Apolipoprotein E Genotype Research Articles

Alzheimer's Disease Protein Targets: Comprehensive Review and Future Directions.

Alzheimer's disease (AD) is a gradual degenerative ailment of the nervous system that is marked by the buildup of amyloid-β plaques and neurofibrillary tangles. This accumulation causes problems with the connections between nerve cells and the loss of these cells. This review paper explores the complex pathophysiology of AD, analyzing the neuronal loss reported in key brain regions like the entorhinal cortex, amygdala, hippocampus, and cortical association areas. The text also examines subcortical nuclei participation, such as the noradrenergic locus coeruleus, serotonergic dorsal raphe, and cholinergic basal nucleus. Also, this review discusses the importance of tau protein hyperphosphorylation, oxidative stress, and metal ion dysregulation in the evolution of AD. Moreover, it explores the cholinergic theory and the influence of the APOE (apolipoprotein E) genotype on the effectiveness of therapy. This article thoroughly summarizes the current knowledge on AD, including its clinical symptoms and possible treatment approaches, by combining several theories and new targets. The study highlights the connection between the degree of tangle development and the severity of dementia, underlining the need for creative methods to tackle the complex difficulties of discovering drugs for AD.

Association of psychosocial state with subsequent risk of dementia: a prospective cohort study based on the UK Biobank

BackgroundMultiple psychosocial factors have been associated with dementia, while the individual or joint effects of various psychosocial states on dementia remain unrevealed due to the complex interplay between those factors. Here, the authors examined the associations of psychosocial factors and patterns with subsequent risk of dementia, and if the associations could be modified by genetic susceptibility to dementia.MethodsUK Biobank dementia-free participants were followed from one year after recruitment (median date: 24 January, 2010) until 31 October, 2022. Psychosocial states were measured by 22 items related to five dimensions, including psychiatric history, recent stressful life events, current psychiatric symptoms, social contact, and individual socioeconomic state. We identified clusters of individuals with distinct psychosocial patterns using latent class analysis. Cox proportional hazards models were used to evaluate the association between psychosocial items, as well as psychosocial patterns, and risk of dementia. We further performed stratification analyses by apolipoprotein E (APOE) genotype, polygenic risk score (PRS) of dementia, and family history of dementia.ResultsOf 497,787 included participants, 54.54% were female. During a median follow-up of 12.70 years, we identified 9,858 (1.98%) patients with newly diagnosed dementia. We identified seven clusters with distinct psychosocial patterns. Compared to individuals with a pattern of ‘good state’, individuals with other unfavorable patterns, featured by varying degrees of poor psychological state (‘fair state’ and ‘mildly, moderately, and extremely poor psychological state’), low social contact or socioeconomic state (‘living alone’ and ‘short education years’), were all at an increased risk of dementia (hazard ratios [HR] between 1.29 and 2.63). The observed associations showed no significant differences across individuals with varying APOE genotypes, levels of PRS, and family histories of dementia.ConclusionUnfavorable psychosocial patterns are associated with an increased risk of dementia, independent of genetic susceptibility. The findings highlight the importance of surveillance and prevention of cognitive decline among individuals with suboptimal psychosocial state.

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.

Genotyping Apolipoprotein E (APOE) Isoforms with Sequence-Specific-Primer (SSP)-PCR in Early‑Onset Alzheimer’s Disease Patients: A Rapid and Revised Methodology

Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive damage to brain cells, leading to impairment in cognitive functions. The Apolipoprotein E (APOE) variants play a significant role in the genetic basis of AD, especially late-onset AD (LOAD), and increase the disease risk at an earlier age. Although controversial, some studies reveal the association between APOE genotype and early-onset AD (EOAD) regardless of family history. Therefore, diagnostic laboratories widely perform routine tests to determine the APOE genotype. In the present study, we implemented a revised methodology for the Sequence-Specific-Primer-PCR (SSP-PCR) test for rapid APOE genotyping in 67 EOAD patients. Then, the findings were validated using automatic sequencing with newly designed primers for the related region of the APOE. We state clearly that the applicability of the SSP-PCR method was improved when the primer concentrations of control genes were increased 2-fold, as we reported. All data obtained from SSP-PCR were consistent with Sanger sequencing confirmations. Based on the genotyping results, the four different APOE genotypes were detected: E2/E4, E3/E3, E3/E4, and E4/E4. The frequencies were 1.5% (n=1) for E2/E4, 76.1% (n=51) for E3/E3, 16.4% (n=11) for E3/E4, and 6% (n=4) for E4/E4. In the study group, 23.9% (n=16) of the patients had homozygous or heterozygous APOE E4. However, we detected no significant association between the clinical features and the APOE genotype. As a result, this method is reliable, cost-effective, and rapid for performing genotyping analysis of the APOE for routine tests and research studies with larger EOAD cohorts.

