Late-onset Alzheimer's Disease Research Articles

Therapeutic Challenges Derived from the Interaction Among Apolipoprotein E, Cholesterol, and Amyloid in Alzheimer’s Disease

The isoform E4 of the Apolipoprotein E (ApoE) represents one of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD). ApoE has key roles in cholesterol transport and amyloid-β (Aβ) metabolism, which are both central to AD pathogenesis. The E4 isoform has been implicated in reduced cholesterol homeostasis, increased Aβ aggregation, and heightened tau phosphorylation, contributing to amyloid plaques and neurodegeneration. This manuscript examines the complex interactions among ApoE isoforms, cholesterol metabolism, and amyloid pathology. Moreover, the therapeutic challenges associated with lipid-lowering agents (e.g., statins, PCSK9 inhibitors), anti-amyloid immunotherapies, and anticoagulants are described, focusing on ApoE4 carriers. Decision-making challenges are discussed by analyzing the pros and cons of these therapies.

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.

Anthropometric and Demographic Features Affect the Interpretation of Cerebrospinal Fluid Biomarkers in Patients with Different Dementia Syndromes and Cognitively Healthy Adults.

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ42,Aβ40,Aβ38), tau, and phospho-tau Thr181. Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ42/Aβ38 could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr181/Aβ42. These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD.

Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience

BackgroundApolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.MethodsAPOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank.ResultsA total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers.ConclusionsWe identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.

Comprehensive mapping of synaptic vesicle protein 2A (SV2A) in health and neurodegenerative diseases: a comparative analysis with synaptophysin and ground truth for PET-imaging interpretation.

Synaptic dysfunction and loss are central to neurodegenerative diseases and correlate with cognitive decline. Synaptic Vesicle Protein 2A (SV2A) is a promising PET-imaging target for assessing synaptic density in vivo, but comprehensive mapping in the human brain is needed to validate its biomarker potential. This study used quantitative immunohistochemistry and Western blotting to map SV2A and synaptophysin (SYP) densities across six cortical regions in healthy controls and patients with early-onset Alzheimer's disease (EOAD), late-onset Alzheimer's disease (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-GRN). We identified region in SV2A density among controls and observed disease- and region-specific reductions, with the most severe in FTLD-GRN (up to 59.5%) and EOAD. EOAD showed a 49% reduction in the middle frontal gyrus (MFG), while LOAD had over 30% declines in the inferior frontal gyrus (IFG) and hippocampus (CA1). In PSP, smaller but significant reductions were noted in the hippocampal formation, with the inferior temporal gyrus (ITG) relatively unaffected. A strong positive correlation between SV2A and SYP densities confirmed SV2A's reliability as a synaptic integrity marker. This study supports the use of SV2A PET imaging for early diagnosis and monitoring of neurodegenerative diseases, providing essential data for interpreting in vivo PET results. Further research should explore SV2A as a therapeutic target and validate these findings in larger, longitudinal studies.

Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in aging Apolipoprotein E4 mice alter their brains inflammatory profiles.

Aging and Apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimer's disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4 dependent phenotypes. Toll-like receptor 4 (TLR4) is a key player in inflammation, its regulation is associated with cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. In this study, we found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activated ABCA1, and dampened LPS dependent NFkB activation. In vivo, a two-week injections of nanoparticle F12511, which consists of DSPE-PEG 2000 , phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines including IL-1β in APOE4 mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in Drosophila

Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer’s disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE’s role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.

Current insights into apolipoprotein E and the immune response in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E (APOE) as the strongest genetic risk for late-onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid-β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T-cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research.

Effects of Angiotensin-I-Converting Enzyme (ACE) Mutations Associated with Alzheimer's Disease on Blood ACE Phenotype.

Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD). Here, we quantified blood ACE levels in EDTA plasma from 41 subjects with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C, and G325R are truly damaging and likely transport-deficient, with the ACE levels in plasma at only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and likely did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has the potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in our cell model of the transport-deficient ACE mutation Q1069R.

Systematic review and meta-analysis of the association between ABCA7 common variants and Alzheimer's disease in non-Hispanic White and Asian cohorts.

