionals Follow-Up Study (HPFS; 1990-2018). The population included women from the NHS and men from the HPFS who were free of cardiovascular disease and cancer at baseline. Data were analyzed from May 2022 to July 2023. Olive oil intake was assessed every 4 years using a food frequency questionnaire and categorized as (1) never or less than once per month, (2) greater than 0 to less than or equal to 4.5 g/d, (3) greater than 4.5 g/d to less than or equal to 7 g/d, and (4) greater than 7 g/d. Diet quality was based on the Alternative Healthy Eating Index and Mediterranean Diet score. Dementia death was ascertained from death records. Multivariable Cox proportional hazards regressions were used to estimate hazard ratios (HRs) and 95% CIs adjusted for confounders including genetic, sociodemographic, and lifestyle factors. Of 92 383 participants, 60 582 (65.6%) were women and the mean (SD) age was 56.4 (8.0) years. During 28 years of follow-up (2 183 095 person-years), 4751 dementia-related deaths occurred. Individuals who were homozygous for the apolipoprotein ε4 (APOE ε4) allele were 5 to 9 times more likely to die with dementia. Consuming at least 7 g/d of olive oil was associated with a 28% lower risk of dementia-related death (adjusted pooled HR, 0.72 [95% CI, 0.64-0.81]) compared with never or rarely consuming olive oil (P for trend < .001); results were consistent after further adjustment for APOE ε4. No interaction by diet quality scores was found. In modeled substitution analyses, replacing 5 g/d of margarine and mayonnaise with the equivalent amount of olive oil was associated with an 8% (95% CI, 4%-12%) to 14% (95% CI, 7%-20%) lower risk of dementia mortality. Substitutions for other vegetable oils or butter were not significant. In US adults, higher olive oil intake was associated with a lower risk of dementia-related mortality, irrespective of diet quality. Beyond heart health, the findings extend the current dietary recommendations of choosing olive oil and other vegetable oils for cognitive-related health.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Allelic modulation of large (second-order) mesenteric artery mechanical properties in adult APOE3 &amp; APOE4 Mice

Previous studies from our lab have demonstrated age-related changes in vascular structure/function in posterior cerebral arteries (PCA) and left common carotid artery (CA) in male and female mice expressing human-APOE targeted replacement of APOE3 (B6.129P2-APOEtm2(APOE*3)MaeN8) and APOE4 (B6.129P2-APOEtm3(APOE*4)MaeN8) (Taconic Labs). Therefore, we hypothesize that similar changes may be observed in the systemic circulation. We isolated second-order mesenteric arteries (MA) from adult (6-month-old) male and female mice expressing APOE3 (n=3) and APOE4 (n=4). Mesenteric artery segments (5-8 mm in length) were rapidly isolated and cannulated on an arteriograph to assess mechanical properties: lumen diameter (LD), wall thickness (WT), wall:lumen ratio (W:L), distensibility, stress, strain, and stress versus strain (SvS) in the presence of Ca2+-free Krebs + diltiazem at intraluminal pressures ranging from 10mmHg–140mmHg. Phenylephrine and potassium-induced contractions were assessed in Ca2+-containing Krebs at intraluminal pressures ranging from 10-140mmHg. Data were analyzed using two-way ANOVA, Student’s t-test, and analysis of nonlinear fit. Values were considered statistically different at p&lt;0.05. Our preliminary data indicated APOE4 mice had a greater WT and W:L compared to APOE3. Interestingly, there were no significant differences in the remaining passive mechanical properties (LD, distensibility, stress, strain, SvS). In addition, phenylephrine and potassium-induced contractions were similar in the APOE3 and APOE4 mice. This data suggests changes in passive mechanical properties in APOE4 mice which may resemble premature aging. ABRC/ADHS18-205211 (DME, CBJ), Arizona Alzheimer’s Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (IW, SM, DME), Biomedical Sciences Start-up Funds (DME). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Small mesenteric artery passive mechanical properties in adult APOE3 &amp; APOE4 Mice