Relationships between APOE, Type 2 Diabetes, and Cardiovascular Disease in Postmenopausal Women.

The Apolipoprotein E (APOE) ε4 allele, type 2 diabetes mellitus (T2DM), and cardiovascular disease (CVD) are well-established risk factors for dementia. Relationships between APOE and incidence of T2DM and CVD are not fully understood but may shed light on the mechanisms underlying dementia pathogenesis. Postmenopausal women (N=6,795) from the Women's Health Initiative hormone therapy clinical trial with APOE genotyping and no prior diagnosis of T2DM or CVD were included. We examined associations of APOE status (APOE2+ [ε2/ε2, ε2/ε3], APOE3 [ε3/ε3], and APOE4+ [ε4/ε4, ε3/ε4] carriers) with incidence of T2DM, coronary heart disease (CHD), stroke, and total CVD events using Cox regression. CVD outcomes were examined in baseline non-statin users and adjusted for statin initiation over follow-up to account for possible confounding by statins. Among all participants (mean age 66.7±6.5 years, 100% non-Hispanic white), 451 (6.6%) were using statins at baseline. Over the follow-up (mean 14.9 and 16.0 years for T2DM and CVD, respectively), 1,564 participants developed T2DM and 1,578 developed CVD. T2DM incidence did not differ significantly by APOE status (ps≥0.09). Among non-statin users, APOE4+ had higher incidence of total CVD (hazard ratio [95% confidence interval]=1.18 [1.02-1.38], p=0.03) compared to APOE3 carriers, but risks for CHD (1.09 [0.87-1.36], p=0.47) and stroke (1.14 [0.91-1.44], p=0.27) were not significantly elevated when examined individually. CVD outcomes did not differ between APOE2+ and APOE3 carriers (ps≥0.11). T2DM risk did not differ by APOE status among postmenopausal women, but APOE4+ carriers not using statins had an increased risk of total CVD events.

APOE×BDNF Interaction and Poorer Cognitive Outcomes Among Veterans With Mild Traumatic Brain Injury: An Exploratory Study.

The authors examined the interaction between apolipoprotein E (APOE) ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles on neuropsychological functioning among veterans with histories of mild traumatic brain injury (mTBI). Participants were 78 veterans with mTBI (85% males; mean±SD age=32.95±7.00 years; mean time since injury=67.97±34.98 months) who completed a structured clinical interview and underwent a comprehensive neuropsychological assessment. Participants also provided a buccal swab for determination of their APOE and BDNF genotypes. Three cognitive composite scores were calculated from the neuropsychological assessment, reflecting visuospatial speed (seven variables), executive functioning (10 variables), and memory (eight variables). Two-way analyses of covariance (ANCOVAs) adjusted for age, sex, and race-ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning. ANCOVAs revealed no significant main effects of APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE-by-BDNF genotype interaction for all three cognitive composite measures (visuospatial speed: ηp2=0.055; executive functioning: ηp2=0.064; and memory: ηp2=0.068). Specifically, the ε4+/Met+ (N=8) subgroup demonstrated the poorest cognitive functioning relative to all other allele subgroups (ε4+/Met-: N=12, ε4-/Met+: N=23, and ε4-/Met-: N=35). This exploratory study is the first to show that, compared with other allele subgroups assessed, veterans with both ε4 and Met alleles demonstrated the poorest cognitive functioning across several cognitive domains known to be negatively affected in the context of mTBI. Further research with larger sample sizes is needed to replicate these findings.