The relationship between the ABCA7 gene and Alzheimer's disease (AD) has been widely studied across various populations. However, the results have been inconsistent. This meta-analysis aimed to evaluate the association of ABCA7 polymorphisms with AD risk, including specific subtypes such as late-onset Alzheimer's disease (LOAD). Relevant studies were identified through comprehensive database searches, and the quality of each study was assessed using the Newcastle-Ottawa Scale (NOS). Allele and genotype frequencies were extracted from the included studies. The pooled odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models. Multiple testing corrections were conducted using the false discovery rate (FDR) method. The Cochran Q statistic and I2 metric were used to evaluate heterogeneity between studies, while Egger's test and funnel plots were employed to assess publication bias. A total of 36 studies, covering 21 polymorphisms and involving 31,809 AD cases and 44,994 controls, were included in this meta-analysis. NOS scores ranged from 7 to 9, indicating high-quality studies. A total of 11 SNPs (rs3764650, rs3752246, rs4147929, rs3752232, rs3752243, rs3764645, rs4147934, rs200538373, rs4147914, rs4147915, and rs115550680) in ABCA7 were significantly associated with AD risk. Among these SNPs, two (rs3764650 and rs3752246) were also found to be related to the late-onset AD (LOAD) subtype. In addition, two SNPs (rs4147929 and rs4147934) were associated with the susceptibility to AD only in non-Hispanic White populations. A total of 10 SNPs (rs3764647, rs3752229, rs3752237, rs4147932, rs113809142, rs3745842, rs3752239, rs4147918, rs74176364, and rs117187003) showed no significant relationship with AD risk. Sensitivity analyses confirmed the reliability of the original results, and heterogeneity was largely attributed to deviations from Hardy-Weinberg equilibrium, ethnicity, and variations between individual studies. The available evidence suggests that specific ABCA7 SNPs may be associated with AD risk. Future studies with larger sample sizes will be necessary to confirm these results. https://www.crd.york.ac.uk/prospero/, identifier: CRD42024540539.

The Role of Copper in Alzheimer's Disease Etiopathogenesis: An Updated Systematic Review.

Alzheimer's disease (AD) is the most common cause of dementia and cognitive decline in the elderly. Although the etiology of AD is unknow, an increase in amyloid precursor protein (APP) leads to the toxic aggregation of Aβ plaques. Several factors, such as hypertension, diabetes, dyslipidemia, smoking, hormonal changes, and metal exposure, could increase the risk of developing AD. In this review, we will examine the role of copper (Cu) in the pathophysiology of AD, as well as the mechanisms involved in neurotoxicity and cognitive decline. This review was conducted in accordance with PRISMA guidelines. We performed a comprehensive literature analysis over the last ten years on AD and Cu. Only late-onset Alzheimer's disease was considered; only studies on elderly people of both sexes were included. A total of seven articles were picked for this review, three studies focused on non-ceruloplasmin-bound Copper (non-Cp-Cu) and four on ceruloplasmin-bound Copper (Cp-Cu). The results showed higher Cu concentrations in patients compared to healthy controls. Elevated concentrations of Cu may contribute to the progression of AD, potentially interacting with ATP7B mutations, oxidative stress (OS), and amyloid-β plaques. Future research is needed to provide more robust evidence and better characterize the relationship between AD and Cu.

Renal function and risk of dementia: a Mendelian randomization study

Background The burgeoning recognition of the nexus between renal functionality and the prevalence of dementia has precipitated a surge in research endeavors. This study aims to substantiate the causal relationship between kidney functionality and dementia. Methods We utilized clinical renal function metrics from the Chronic Kidney Disease Genetics (CKDGen) Consortium and diverse dementia types (Alzheimer’s disease [AD] and vascular dementia) from the FinnGen Biobank by using Mendelian randomization analysis. At the stratum of genetic susceptibility, we tested the causal relationship between variations index in renal function and the occurrence of dementia. Inverse-variance weighted (IVW) method was the main analysis, and several supplementary analyses and sensitivity analyses were performed to test the causal estimates. Results The findings indicate a significant correlation between each unit increase in cystatin C-based estimated glomerular filtration rate (eGFR-cys) levels was significantly associated with a reduction in the incidence of late-onset Alzheimer’s disease (LOAD) (IVW: OR = 0.35, 95% CI: 0.13–0.91, p = 0.031). After adjusting for creatinine-based eGFR (eGFR-cre) and urinary albumin-to-creatinine ratio (UACR), a causal relationship was still identified between elevated levels of eGFR-cys and decreased risk of LOAD (IVW: OR: 0.08; 95% CI: 0.01–0.97, p = 0.047). Sensitivity tests demonstrated the reliability of causal estimates. Conclusions The association between renal function based on cystatin C and the augmented risk of developing AD lends support to the perspective that regular monitoring of cystatin C may be a valuable investigative biomarker.

