ApoE Research Articles

Abstract 4137155: Relationship between Subclinical Myocardial Injury and Global Cognitive Performance: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background: With demographic trends transitioning towards older adults, dementia and cognitive impairment are predicted to increase dramatically. We aim to elucidate the relationship between subclinical myocardial injury, as indicated by asymptomatic increased levels of high-sensitivity cardiac Troponin (hs-cTnT), and cognitive performance. Methods: We studied MESA participants from Exam 1 (2000-02) to Exam 6 (2016-18), categorizing them based on baseline hs-cTnT at Exam 1. Cognitive decline was defined as a decrease of ≥5 units in CASI between Exam 5&6. We used Pearson correlation and linear regression to analyze the association of hs-cTnT levels with CASI scores, and logistic regression to examine the association with cognitive decline. We also explored the relationship between different hs-cTnT categories and cognitive measures. Models were adjusted for demographics, lifestyle, APOE status, comorbidities, and medication use ( Figure ). Results: 4445 participants had both baseline hs-cTnT and valid Exam 5 CASI scores while only 1776 participants had valid Exam 6 CASI scores. Cohort was predominantly female (53%), mean age of 60 years, and 27% had at least one APOE e4 allele. Median hs-cTnT was 6.32 ng/L, and median CASI scores were 89 at Exam 5 and 91.5 at Exam 6. We found a negative correlation between the log-hs-cTnT at Exam 1 and Exam 5 with CASI scores at Exam 5. An increase of one unit in log-hs-cTnT level was associated with a decrease of 0.67 (CI -1.17, -0.17) in CASI and corresponded to higher odds (OR: 1.44; CI 1.05-1.95) of cognitive decline, after adjusting for covariates. When comparing various categories of hs-cTnT with category 1, we observe that the odd of cognitive decline increases as the category increases. However, this trend does not hold for category 5 with significantly lower sample size ( Figure ). Conclusion: Our findings indicate an inverse relationship between hs-cTnT and cognitive function years later, which is significantly attenuated by known risk factors for cognitive decline. Further research is needed to determine hs-cTnT as a predictor of future global cognitive functions.

APOE4 rat model of Alzheimer’s disease: sex differences, genetic risk and diet

The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of apolipoprotein E (ApoE ε4). A high fat diet also adds to the risk of dementia and AD. In addition, there are sex differences as women carriers have a higher risk of an earlier onset and rapid decline in memory than men. The present study looked at the effect of the genetic risk of ApoE ε4 together with a high fat/high sucrose diet (HFD/HSD) on brain function in male and female rats using magnetic resonance imaging. We hypothesized female carriers would present with deficits in cognitive behavior together with changes in functional connectivity as compared to male carriers. Four-month-old wildtype and human ApoE ε4 knock-in (TGRA8960), male and female Sprague Dawley rats were put on a HFD/HSD for four months. Afterwards they were imaged for changes in function using resting state BOLD functional connectivity. Images were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on 173 different brain areas. Resting state functional connectivity showed male wildtype had greater connectivity between areas involved in feeding and metabolism while there were no differences between female and male carriers and wildtype females. The data were unexpected. The genetic risk was overshadowed by the diet. Male wildtype rats were most sensitive to the HFD/HSD presenting with a deficit in cognitive performance with enhanced functional connectivity in neural circuitry associated with food consumption and metabolism.