Insights into lipid-modified recognition of Apolipoprotein E3 to extra-cellular domain of TREM2 associated with Alzheimer’s disease

E3 genotype of apolipoprotein E (ApoE) and triggering receptor expressed on myeloid cells 2 (TREM2) are critical genetic risk factors for late-onset Alzheimer’s diseases (AD) that influences the formation of plaques and neurofibrillary tangles associated with AD pathogenesis. In addition, variation in genetic association of ApoE and TREM2 in presence of lipids have been advocated to potentially regulate different aspects of AD pathology by facilitating the clearance of amyloid beta (Aβ) from brain. However, the proteinopathy and functional mechanism underlying their molecular interaction in presence of lipid remains poorly understood. Herein, to shed inherent insights into the mode of ApoE3-TREM2 interaction in both lipid and aqueous medium, we have used a combination of different state-of-the-art computational tools including knowledge-based protein–protein docking and molecular dynamics (MD) simulations. Remarkably, we find the direct involvement of regulatory complementarity-determining region-2 (CDR2) loop of TREM2 in interaction with the major hinge region and helix H4 of ApoE3. We further anticipate that ApoE3 attains distinct conformational states and forms an open and extended cavity-like structure in ApoE3-TREM2 complex in presence of lipids. Our data also exhibits reduced hydrophobicity in the ApoE3 binding interface of TREM2, which sets a baseline for reduced binding affinity towards ApoE3. Therefore, we hypothesize that this decline in hydrophobic index might have resulted due to structural variations in the H4 helix and major hinge region leading to altered TREM2 conformation in presence of lipids. Altogether, our findings demonstrate the effect of phospholipids on the structural dynamics and conformation of ApoE3, which contributes to our understanding of how APOE and TREM2 influences the development of AD. However, further experimental studies are necessary to validate and explore our findings which will open up new avenues towards development of novel therapeutic strategies for AD.

Further validation of the association between MAPT haplotype-tagging polymorphisms and Alzheimer's disease: neuropsychological tests, cerebrospinal fluid biomarkers, and APOE genotype.

Genetic studies have shown that variants in the microtubule-associated protein tau (MAPT) gene, which encodes tau protein, can increase the risk for Alzheimer's disease (AD). Additionally, two haplotypes of the MAPT gene (H1 and H2) are associated with various neurodegenerative disorders, including AD. This study aimed to test the association of MAPT haplotypes (H1 and H2) and MAPT haplotype-tagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, del-In9, rs7521) with AD. The study included 964 individuals: 113 with AD, 53 with mild cognitive impairment (MCI), 54 with other dementias, and 744 healthy controls. The results showed that individuals carrying the A allele in the MAPT rs1467967 polymorphism, the GG genotype in the MAPT rs7521 polymorphism, and the G allele in the MAPT rs242557 polymorphism had worse performance on various neuropsychological tests. Carriers of the C allele in MAPT rs2471738 polymorphism and CC homozygotes also showed worse performance on neuropsychological tests and pathological levels of several cerebrospinal fluid (CSF) biomarkers. However, T allele carriers in the MAPT rs2471738 polymorphism were more represented among patients with dementia and apolipoprotein E (APOE) ɛ4 carriers. Carriers of the H2 MAPT haplotype had worse performance on various neuropsychological tests, consistent with our previous study, which associated the H2 MAPT haplotype with pathological levels of CSF AD biomarkers. Regarding the MAPT rs3785883 polymorphism, further research is needed since both the AA and GG genotypes were associated with pathological levels of CSF and plasma AD biomarkers. In conclusion, further genetic studies are needed to elucidate the role of MAPT haplotypes and MAPT haplotype-tagging polymorphisms in the development of AD.

Machine Learning-Driven Prediction of Brain Age for Alzheimer's Risk: APOE4 Genotype and Gender Effects.

Background: Alzheimer's disease (AD) is a leading cause of dementia, and it is significantly influenced by the apolipoprotein E4 (APOE4) gene and gender. This study aimed to use machine learning (ML) algorithms to predict brain age and assess AD risk by considering the effects of the APOE4 genotype and gender. Methods: We collected brain volumetric MRI data and medical records from 1100 cognitively unimpaired individuals and 602 patients with AD. We applied three ML regression models-XGBoost, random forest (RF), and linear regression (LR)-to predict brain age. Additionally, we introduced two novel metrics, brain age difference (BAD) and integrated difference (ID), to evaluate the models' performances and analyze the influences of the APOE4 genotype and gender on brain aging. Results: Patients with AD displayed significantly older brain ages compared to their chronological ages, with BADs ranging from 6.5 to 10 years. The RF model outperformed both XGBoost and LR in terms of accuracy, delivering higher ID values and more precise predictions. Comparing the APOE4 carriers with noncarriers, the models showed enhanced ID values and consistent brain age predictions, improving the overall performance. Gender-specific analyses indicated slight enhancements, with the models performing equally well for both genders. Conclusions: This study demonstrates that robust ML models for brain age prediction can play a crucial role in the early detection of AD risk through MRI brain structural imaging. The significant impact of the APOE4 genotype on brain aging and AD risk is also emphasized. These findings highlight the potential of ML models in assessing AD risk and suggest that utilizing AI for AD identification could enable earlier preventative interventions.