Default mode network tau predicts future clinical decline in atypical early Alzheimer's disease.

Identifying individuals with early-stage Alzheimer's disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support, and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau positron emission tomography (PET) in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD. Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16), logopenic variant Primary Progressive Aphasia (n = 15), and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent magnetic resonance imaging (MRI), tau PET, and amyloid PET scans at baseline. Each patient's longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months). Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, p < .001, Cohen's d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = .30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = .10), tau in other functional networks (R2 = .11-.26), and the magnitude of cortical atrophy (R2 = .20) and amyloid burden (R2 = .09) in the default mode network. Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients one year later. This simple measure could aid the development of a personalized prognostic, monitoring, and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient's tau burden while still early in the disease course.

The Alzheimer's disease risk gene CD2AP functions in dendritic spines by remodeling F-actin.

CD2AP was identified as a genetic risk factor for late-onset Alzheimer's disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases β-amyloid (Aβ) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP, but not blocking Aβ-production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics.Significance statement CD2AP is a candidate genetic risk factor of late-onset Alzheimer's disease (LOAD) expressed in neurons with an unknown impact on synapse dysfunction, one of the causal LOAD mechanisms. Our research has revealed CD2AP as a new synaptic protein and established a connection between a LOAD genetic variant in CD2AP and synaptic dysfunction independent of beta-amyloid accumulation. This study suggests an explanation for the CD2AP-mediated predisposition to AD. Furthermore, we have found that controlling CD2AP's impact on spinal F-actin could be a potential target for therapeutic intervention against LOAD.

Association between dietary fat intake and the risk of Alzheimer's disease: Mendelian randomisation study.

Observational studies have shown a controversial relationship between dietary fat intake and Alzheimer's disease, and the causal effects are unclear. To assess the causal effects of total fat, saturated fat and polyunsaturated fat (PUF) intakes on the risk of Alzheimer's disease. A two-sample Mendelian randomisation analysis was performed using genome-wide association study summary statistics on different types of fat intake from UK Biobank (n = 51 413) and on late-onset Alzheimer's disease (LOAD; 4282 cases, n = 307 112) and all forms of Alzheimer's disease (6281 cases, n = 309 154) from the FinnGen consortium. In addition, a multivariable Mendelian randomisation (MVMR) analysis was conducted to estimate the effects independent of carbohydrate and protein intakes. Genetically predicted per standard deviation increase in the total fat and saturated fat intakes were associated with 44 and 38% higher risks of LOAD (total fat: odds ratio = 1.44, 95% CI 1.03-2.02; saturated fat: odds ratio = 1.38, 95% CI 1.002-1.90; P = 0.049). The associations remained significant in the MVMR analysis (total fat: odds ratio = 3.31, 95% CI 1.74-6.29; saturated fat: odds ratio = 2.04, 95% CI 1.16-3.59). Total fat and saturated fat intakes were associated with a higher risk of all forms of Alzheimer's disease in the MVMR analysis (total fat: odds ratio = 2.09, 95% CI 1.22-3.57; saturated fat: odds ratio = 1.60, 95% CI 1.01-2.52). The PUF intake was not associated with LOAD or all forms of Alzheimer's disease. This study indicated that total dietary fat intake, especially saturated fat, contributed to the risk of Alzheimer's disease, and the effects were independent of other nutrients. These findings informed prevention strategies and management for Alzheimer's disease directly towards reducing dietary saturated fat intake.

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform MRAD developed based on Mendelian randomization analysis.