Facial aging, cognitive impairment, and dementia risk

BackgroundFacial aging, cognitive impairment, and dementia are all age-related conditions. However, the temporal relation between facial age and future risk of dementia was not systematically examined.ObjectivesTo investigate the relationship between facial age (both subjective/perceived and objective) and cognitive impairment and/or dementia risk.MethodsThe study included 195,329 participants (age ≥ 60 y) from the UK Biobank (UKB) with self-perceived facial age and 612 participants from the Nutrition and Health of Aging Population in China Project (NHAPC) study (age ≥ 56 y) with objective assessment of facial age. Cox proportional hazards model was used to prospectively examine the hazard ratios (HRs) and their 95% confidence intervals (CIs) of self-perceived facial age and dementia risk in the UKB, adjusting for age, sex, education, APOE ε4 allele, and other potential confounders. Linear and logistic regressions were performed to examine the cross-sectional association between facial age (perceived and objective) and cognitive impairment in the UKB and NHAPC, with potential confounders adjusted.ResultsDuring a median follow-up of 12.3 years, 5659 dementia cases were identified in the UKB. The fully-adjusted HRs comparing high vs. low perceived facial age were 1.61 (95% CI, 1.33 ~ 1.96) for dementia (P-trend ≤ 0.001). Subjective facial age and cognitive impairment was also observed in the UKB. In the NHAPC, facial age, as assessed by three objective wrinkle parameters, was associated with higher odds of cognitive impairment (P-trend < 0.05). Specifically, the fully-adjusted OR for cognitive impairment comparing the highest versus the lowest quartiles of crow’s feet wrinkles number was 2.48 (95% CI, 1.06 ~ 5.78).ConclusionsHigh facial age was associated with cognitive impairment, dementia and its subtypes after adjusting for conventional risk factors for dementia. Facial aging may be an indicator of cognitive decline and dementia risk in older adults, which can aid in the early diagnosis and management of age-related conditions.

APOE ε4 and Dietary Patterns in Relation to Cognitive Function: An Umbrella Review of Systematic Reviews.

Carrying the apolipoprotein ε4 allele (APOE ε4) is the strongest genetic risk factor for late-onset Alzheimer's disease. There is some evidence suggesting that APOE ε4 may modulate the influence of diet on cognitive function. This umbrella review of systematic reviews evaluates the existing literature on the effect of dietary interventions on cognitive and brain-imaging outcomes by APOE status. PubMed, EMBASE, Web of Science, and Scopus were searched using terms appropriate to each area of research, from their respective starting dates of coverage until March 2023. Two independent reviewers conducted data extraction and performed a quality appraisal using the Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. Six total reviews were included in the final analysis. Four reviews evaluated randomized controlled trials on individuals aged 50-93 years ranging the entire cognitive continuum. One review combined observational studies and clinical trials conducted on both cognitively healthy and cognitively impaired individuals (age range: 50-90), and 1 review included observational studies of both cognitively healthy and cognitively impaired adults (age range: 50-75). Both observational studies and clinical trials yielded inconclusive results attributed to both practical limitations associated with longitudinal follow-up and issues of methodological quality. Except for the Mediterranean diet, dietary interventions, such as the ketogenic diet, nutraceuticals, and supplements, were generally not effective in older APOE ε4 carriers. This review considers plausible biological mechanisms that might explain why older and cognitively impaired APOE ε4 carriers were less likely to benefit. This review identifies notable gaps in the literature, such as a shortage of studies conducted in middle-aged and cognitively healthy APOE ε4 carriers assessing the impact of dietary interventions and provides suggestions for novel trial designs.

The Icelandic mutation (APP-A673T) is protective against amyloid pathology in vivo.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (AppG-F mice) to avoid potential deleterious effects of the Swedish mutation and generated AppG-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.Significance statement The A673T mutation (Icelandic mutation) in the APP gene can protect against AD. The effect of the A673T mutation on amyloid pathology has not been evaluated in vivo. Utilizing a new AD mouse model that we have recently developed, we show that the APP-A673T attenuates amyloid pathology in vivo. We demonstrate that its protective effects are exerted by inhibiting β-cleavage and reducing the production of Aβ in the brain. Furthermore, we reveal that the Icelandic mutation also reduced neuroinflammation and neuritic alterations. Our findings indicate that specific inhibition of the APP-BACE1 interaction or introduction of protective variants via in vivo genome editing could be a promising therapeutic approach.

Is KIBRA polymorphism associated with memory performance and cognitive impairment in Alzheimer's disease?