Previous studies from our lab have demonstrated changes in vascular structure and function in posterior cerebral arteries and left common carotid artery (CA) in adult male and female mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)MaeN8) and APOE4 (B6.129P2-Apoetm3(APOE*4)MaeN8) (Taconic Labs). Therefore, we hypothesized that similar changes may be observed in the systemic circulation. We isolated 4thor 5th-order mesenteric arteries from adult 6-month-old male and female mice expressing hAPOE3 (n=5) or hAPOE4 (n=4). Mesenteric artery segments (5-8 mm in length) were isolated and cannulated on an arteriograph to assess vascular mechanical properties; lumen diameter, wall thickness, wall:lumen ratio, distensibility, stress versus strain (SvS), compliance, incremental modulus of elasticity (Einc), and calculated pulse wave velocity under passive conditions (Ca2+-free Krebs plus diltiazem) at intraluminal pressures ranging from 10mmHg to 140mmHg. In addition, phenylephrine-induced contraction and potassium-induced contraction were assessed using Ca2+-containing Krebs. Data was analyzed using two-way ANOVA, Student’s t-test, and analysis of nonlinear fit. Values were considered statistically different at p&lt;0.05. In our preliminary data, lumen diameter, distensibility, compliance, strain, and calculated pulse wave velocity were similar in APOE3 and APOE4 mice. Wall thickness and wall:lumen ratio were significantly greater in APOE4 compared to APOE3 mice. Wall stress and Einc were significantly less in APOE4 compared to APOE3 mice. Interestingly, the APOE4 mice exhibited a significantly lesser stress per given amount of strain compared to the APOE3 mice. Phenylephrine- and potassium-induced contractions were similar in APOE3 and APOE4 mice. This data suggests there are changes in passive mechanical properties in small mesenteric arteries from APOE4 mice, which resemble a hypertensive phenotype. ABRC/ADHS18-205211 (DME, CBJ), Arizona Alzheimer’s Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (SM, IW, DME), Biomedical Sciences Start-up Funds (DME). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of the apolipoprotein E ε4 allele and olfactory function on odor identification networks.

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). 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. 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. 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.

Proteomic Signatures of Coronary Artery Disease and Hypercholesterolemia

Background: Coronary artery disease (CAD) is the most common type of cardiovascular disease (CVD), it causes narrowing of the blood vessel lumen due to atherosclerotic plaque formation. Atherosclerosis, is strongly influenced by hypercholesterolemia (HC). Proteomics offers advantages over traditional studies that focus on individual biomarkers. This method provides a holistic view by examining the entire proteomic spectrum in a biological sample, making it an indispensable asset for spotting potential novel protein biomarkers directly linked to atherosclerosis occurrence, progression, and complications such as plaque instability or rupture. Methods: Slow Off-rate Modified Aptamer (SOMAmer)-based protein array was used to quantify proteins. Our cross-sectional study involved healthy controls (n=45), and patients diagnosed with HC (n=51) or CAD (n=32). Proteome data was analyzed using multiple statistical methods. Results: The orthogonal partial least square discriminant analysis (OPLS-DA) revealed a clear separation of the 3 study groups based on two principal components, with R2X= 0.267, R2Y= 0.9, and Q2= 0.28, indicating distinct protein alterations between groups. A total of 1,305 proteins were analyzed and 156 of them in CAD vs control, 140 of them in HC vs control, and 326 of the proteins in CAD vs HC comparisons, were significantly differentially expressed with a p-value&lt;0.05. Among those, q-value&lt;0.05 were determined. As a result, in CAD patients, 2 proteins exhibited significantly differential expressions compared to healthy controls. In contrast, HC patients had 15 significantly altered proteins compared to controls. Furthermore, a comparison between CAD and HC patients revealed 87 significantly regulated proteins. The receiver operating characteristic (ROC) was performed on proteins with distinct expressions ( q&lt;0.05) in pairwise group comparisons. The AUC was calculated to identify potential biomarker candidates for the disease groups. In the CAD vs. control analysis, both significant proteins (PCSK9, SDF-1) exhibited an AUC of 0.75. In the comparison between HC and control groups, out of 15 significantly altered proteins, 7 had an AUC of 0.75 or higher (LRP1B, Apo E, QORL1, Apo E3, Apo B, Transferrin, MMP-3). Among the 87 proteins significantly differentially expressed in CAD versus HC, 59 had an AUC ≥ 0.75. Sixteen of these proteins had an AUC ≥ 0.80. Conclusion: Distinct protein patterns associated with each condition were identified. CAD patients showed a significant increase in the cholesterol-metabolizing protein PCSK9 and varying levels of the angiogenesis-related protein SDF-1. Several other proteins (LRP1B, VAV, CSRP3, HSP 60, and TAK1-TAB1) also exhibited unique expressions in disease groups, suggesting potential roles in atherosclerosis development. Moreover, a statistically significant correlation between SDF-1, ApoB levels, and LDL levels was found in CAD patients but not in healthy controls. This discovery phase cohort study unveils potential biomarkers for atherosclerosis within the HC context. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Metabolomics profiling reveals distinct, sex-specific signatures in serum and brain metabolomes in mouse models of Alzheimer's disease.

Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species can facilitate translation. We investigated differences in serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at 6 months of age. We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum. Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of apolipoprotein E (apoE) ε4 carriers and replicating the serum metabolic imprint of the APOE ε4 genotype. Our work thus represents a significant step toward translating metabolic dysregulation from model organisms to human AD. This was a metabolomic assessment of two mouse models relevant to Alzheimer's disease. Mouse models exhibit broad sex-specific metabolic differences, similar to human study cohorts. The early-onset 5XFAD mouse model primarily alters brain metabolites while the late-onset LOAD1 model primarily changes serum metabolites. Apolipoprotein E (apoE) ε4 mice recapitulate glycerophospolipid signatures of human APOE ε4 carriers in both brain and serum.

Associations between accelerometer-measured circadian rest-activity rhythm, brain structural and genetic mechanisms, and dementia.

Knowledge of how circadian rhythm influences brain health remains limited. We aimed to investigate the associations of accelerometer-measured circadian rest-activity rhythm (CRAR) with incident dementia, cognitive dysfunction, and structural brain abnormalities in the general population and underlying biological mechanisms. Fifty-seven thousand five hundred and two participants aged over 60 years with accelerometer data were included to investigate the association of CRAR with incidental dementia. Non-parametric CRAR parameters were utilized, including activity level during active periods of the day (M10), activity level during rest periods of the day (L5), and the relative difference between the M10 and L5 (relative amplitude, RA). Associations of CRAR with cognitive dysfunction and brain structure were studied in a subset of participants. Neuroimaging-transcriptomics analysis was utilized to identify the underlying molecular mechanisms. Over 6.86 (4.94-8.78) years of follow-up, 494 participants developed dementia. The risk of incident dementia was associated with decreasing M10 (hazard ratio [HR] 1.45; 95% conference interval [CI], 1.28-1.64) and RA (HR 1.37; 95% CI, 1.28-1.64), increasing L5 (HR 1.14, 95% CI 1.07-1.21) and advanced L5 onset time (HR 1.12; 95% CI, 1.02-1.23). The detrimental associations were exacerbated by APOE ε4 status and age (>65 years). Decreased RA was associated with lower processing speed (Beta -0.04; SE 0.011), predominantly mediated by abnormalities in subcortical regions and white matter microstructure. The genes underlying CRAR-related brain regional structure variation were enriched for synaptic function. Our study underscores the potential of intervention targeting at maintaining a healthy CRAR pattern to prevent dementia risk.

DNA tetrahedron-based dual-signal fluorescence detection of apoE4 gene sites on a microplate reader.

As a neurodegenerative disorder, Alzheimer's disease (AD) is characterized by cognitive dysfunction and behavioral impairment. Among the various genetic risk factors for AD, apoE4 gene plays a pivotal role in the onset and progression of AD, and detection of apoE4 gene holds significance for prevention and early diagnosis of AD. Herein, dual-signal fluorescence detection of fragments associated with apoE ε4 allele near codon 112 (Tc1) and codon 158 (Tc2) was achieved using DNA tetrahedron nanostructure (DTN). The Förster resonance energy transfer (FRET) process in the DTN was initiated in which the nucleic acid intercalating dye thiazole orange (TO) served as the donor and the cyanine dyes of cyanine3 (Cy3) and cyanine5 (Cy5) at the two vertices of DTN served as the acceptors. In the presence of Tc1 and Tc2, the FRET process between TO and the cyanine dyes was hindered by the enzymatic cleavage reaction, which ensures the dual-signal fluorescence assay of apoE4 gene sites. The limit of detection for Tc1 and Tc2 was estimated to be 0.82nM and 0.77nM, respectively, and the whole assay was accomplished within 1h on a microplate reader. The proposed method thus possesses the advantages of easy operation, short detection time, and high-throughput capability.

The association between neighborhood deprivation and DNA methylation in an autopsy cohort.