Association of apolipoprotein E gene polymorphism with gallstone disease in Iraqi Kurdish women

Gallstone disease (GSD) is a worldwide problem; the frequency of GSD varies greatly amongst different ethnic groups, possibly due to environmental and genetic factors. One circulating lipoprotein involved in lipid metabolism is apolipoprotein E (APOE). The APOE gene is polymorphic, has three distinct alleles, APOE2, APOE3, and APOE4. The an APOE polymorphism is linked to a variety of diseases, including Alzheimer's and type-two diabetes, so this study aimed to assess the relationship among various APOE genotypes and alleles with gallstone cases in Iraqi Kurdish women. The present case-control study involved 81 cases with laparoscopic cholecystectomy for gallstone disease and 80 healthy women without GSD. Genomic DNA samples were taken from blood to find the genotype of APOE using allele-specific sequence-primers and a method based on polymerase chain reaction (PCR). lipid profiles were examined using an automated biochemical analyzer. SPSS and GraphPad Prism 9.1.1 software were used to conduct the statistical analysis. No significant relationships were found between healthy people and GSD patients in genotype and allele frequencies. However, the genotype for E3/E4 and the APOE4 allele in GSD patients were higher than the controls (9.88% vs. 5.0% and 4.94% vs. 2.5%, respectively; P <0.05) but statistically nonsignificant. serum levels of cholesterol, low-density lipoproteins, and very low-density lipoproteins were higher, and the levels of serum high-density lipoprotein was lower than controls. These findings revealed no connection between the examined polymorphisms and gallstone cases. Additionally, it was demonstrated that gallstone disease and lipid parameters had a favorable relationship. Keywords: Apolipoprotein E, APOE, Gallstone disease, Genotype, Polymorphisms.

The biphasic impact of apolipoprotein E ε4 allele on age-related hearing loss

Both the ε4 variant of the apolipoprotein E (APOE) gene and hearing loss are well-known risk factors for Alzheimer's disease. However, previous studies have produced inconsistent findings regarding the association between APOE genotypes and hearing levels, necessitating further investigation. The aim of this study was to investigate the relationship between APOE genotypes and hearing levels. This retrospective study analyzed clinical data from a clinical data warehouse of seven affiliated Catholic Medical Center hospitals. The study included 1,162 participants with records of APOE genotypes, audiometric tests, and cognitive function tests. In Generalized linear mixed model analysis, ε4 carriers exhibited lower pure tone audiometry thresholds with an estimate of -0.353 (SE = 0.126, p = 0.005). However, the interaction term for age and APOE ε4 had a coefficient of 0.577 (SE = 0.214 p = 0.006), suggesting that the APOE ε4 gene may accelerate hearing deterioration with age. Subgroup analysis based on an age cut-off of 75 revealed that ε4 carriers had better hearing at younger ages, but showed no significant difference at older ages. These results indicate that the ε4 allele may have a biphasic effect on hearing levels depending on age.

Plasma proteomics for risk prediction of Alzheimer's disease in the general population.

We aimed to develop and validate a protein risk score for predicting Alzheimer's disease (AD) and compare its performance with a validated clinical risk model (Cognitive Health and Dementia Risk Index for AD [CogDrisk-AD]) and apolipoprotein E (APOE) genotypes. The development cohort, consisting of 35,547 participants from England in the UK Biobank, was randomly divided into a 7:3 training-testing ratio. The validation cohort included 4667 participants from Scotland and Wales in the UK Biobank. In the training set, an AD protein risk score was constructed using 31 proteins out of 2911 proteins. In the testing set, the AD protein risk score had a C-index of 0.867 (95% CI, 0.828, 0.906) for AD prediction, followed by CogDrisk-AD risk factors (C-index, 0.856; 95% CI, 0.823, 0.889), and APOE genotypes (C-index, 0.705; 95% CI, 0.660, 0.750). Adding the AD protein risk score to CogDrisk-AD risk factors (C-index increase, 0.050; 95% CI, 0.008, 0.093) significantly improved the predictive performance for AD. However, adding CogDrisk-AD risk factors (C-index increase, 0.040; 95% CI, -0.007, 0.086) or APOE genotypes (C-index increase, 0.000; 95% CI, -0.054, 0.055) to the AD protein risk score did not significantly improve the predictive performance for AD. The top 10 proteins with the highest coefficients in the AD protein risk score contributed most of the predictive power for AD risk. These results were verified in the external validation cohort. EGFR, GFAP, and CHGA were identified as key proteins within the protein network. Our result suggests that the AD protein risk score demonstrated a good predictive performance for AD risk.