Genetic variations in a common single nucleotide polymorphism in the ninth intron of the KIBRA gene have been linked to memory performance and risk of Alzheimer's disease (AD). We examined the risk of AD related to presence of KIBRA T allele (versus CC homozygote) and to memory performance. The role of established genetic risk factors APOE ε4 and BDNF Met was also considered. Participants were cognitively healthy individuals (n = 19), participants with amnestic mild cognitive impairment (aMCI) due to AD (n = 99) and AD dementia (n = 37) from the Czech Brain Aging Study. Binary and multinomial logistic regressions compared odds of belonging to a certain diagnostic category and multivariate linear regressions assessed associations with memory. KIBRA T allele was associated with increased AD dementia risk (odds ratio [OR] = 5.98, p = 0.012) compared to KIBRA CC genotype. In APOE ε4 negative individuals, KIBRA T allele was associated with a greater risk of both aMCI due to AD (OR = 6.68, p = 0.038) and AD dementia (OR = 15.75, p = 0.009). In BDNF Met positive individuals, the KIBRA T allele was associated with a greater risk of AD dementia (OR = 10.98, p = 0.050). In AD dementia, the association between KIBRA T allele and better memory performance approached significance (β = 0.42; p = 0.062). The link between possessing the KIBRA T allele and better memory reached statistical significance only among BDNF Met carriers (β = 1.21, p = 0.027). Findings suggest that KIBRA T allele may not fully protect against AD dementia but could potentially delay progression of post-diagnosis cognitive deficits.

Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study.This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction.Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50%), critically stenosed arteries (obstruction ≥ 70%), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26% (95% CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17% (95% CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.

Label-free electrochemical biosensor with magnetic self-assembly constructed via PNA-DNA hybridization process on α-Fe2O3/Fe3O4 nanosheets for APOE ε4 genes ultrasensitive detection

Label-free electrochemical biosensor with magnetic self-assembly constructed via PNA-DNA hybridization process on α-Fe2O3/Fe3O4 nanosheets for APOE ε4 genes ultrasensitive detection

Slowing Cognitive Decline in Major Depressive Disorder and Mild Cognitive Impairment

Older adults with major depressive disorder (MDD) or mild cognitive impairment (MCI) are at high risk for cognitive decline. To assess the efficacy of cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) targeting the prefrontal cortex in slowing cognitive decline, acutely improving cognition, and reducing progression to MCI or dementia in older adults with remitted MDD (rMDD), MCI, or both. This randomized clinical trial was conducted at 5 academic hospitals in Toronto, Ontario, Canada. Participants were older adults who had rMDD (with or without MCI, age ≥65 y) or MCI without rMDD (age ≥60 y). Assessments were made at baseline, month 2, and yearly from baseline for 3 to 7 years. CR plus tDCS (hereafter, active) or sham plus sham 5 days a week for 8 weeks followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. The primary outcome was change in global composite cognitive score. Secondary outcomes included changes in 6 cognitive domains, moderating effect of the diagnosis, moderating effect of APOE ε4 status, change in composite score at month 2, and progression to MCI or dementia over time. Of 486 older adults who provided consent, 375 (with rMDD, MCI, or both) received at least 1 intervention session (mean [SD] age, 72.2 [6.4] years; 232 women [62%] and 143 men [38%]). Over a median follow-up of 48.3 months (range, 2.1-85.9), CR and tDCS slowed cognitive decline in older adults with rMDD or MCI (adjusted z score difference [active - sham] at month 60, 0.21; 95% CI, 0.07 to 0.35; likelihood ratio test [LRT] P = .006). In the preplanned primary analysis, CR and tDCS did not improve cognition acutely (adjusted z score difference [active - sham] at month 2, 0.06, 95% CI, -0.006 to 0.12). Similarly, the effect of CR and tDCS on delaying progression from normal cognition to MCI or MCI to dementia was weak and not significant (hazard ratio, 0.66; 95% CI, 0.40 to 1.08; P = .10). Preplanned analyses showed treatment effects for executive function (LRT P = .04) and verbal memory (LRT P = .02) and interactions with diagnosis (P = .01) and APOE ε4 (P < .001) demonstrating a larger effect among those with rMDD and in noncarriers of APOE ε4. The study showed that CR and tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in older adults at risk of cognitive decline, particularly those with rMDD (with or without MCI) and in those at low genetic risk for Alzheimer disease. ClinicalTrials.gov Identifier: NCT02386670.