Previous research has found that living in a disadvantaged neighborhood is associated with poor health outcomes. Living in disadvantaged neighborhoods may alter inflammation and immune response in the body, which could be reflected in epigenetic mechanisms such as DNA methylation (DNAm). We used robust linear regression models to conduct an epigenome-wide association study examining the association between neighborhood deprivation (Area Deprivation Index; ADI), and DNAm in brain tissue from 159 donors enrolled in the Emory Goizueta Alzheimer's Disease Research Center (Georgia, USA). We found one CpG site (cg26514961, gene PLXNC1) significantly associated with ADI after controlling for covariates and multiple testing (p-value=5.0e-8). Effect modification by APOE ε4 was statistically significant for the top ten CpG sites from the EWAS of ADI, indicating that the observed associations between ADI and DNAm were mainly driven by donors who carried at least one APOE ε4 allele. Four of the top ten CpG sites showed a significant concordance between brain tissue and tissues that are easily accessible in living individuals (blood, buccal cells, saliva), including DNAm in cg26514961 (PLXNC1). Our study identified one CpG site (cg26514961, PLXNC1 gene) that was significantly associated with neighborhood deprivation in brain tissue. PLXNC1 is related to immune response, which may be one biological pathway how neighborhood conditions affect health. The concordance between brain and other tissues for our top CpG sites could make them potential candidates for biomarkers in living individuals.

A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings.

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease.

Adaptive immune changes associate with clinical progression of Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear.MethodsWe comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF).ResultsWe found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity.ConclusionsOur findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology.

1032 Association of Sleep Duration and APOE ε4 Status on Brain Regional Tau Deposition in Clinically Normal Older Adults

1032 Association of Sleep Duration and APOE ε4 Status on Brain Regional Tau Deposition in Clinically Normal Older Adults

Synaptic vesicle glycoprotein 2 A in serum is an ideal biomarker for early diagnosis of Alzheimer’s disease

BackgroundPrevious studies have demonstrated that early intervention was the best plan to inhibit the progression of Alzheimer’s disease (AD), which relied on the discovery of early diagnostic biomarkers. In this study, synaptic vesicle glycoprotein 2 A (SV2A) was examined to improve the early diagnostic efficiency in AD.MethodsIn this study, biomarker testing was performed through the single-molecule array (Simoa). A total of 121 subjects including cognitively unimpaired controls, amnestic mild cognitive impairment (aMCI), AD and other types of dementia underwent cerebrospinal fluid (CSF) SV2A testing; 430 subjects including health controls, aMCI, AD and other types of dementia underwent serum SV2A, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and p-tau217 testing; 92 subjects including aMCI and AD underwent both CSF SV2A and serum SV2A testing; 115 cognitively unimpaired subjects including APOE ε4 carriers and APOE ε4 non-carriers were tested for serum SV2A, GFAP, NfL and p-tau217. Then, the efficacy of SV2A for the early diagnosis of AD and its ability to identify those at high risk of AD from a cognitively unimpaired population were further analyzed.ResultsBoth CSF and serum SV2A significantly and positively correlated with cognitive performance in patients with AD, and their levels gradually decreased with the progression of AD. Serum SV2A demonstrated excellent diagnostic efficacy for aMCI, with a sensitivity of 97.8%, which was significantly higher than those of NfL, GFAP, and p-tau217. The SV2A-positive rates ranged from 92.86 to 100% in aMCI cases that were negative for the above three biomarkers. Importantly, of all the biomarkers tested, serum SV2A had the highest positivity rate (81.82%) in individuals at risk for AD.ConclusionsSerum SV2A was demonstrated to be a novel and ideal biomarker for the early diagnosis of AD, which can effectively distinguish those at high risk of AD in cognitively unimpaired populations.

Association of glycogen synthase kinase-3β with cognitive impairment in type 2 diabetes patients: a six-year follow-up study.