APOE gene polymorphism in ischemic stroke patients from Huizhou and its correlation with blood lipids and homocysteine

ObjectivesTo investigate the correlation between apolipoprotein E (APOE) gene polymorphisms and ischemic stroke and its relationship with blood lipids and homocysteine (HCY) level in Huizhou City. Materials and methodsIn this analytical cross-sectional study, we selected 2612 patients who underwent APOE genotyping from November 2019 to November 2021 at the Third People's Hospital of Huizhou. Among them, 2014 were ischemic stroke patients and 598 were non-stroke patients. The independent variables were ischemic stroke, different genotypes, and different alleles, while the dependent variables were blood lipid levels and HCY levels. ResultsThe distribution frequency of ε4 allele in stroke group was higher than that in non-stroke group (P < 0.05). Compared with ε4 allele carriers in the stroke group, the levels of lipid total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in ε2 and ε3 allele carriers were significantly lower, while the levels of high-density lipoprotein cholesterol (HDL-C) were significantly higher (P < 0.01). The levels of lipid Lipoprotein a (LPa) and small dense low-density lipoprotein (sdLDL) in ε2 allele carriers in stroke group were significantly lower than those of ε4 allele carriers (P < 0.05). Logistics regression analysis showed that age, TC, HCY level and allele ε4 were positively correlated with the risk of ischemic stroke (P < 0.01), TG level was positively correlated with the risk of ischemic stroke in females (P < 0.01). ConclusionsAPOE gene polymorphism is associated with ischemic stroke, and ε4 allele carriers have a higher risk than ε3 allele carriers.

The links among age, sex, and glutathione: A cross-sectional magnetic resonance spectroscopy study

Glutathione (GSH) is a brain marker for oxidative stress and has previously been associated with cerebral amyloid deposition and memory decline. However, to date, no study has examined the links among GSH, sex, age, amyloid, and Apolipoprotein E (APOE) genotype in a large non-clinical cohort of older adults. We performed APOE genotyping, magnetic resonance spectroscopy (MRS) as well as simultaneous positron emission tomography with the radiotracer Flutemetamol (Amyloid-PET), in a group of older adults. The final analysis set comprised 140 healthy older adults (mean age: 64.7 years) and 49 participants with mild cognitive impairment (mean age: 71.4 years). We recorded metabolites in the posterior cingulate cortex (PCC) by a GSH-edited MEGAPRESS sequence. Structural equation modeling revealed that higher GSH levels were associated with female sex, but neither APOE- epsilon 4 carrier status nor age showed significant associations with GSH. Conversely, older age and the presence of an APOE4 allele, but not sex, are linked to higher global amyloid load. Our results suggest that the PCC shows sex-specific GSH alterations in older adults.

Effects of a high-fat diet on cognition and brain distribution of intranasal insulin in E3 and E4 male and female mice

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer’s disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.

Amyloid, Tau, and APOE in Alzheimer's Disease: Impact on White Matter Tracts.