Pharmacogenomics of CRP response to statins: a GIST consortium study

Abstract Introduction Statins are first line treatments in the primary and secondary prevention of cardiovascular disease. Prior clinical studies have shown that statins act independently of lipid lowering mechanisms to decrease C-reactive protein (CRP), a marker of inflammation. Purpose To elucidate genetic loci associated with CRP response to statins. Methods CRP response was specified as the change from baseline in log CRP after at least 4 weeks of statin therapy. Cohort level Genome-wide Association Studies (GWAS) of this CRP response was performed by linear regression analysis adjusted for baseline CRP, age, sex and BMI covariates using genetic data imputed to 1000 Genomes, testing ~10 million single nucleotide polymorphisms (SNPs) of minor allele frequency (MAF) &amp;gt;2%. Following quality control with EasyQC, a meta-analysis was conducted with METAL to combine GWAS results from six different cohorts of European ancestry (CARDS, FHS, JUPITER, MESA, PARC, PROSPER) within the GIST consortium. 1Mb loci regions were defined, centred +/-500kb around the lead SNP. Conditional analysis was performed using GCTA. Results There were 11,075 statin-treated individuals. The meta-analysis results revealed two loci achieving genome wide significance (P&amp;lt;5e-8): APOE (chr 19) and HNF1A (chr 12) (Figure 1). A signal at the CRP locus was highly suggestive (P=2.3e-7). All three loci are known to be associated with CRP levels in the absence of statin. Conditional analysis did not reveal secondary signals. The most associated variant at the APOE locus was the missense SNP rs429358, which contributes to the APOE E4 haplotype and is a risk locus for both dyslipidaemia and Alzheimer’s dementia. It is a C&amp;gt;T missense variant of MAF 0.12 leading to a R/C amino acid change, more common in African ancestry populations (MAF 0.27), and least common in Asian populations (MAF 0.09). A nominally significant association (P=0.09) for interaction with randomized allocation to statin v. placebo within samples derived from clinical trials supports this pharmacogenetic effect at APOE beyond genetic effects on baseline CRP levels. The most associated variant at the HNF1A locus was the intronic SNP rs11065384, which is in strong LD with the HNF1A missense SNP (rs1169288). The HNF1A locus is associated with diabetes, cholesterol levels, and coronary artery disease. There was no between-study heterogeneity at the top three loci (P&amp;gt;0.1), and forest plots show contribution to these signals from all 6 studies within the meta-analysis (Figure 2 A,B,C). Conclusions APOE and HNF1A are associated with CRP response to statins at the level of genome-wide significance. TheAPOE E4 signal is also known to be associated with LDL-Cholesterol response to statins, whereas the HNF1A locus is identified here for the first time as a pharmacogenetic determinant of statin response. The effect of this interindividual variability in CRP response on non-cardiovascular clinical outcomes should be elucidated.Figure 1Figure 2 A,B,C

Association of polymorphism of apolipoprotein e gene with acute myocardial infarction and its short term clinical outcome