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

Systematic evaluation of multifactorial causal associations for Alzheimer’s disease and an interactive platform MRAD developed based on Mendelian randomization analysis

Alzheimer’s disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

IPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta

BackgroundThree common isoforms of the apolipoprotein E (APOE) gene - APOE2, APOE3, and APOE4 - hold varying significance in Alzheimer’s Disease (AD) risk. The APOE4 allele is the strongest known genetic risk factor for late-onset Alzheimer’s Disease (AD), and its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition and accelerated neurodegeneration. Conversely, APOE2 is associated with reduced AD risk and lower CNS amyloid burden. Recent clinical data have suggested that increased blood-brain barrier (BBB) leakage is commonly observed among AD patients and APOE4 carriers. However, it remains unclear how different APOE isoforms may impact AD-related pathologies at the BBB.MethodsTo explore potential impacts of APOE genotypes on BBB properties and BBB interactions with amyloid beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines with different APOE genotypes into both brain microvascular endothelial cell-like cells (BMEC-like cells) and brain pericyte-like cells. We then compared the effect of different APOE isoforms on BBB-related and AD-related phenotypes. Statistical significance was determined via ANOVA with Tukey’s post hoc testing as appropriate.ResultsIsogenic BMEC-like cells with different APOE genotypes had similar trans-endothelial electrical resistance, tight junction integrity and efflux transporter gene expression. However, recombinant APOE4 protein significantly impeded the “brain-to-blood” amyloid beta 1–40 (Aβ40) transport capabilities of BMEC-like cells, suggesting a role in diminished amyloid clearance. Conversely, APOE2 increased amyloid beta 1–42 (Aβ42) transport in the model. Furthermore, we demonstrated that APOE-mediated amyloid transport by BMEC-like cells is dependent on LRP1 and p-glycoprotein pathways, mirroring in vivo findings. Pericyte-like cells exhibited similar APOE secretion levels across genotypes, yet APOE4 pericyte-like cells showed heightened extracellular amyloid deposition, while APOE2 pericyte-like cells displayed the least amyloid deposition, an observation in line with vascular pathologies in AD patients.ConclusionsWhile APOE genotype did not directly impact general BMEC or pericyte properties, APOE4 exacerbated amyloid clearance and deposition at the model BBB. Conversely, APOE2 demonstrated a potentially protective role by increasing amyloid transport and decreasing deposition. Our findings highlight that iPSC-derived BBB models can potentially capture amyloid pathologies at the BBB, motivating further development of such in vitro models in AD modeling and drug development.

TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis.

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimer's disease (AD) and longevity, remains unclear. APOE's neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues. T9A2 translation tethers APOE (normal APOE3 or APOE4) to near-full-length TOM40 that is targeted to mitochondria. Importantly, T9A2-APOE3 boosts mitochondrial bioenergetic capacity and decreases oxidative stress significantly more than T9A2-APOE4 and APOE3, and lacking in APOE4. We describe detailed interactomes of these actors that may inform about the activities and roles in pathogenesis. T9A2 uncovers a new candidate pathway for mitochondria regulation and oxidative stress-protection that are impaired in APOE4 genotypes and could initiate neurodegeneration.

Effect of ACE mutations on blood ACE phenotype parameters.

Analysis of existing mutations of Angiotensin-I-Converting Enzyme (ACE) led us to hypothesize that the carriers of damaging ACE mutations (accompanied by low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD). We quantified blood ACE levels in EDTA-containing plasma from 15 patients with 11 different heterozygous ACE mutations and estimated the effects of these mutations on ACE phenotypes, using a set of mAbs to ACE and two ACE substrates. We confirmed prior observations that the relatively frequent Y215C mutation in the N domain of ACE (present in ~1% of the population) is associated with both Alzheimer's disease (AD) and reduced plasma levels of ACE (~50% of controls), indicating that it likely results in a transport-deficient protein. In addition, we identified another 4 mutations in both ACE domains (M118T, C734Y, V992M and V997M) which are also associated with decreased ACE levels in the blood, and, thus, could be putative risk factors for late-onset AD. One of these mutations, C734Y, is likely transport-deficient, while the other mutations appear to influence ACE catalytic properties. The precipitation of mutant M118T by mAb 2D1 and ACE mutant C734Y by mAb 3F10 increased 2-3-fold compared to native ACE, and therefore, these mAbs could be markers of these mutations. Also, we identified a mutation I989T, which is associated with increased ACE levels in the blood. Conducting a systematic analysis of blood ACE levels in patients with ACE mutations holds promise for identifying individuals with low blood ACE levels. Such individuals may be at increased risk for late-onset AD. The patients with transport-deficient ACE mutations may benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously using a cell model of the transport-deficient ACE mutation, Q1069R [Danilov et al, PLoS One, 2010].