Alzheimer's disease (AD) is characterized by cognitive decline and memory loss due to the abnormal accumulation of amyloid-beta (Aβ) plaques and tau tangles in the brain; its onset and progression also depend on genetic factors such as the apolipoprotein E (APOE) genotype. Understanding how these factors affect the brain's neural pathways is important for early diagnostics and interventions. Tractometry is an advanced technique for 3D quantitative assessment of white matter tracts, localizing microstructural abnormalities in diseased populations in vivo. In this work, we applied BUAN (Bundle Analytics) tractometry to 3D diffusion MRI data from 730 participants in ADNI3 (phase 3 of the Alzheimer's Disease Neuroimaging Initiative; age range: 55-95 years, 349M/381F, 214 with mild cognitive impairment, 69 with AD, and 447 cognitively healthy controls). Using along-tract statistical analysis, we assessed the localized impact of amyloid, tau, and APOE genetic variants on the brain's neural pathways. BUAN quantifies microstructural properties of white matter tracts, supporting along-tract statistical analyses that identify factors associated with brain microstructure. We visualize the 3D profile of white matter tract associations with tau and amyloid burden in Alzheimer's disease; strong associations near the cortex may support models of disease propagation along neural pathways. Relative to the neutral genotype, APOE ϵ3/ϵ3, carriers of the AD-risk conferring APOE ϵ4 genotype show microstructural abnormalities, while carriers of the protective ϵ2 genotype also show subtle differences. Of all the microstructural metrics, mean diffusivity (MD) generally shows the strongest associations with AD pathology, followed by axial diffusivity (AxD) and radial diffusivity (RD), while fractional anisotropy (FA) is typically the least sensitive metric. Along-tract microstructural metrics are sensitive to tau and amyloid accumulation, showing the potential of diffusion MRI to track AD pathology and map its impact on neural pathways.

Phishing vulnerability compounded by older age, apolipoprotein E e4 genotype, and lower cognition.

With technological advancements, financial exploitation tactics have expanded into the online realm. Older adults may be particularly susceptible to online scams due to age- and Alzheimer's disease-related changes in cognition. In this study, 182 adults ranging from 18 to 90 years underwent cognitive assessment, genotyping for apolipoprotein E e4 (APOE4), and completed the lab-based Short Phishing Email Suspicion Test (S-PEST) as well as the real-life PHishing Internet Task (PHIT). Across both paradigms, older age predicted heightened susceptibility to phishing, with this enhanced susceptibility pronounced among older APOE4 allele carriers with lower working memory. Additionally, performance in both phishing tasks was correlated in that reduced ability to discriminate between phishing and safe emails in S-PEST predicted greater phishing susceptibility in PHIT. The current study identifies older age, APOE4, and lower cognition as risk factors for phishing vulnerability and introduces S-PEST as an easy-to-administer, ecologically valid tool for assessing phishing susceptibility.

Cancer-Related Cognitive Impairment Associated with APOE rs7412 and BDNF rs6265 in Breast Cancer Survivors

ObjectivesCancer-related cognitive impairment (CRCI) is a highly prevalent and debilitating symptom reported by breast cancer survivors (BCS). The etiology of CRCI remains unclear, leading to poor symptom management. Building from prior studies, BCS with the C/C genotype of apolipoprotein E (APOE) rs7412 and the T/T genotype of brain-derived neurotrophic factor (BDNF) rs6265 were hypothesized to experience more severe CRCI. Therefore, we investigated the relationships between the severity of CRCI and polymorphisms of APOE and BDNF among BCS. MethodsThis was a subanalysis of data from a larger descriptive, correlational, and cross-sectional study. Subjective and objective CRCI were measured using the Patient-Reported Outcomes Measurement Information System and CANTAB Cambridge Cognitive assessment, respectively. Buccal swab samples were collected to evaluate the single nucleotide polymorphisms. Multivariable generalized linear regression models were used to analyze data. ResultsAPOE rs7412 and BDNF rs6265 were significantly associated with lower self-reported cognitive abilities in a total of 353 BCS. Age was positively associated with self-reported cognitive scores, indicating that younger BCS perceived lower cognitive abilities. Individuals carrying genotype of C/T for APOE with the C/C or C/T for BDNF showed positive associations with cognitive abilities. ConclusionsYounger BCS with the C/C genotype for APOE rs7412 and the T/T genotype for BDNF rs6265 may be at risk for CRCI. Knowledge regarding predictive markers for CRCI symptoms is essential for precision symptom management. Further investigation with a longitudinal and translational design is necessary to explore the etiologies for CRCI. Implications for Nursing PracticeIntegrating genetic phenotyping into routine clinical practice will provide nurses with unique opportunities to understand individual susceptibilities, and how symptoms may trigger other symptoms. Further, findings from these innovative investigations will provide symptom interventionists and implementation scientists with critical data to optimize individualized strategies for symptom prevention, detection, and management.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population.

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.

Classifying Alzheimer's Disease Neuropathology Using Clinical and MRI Measurements.

Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.