Abstract Background/Introduction Myocardial infarction (MI) is a multifactorial disease influenced by environmental and genetic factors. Apolipoprotein E (ApoE) is a protein incorporated into serum lipoproteins directing their catabolism via binding to receptors. It is a structural component of both chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE is thought to play a central role in atherosclerosis by participating in overall plasma cholesterol homeostasis. In addition to other classical risk factors, positive family history of cardiovascular disease (CVD) has been found to be significantly and independently associated with MI in epidemiological studies (1). Besides traditional cardiovascular risk factors it is likely that additional genetic factors like ApoE gene polymorphism may interact with environmental factors to determine overall cardiovascular risk of an individual to develop MI. Purpose The purpose of our study was to determine the risk of association of variants of ApoE gene with Acute Myocardial Infarction. Moreover, we also wanted to study the impact of ApoE gene polymorphism in short term major adverse cardiac events (MACE) in patients with MI not willing for coronary intervention. Methods In this case control study a total of 200 consecutively admitted AMI patients admitted to the coronary care unit of our hospital were enrolled to the study along with 200 age and gender matched controls admitted during the same time period . ApoE gene polymorphism was detected by DNA extraction, DNA amplification by PCR in a DNA thermal cycler followed by restriction enzyme digestion(2). Chi square test was used to investigate the difference in genotype and allele frequencies in casend controls and also between observed and expected frequencies in the realm of Hardy-Weinberg equilibrium. Odds Ratio (OR) with 95 % confidence interval and p values were calculated while analysing the association of different genotypes of ApoE genetic polymorphism with the disease and MACE. Logistic regression analysis was carried out amongst the groups under consideration to find the unadjusted OR and adjusted OR of the genotypes in relation to the disease.p&amp;lt;0.05 was considered as significant Analysis was done in SPSS software. Results Besides the traditional risk factors Apo E4 allele (OR 2.298, CI 1.305-4.044 ) and Apo E3/E4 genotype (OR 2.116, CI 1.008-4.443, p=0.048) showed strong of association with the disease. There was a higher population of Apo E3/E4 genotypes and Apo E2/E3 genotypes with MACE events (25.6% and 28.6%), while the common ApoE3/E3 genotypes had a MACE event of 10.5 %. However, the difference was not significant (p=0.071, Χ 2 =8.63 df =4). Similarly, ApoE4 allele showed a non significantly higher MACE events (p=0.22, Χ 2 =3.01 df =4) Conclusion ApoE4 allele and ApoE3/E4 genotype are strongly and independently associated with AMI.RISK FACTORS AND RISK OF MIGenotype and MACE

Unraveling the proteomic signatures of coronary artery disease and hypercholesterolemia.

Atherosclerosis, a leading cause of coronary artery disease (CAD), is heavily influenced by hypercholesterolemia (HC). Proteomics research has shown promise in identifying biological markers for CAD diagnosis and prognosis. This cross-sectional study aimed to identify novel biomarkers for detecting HC and CAD. Through the analysis of proteome data from healthy controls (n=45) and patients diagnosed with HC (n=51) or CAD (n=32), distinct protein patterns associated with each condition were identified. Significant alterations in protein levels were identified with a false discovery rate (FDR)-corrected q-value of <0.05. Subsequent receiver operating characteristic (ROC) analysis, with an area under the curve (AUC) greater than 0.75, was conducted. CAD patients exhibited significantly increased levels of the cholesterol-metabolizing protein PCSK9 and varied levels of the angiogenesis-related protein SDF-1 compared to controls. In pairwise comparisons among the study groups, 65 proteins showed significant differential expression. Notably, 14 of these proteins had significant correlations with blood cholesterol levels. Additionally, 22 of the identified proteins were associated with CAD or HC pathways, with nine proteins being common to both conditions (Apo E, Apo E3, MMP-3, PCSK9, SDF-1, Apo B, PAFAH, HSP 60, and TAK1-TAB1). Nevertheless, this is an exploratory study, and validation studies are needed to confirm these potential protein biomarkers for CAD in the context of HC.

The Association Between Constipation and Positron Emission Tomography and Blood-Based Biomarkers in Older Cognitively Unimpaired Adults with Higher Amyloid-β Burden.

Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with lessTau burden evaluated by 18F-MK6240 PET Braak stages. Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

Whole-genome sequencing study in Koreans identifies novel loci for Alzheimer's disease.