Our previous multicenter case-control study showed that aging, up-regulation of platelet glycogen synthase kinase-3β (GSK-3β), impaired olfactory function, and ApoE ϵ4 genotype were associated with cognitive decline in type 2 diabetes mellitus (T2DM) patients. However, the causal relationship between these biomarkers and the development of cognitive decline in T2DM patients remains unclear. To further investigate this potential relationship, we designed a 6-year follow-up study in 273 T2DM patients with normal cognitive in our previous study. Baseline characteristics of the study population were compared between T2DM patients with and without incident mild cognitive impairment (MCI). We utilized Cox proportional hazard regression models to assess the risk of cognitive impairment associated with various baseline biomarkers. Receiver operating characteristic curves (ROC) were performed to evaluate the diagnostic accuracy of these biomarkers in predicting cognitive impairment. During a median follow-up time of 6 years (with a range of 4 to 9 years), 40 patients (16.13%) with T2DM developed MCI. Participants who developed incident MCI were more likely to be older, have a lower education level, have more diabetic complications, a higher percentage of ApoE ϵ4 allele and a higher level of platelet GSK-3β activity (rGSK-3β) at baseline (P<0.05). In the longitudinal follow-up, individuals with higher levels of rGSK-3β were more likely to develop incident MCI, with an adjusted hazard ratio (HR) of 1.60 (95% confidence interval [CI] 1.05, 2.46), even after controlling for potential confounders. The AUC of the combination of age, rGSK-3β and ApoEϵ4 allele predicted for incident MCI was 0.71. Platelet GSK-3β activity could be a useful biomarker to predict cognitive decline, suggesting the feasibility of identifying vulnerable population and implementing early prevention for dementia.

Sex differences in interacting genetic and functional connectivity biomarkers in Alzheimer's disease.

As of 2023, it is estimated that 6.7 million individuals in the United States live with Alzheimer's disease (AD). Prior research indicates that AD disproportionality affects females; females have a greater incidence rate, perform worse on a variety of neuropsychological tasks, and have greater total brain atrophy. Recent research shows that hippocampal functional connectivity differs by sex and may be related to the observed sex differences in AD, and apolipoprotein E (ApoE) ε4 carriers have reduced hippocampal functional connectivity. The purpose of this study was to determine if the ApoE genotype plays a role in the observed sex differences in hippocampal functional connectivity in Alzheimer's disease. The resting state fMRI and T2 MRI of individuals with AD (n = 30, female = 15) and cognitively normal individuals (n = 30, female = 15) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed using the functional connectivity toolbox (CONN). Our results demonstrated intrahippocampal functional connectivity differed between those without an ε4 allele and those with at least one ε4 allele in each group. Additionally, intrahippocampal functional connectivity differed only by sex when Alzheimer's participants had at least one ε4 allele. These results improve our current understanding of the role of the interacting relationship between sex, ApoE genotype, and hippocampal function in AD. Understanding these biomarkers may aid in the development of sex-specific interventions for improved AD treatment.

Cost-Effectiveness of Lecanemab for Individuals With Early-Stage Alzheimer Disease.

Little is known regarding the cost-effectiveness of lecanemab (Leqembi), a monoclonal antibody approved by the US Food and Drug Administration in January 2023 for the treatment of mild cognitive impairment (MCI) or mild dementia due to Alzheimer disease (AD). This study aims to quantify the cost-effectiveness of lecanemab and how it varies based on the accuracy of AD testing and individuals' APOE ε4 status. Seven alternative test-treat-target strategies defined by combinations of testing approaches (PET, CSF, or plasma assay), treatment choices (standard of care [SoC] alone or lecanemab in addition to SoC), and targeting strategies (targeting APOE ε4 noncarriers or heterozygous patients or not) were compared. A hybrid decision tree-Markov cohort model was constructed with 5 states: (1) MCI (Clinical Dementia Rating-Sum of Boxes [CDR-SB] 0-4.5); (2) mild dementia (CDR-SB 4.6-9.5); (3) moderate dementia (CDR-SB 9.6-16); (4) severe dementia (CDR-SB >16); and (5) death. Effectiveness was measured by quality-adjusted life years and costs from third-party and societal perspectives were estimated in 2022 US dollars over a lifetime horizon. Among the 7 test-treat-target strategies, SoC alone was the optimal strategy from a cost-effectiveness perspective. Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype was cost-effective vs SoC alone, regardless of the test used to diagnose patients with early-stage AD. However, CSF assay followed by targeted treatment would become cost-effective if lecanemab is priced below $5,100 per year. These results were robust to the accuracy of diagnostic testing and rates of lecanemab discontinuation and adverse events. Neither targeted lecanemab treatment nor treatment unrestricted by APOE ε4 genotype is cost-effective vs SoC alone for patients with MCI or mild dementia due to AD. Lecanemab would be cost-effective in some settings if priced below $5,100 per year.