The genetic basis of Alzheimer's disease (AD) in Koreans is poorly understood. We performed an AD genome-wide association study using whole-genome sequence data from 3540 Koreans (1583 AD cases, 1957 controls) and single-nucleotide polymorphism array data from 2978 Japanese (1336 AD cases, 1642 controls). Significant findings were evaluated by pathway enrichment and differential gene expression analysis in brain tissue from controls and AD cases with and without dementia prior to death. We identified genome-wide significant associations with APOE in the total sample and ROCK2 (rs76484417, p=2.71×10-8) among APOE ε4 non-carriers. A study-wide significant association was found with aggregated rare variants in MICALL1 (MICAL like 1) (p=9.04×10-7). Several novel AD-associated genes, including ROCK2 and MICALL1, were differentially expressed in AD cases compared to controls (p<3.33×10-3). ROCK2 was also differentially expressed between AD cases with and without dementia (p=1.34×10-4). Our results provide insight into genetic mechanisms leading to AD and cognitive resilience in East Asians. Novel genome-wide significant associations for AD identified with ROCK2 and MICALL1. ROCK2 and MICALL1 are differentially expressed between AD cases and controls in the brain. This is the largest whole-genome-sequence study of AD in an East Asian population.

APOE 𝜀4-related blood-brain barrier breakdown is associated with microstructural abnormalities.

Blood-brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear. Older adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE 𝜀4 and amyloid positivity, underwent dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4. Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4. BBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid-negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4, with the strongest relationships in amyloid-positive individuals and APOE4 carriers. APOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade. Gray matter blood-brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4-related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid-positive APOE4 carriers.

Longitudinal trajectories of general cognitive and daily functions in data-driven subtypes of MCI: A longitudinal cohort analysis of older adults

ObjectivesTo derive data-driven subtypes of mild cognitive impairment (MCI) and characterize the complicated changes of general cognitive and daily functions over time in MCI subtypes. MethodsA total of 813 subjects diagnosed as MCI at baseline from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. Data-driven MCI subtypes were derived from group-based multi-trajectory modeling (GBMTM) analyses using longitudinal measurement scores in the cognitive domains of visuospatial function, language, and executive function. General cognitive and daily functions were measured by the Mini-Mental State Examination (MMSE) and the Functional Assessment Questionnaire (FAQ), respectively, whose longitudinal trajectory changes were depicted by Linear mixed models. ResultsThree MCI subtypes were derived, which were defined as “Cognitive decline group”, “Mild cognitive decline group” and “No cognitive decline group”. The “Mild cognitive decline group” had the highest percentage in the sample (46.2 %), followed by the “No cognitive decline group” (35.2 %). Patients in the “Cognitive decline group” had the highest mean age (74.69 years) at baseline, the highest APOE ε4 carriers (63.2 %), and the greatest dementia conversion rate (77.0 %). The changes in MMSE and FAQ score trajectories were fastest in the “Cognitive decline group” in the first 36 months and most slowly in the “No cognitive decline group”. ConclusionMCI individuals could be subdivided into more fine-grained cognitive subtypes, and identifying these distinct MCI subtypes and their different trajectories of cognitive decline may have important prognostic value for improving clinical course prediction.

Disease trajectories before dementia: evidence from a large-scale community-based prospective study.

Systemic changes in multiple diseases may influence the onset of dementia. However, the specific temporality between exposure diseases and dementia remains uncertain. By characterising the full spectrum of temporal disease trajectories before dementia, this study aims to yield a global picture of precursor diseases to dementia and to provide detailed instructions for risk management and primary prevention of dementia. Using the multicentre, community-based prospective UK Biobank, we constructed disease trajectories before dementia utilising the phenome-wide association analysis, paired directional test and association quantification. Stratified disease trajectories were constructed by dementia subtypes, gender, age of diagnosis and Apolipoprotein E (ApoE) status, respectively. Our study population comprised 434 266 participants without baseline dementia and 4638 individuals with all-cause dementia. In total, 1253 diseases were extracted as potential components of the disease trajectory before dementia. We identified three clusters of disease trajectories preceding all-cause dementia, initiated by circulatory, metabolic and respiratory diseases occurring approximately 5-15 years before dementia. Cerebral infarction or chronic renal failure following chronic ischaemic heart disease was the specific trajectory before vascular dementia. Apolipoprotein E (ApoE) ε4 non-carriers exhibited more complex trajectories compared with carriers. Lipid metabolism disorders remained in the trajectories regardless of dementia subtypes, gender, age of diagnosis and ApoE status. This study provides a comprehensive view of the longitudinal disease trajectories before dementia and highlights the potential targets of midlife cardiometabolic dysfunction for dementia screening and prevention.

Alzheimer's Disease: Exploring the Landscape of Cognitive Decline.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer's disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer’s disease

BackgroundBlood-based biomarkers are gaining grounds for the detection of Alzheimer’s disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel.MethodsThe NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers.ResultsNULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878–0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype.ConclusionsTogether, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consistent with the recently revised biological and diagnostic framework. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Novel plasma protein biomarkers: A time-dependent predictive model for Alzheimer's disease

BackgroundThe accurate prediction of Alzheimer's disease (AD) is crucial for the efficient management of its progression. The objective of this research was to construct a new risk predictive model utilizing novel plasma protein biomarkers for predicting AD incidence in the future and analyze their potential biological correlation with AD incidence. MethodsA cohort of 440 participants aged 60 years and older from the Alzheimer's Disease Neuroimaging Initiative (ADNI) longitudinal cohort was utilized. The baseline plasma proteomics data was employed to conduct Cox regression, LASSO regression, and cross-validation to identify plasma protein signatures predictive of AD risk. Subsequently, a multivariable Cox proportional hazards model based on these signatures was constructed. The performance of the risk prediction model was evaluated using time-dependent receiver operating characteristic (t-ROC) curves and Kaplan-Meier curves. Additionally, we analyzed the correlations between protein signature expression in plasma and predicted AD risk, the time of AD onset, the expression of protein signatures in cerebrospinal fluid (CSF), the expression of CSF and plasma biomarkers, and APOE ε4 genotypes. Colocalization and Mendelian randomization analyses was conducted to investigate the association between protein features and AD risk. GEO database was utilized to analyze the differential expression of protein features in the blood and brain of AD patients. ResultsWe identified seven protein signatures (APOE, CGA, CRP, CCL26, CCL20, NRCAM, and PYY) that independently predicted AD incidence in the future. The risk prediction model demonstrated area under the ROC curve (AUC) values of 0.77, 0.76, and 0.77 for predicting AD incidence at 4, 6, and 8 years, respectively. Furthermore, the model remained stable in the range of the 3rd to the 12th year (ROC ≥ 0.74). The low-risk group, as defined by the model, exhibited a significantly later AD onset compared to the high-risk group (P < 0.0001). Moreover, all protein signatures exhibited significant correlations with AD risk (P < 0.001) and the time of AD onset (P < 0.01). There was no strong correlation between the protein expression levels in plasma and CSF, as well as AD CSF biomarkers. APOE, CGA, and CRP exhibited significantly lower expression levels in APOE ε4 positive individuals (P < 0.05). Additionally, colocalization analysis reveals a significant association between AD and SNP loci in APOE. Mendelian randomization analysis shows a negative correlation between NRCAM and AD risk. Transcriptomic analysis indicates a significant downregulation of NRCAM and PYY in the peripheral blood of AD patients (P < 0.01), while APOE, CGA, and NRCAM are significantly downregulated in the brains of AD patients (P < 0.0001). ConclusionOur research has successfully identified protein signatures in plasma as potential risk biomarkers that can independently predict AD onset in the future. Notably, this risk prediction model has demonstrated commendable predictive performance and stability over time. These findings underscore the promising utility of plasma protein signatures in dynamically predicting the risk of AD, thereby facilitating early screening and intervention strategies.