APOE Genotype Research Articles

Role of Angiotensin II on Cardiovascular/Autonomic Function and Cognition in a Novel Mouse Model of Alzheimer’s Disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Despite being the most common form of dementia in the elderly, mechanisms causing AD remain elusive. Emerging evidence have associated brain renin-angiotensin system (RAS) to AD neuropathology. RAS actions are predominantly mediated by angiotensin II (Ang II) binding to type 1 receptors. Previously, we have observed that human apolipoprotein E4-knockin (risk factor for AD) mice develop progressive hypertension and increases in Ang II levels in CSF with aging [FASEB J 36(S1): R3532]. Thus, we hypothesize that Ang II-mediated hypertension contributes to cognitive decline in AD. We have generated a novel transgenic mouse model of AD i.e. 3XE4 by breeding E4-knockin mouse with APPsw, PS1dE9, and tauP301S transgenes, to mimic human AD pathology in mice. Blood pressure (BP) and heart rate (HR) were measured by radiotelemetry in 3XE4 (n=6) and control 3XE3 (n=6) mice, before and after 28-days of Ang II infusion (1000 ng/kg/min, osmotic pump). Diurnal BP variability was calculated as the difference between night-time (11:00 PM-3:00 AM) and day-time (8:00 AM-12:00 PM). Cardiac vagal and sympathetic tones were calculated as changes in HR with atropine and propranolol (1 mg/kg each, IP), respectively. Cardiac function (echocardiography) and cognitive behavior (novel object recognition test) were measured. At baseline, BP was similar in control (127±11 mmHg) and 3XE4 (123±5 mmHg) mice. Unlike the control mice, 3XE4 mice exhibit reduced vagal tone (ΔHR= +119±22 vs. +25±24 bpm) and increased sympathetic tone (ΔHR= -76±33 vs. -212±40 bpm), which worsens with Ang II (p<0.05 vs. baseline). Interestingly, Ang II increased BP (24%), induced LV hypertrophy (26%), impaired diurnal BP variability, and evoked learning and memory deficits; albeit only in the 3XE4 mice (p<0.05 vs. control mice). These results demonstrate that Ang II-mediated hypertension and autonomic dysfunction likely exacerbate disease progression and cognitive decline in the 3XE4 mouse model of AD. Therefore, our study provides a proof-of- concept in delineating the association of ApoE4 genotype and Ang II with Alzheimer’s disease. NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex differences in a novel transgenic mouse model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia characterized by memory deficits, cognitive impairment, and presence of amyloid plaques and tau tangles in the brain. In the United States, six million people over the age of 65 live with AD, four million of whom are women. The apolipoprotein ( APOE) gene is the strongest genetic risk factor for late-onset AD, with the ε4 allele increasing AD risk relative to the ε3 allele. Mechanisms driving sex-based prevalence in the APOE4 genotype remain unknown. Previously, we have reported that female APOE4 mice develop hypertension and increased levels of vasoconstrictor angiotensin II (Ang II) in CSF with aging [FASEB J 2022: 36S1]. To better recapitulate human AD pathology and phenotype, we have recently generated unique mouse strains - 3XE4 and 3XE3 mice, by breeding human APOE4/APOE3-knockin with APPsw, PS1dE9, and tauP301S transgenes. Our goal is to study sex differences in the 3XE4 mice with AD. Blood pressure (BP, tail cuff), cognition (novel object recognition test), and cardiac function (echocardiography) were measured in both control 3XE3 (n=6) mice and 3XE4 (n=6) mice before and after Ang II (osmotic minipump, 1000 ng/kg/min). As expected, female mice weighed less than the male mice (Table). Basal BP and ejection fraction were higher in male 3XE4 mice compared to female 3XE4 mice (p<0.05). Total exploration time of novel object was significantly delayed in 3XE4 mice (p<0.05); the impairment was greater in the female 3XE4 mice. Notably, Ang II increased BP in male 3XE4 mice (151±5 mmHg) but not in female 3XE4 mice (125±2 mmHg). Unlike the 3XE3 mice, total exploration time of novel object was delayed (impaired) in both male and female 3XE4 mice at baseline and during Ang II. Although additional studies are needed to explore the underlying mechanisms, our results implicate potential sexual dimorphism in blood pressure regulation and cognition in Alzheimer’s Disease. [Formula: see text] Funding: NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60-80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

Clinical predictors of Alzheimer's disease-like brain atrophy in individuals with memory complaints.

The definition and assessment methods for subjective cognitive decline (SCD) vary among studies. We aimed to investigate which features or assessment methods of SCD best predict Alzheimer's disease (AD)-related structural atrophy patterns. We assessed 104 individuals aged 55+ with memory complaints but normal cognitive screening. Our research questions were as follows: To improve the prediction of AD related morphological changes, (1) Would the use of a standardized cognitive screening scale be beneficial? (2) Is conducting a thorough neuropsychological evaluation necessary instead of relying solely on cognitive screening tests? (3) Should we apply SCD-plus research criteria, and if so, which criterion would be the most effective? (4) Is it necessary to consider medical and psychiatric comorbidities, vitamin deficiencies, vascular burden on MRI, and family history? We utilized Freesurfer to analyze cortical thickness and regional brain volume meta-scores linked to AD or predicting its development. We employed multiple linear regression models for each variable, with morphology as the dependent variable. AD-like morphology was associated with subjective complaints in males, individuals with advanced age, and higher education. Later age of onset for complaints, complaints specifically related to memory, excessive deep white matter vascular lesions, and using medications that have negative implications for cognitive health (according to the Beers criteria) were predictive of AD-related morphology. The subjective cognitive memory questionnaire scores were found to be a better predictor of reduced volumes than a single-question assessment. It is important to note that not all SCD-plus criteria were evaluated in this study, particularly the APOE genotype, amyloid, and tau status, due to resource limitations. The detection of AD-related structural changes is impacted by demographics and assessment methods. Standardizing SCD assessment methods can enhance predictive accuracy.

The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes.

By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. To develop a genomic-informed risk assessment composed of family history, genetic, and clinical risk factors and, in turn, evaluate how the risk assessment predicted incident dementia. This longitudinal study included data from two clinical case-control cohorts with an average of 6.6 visits. Secondary analyses were conducted from July 2023 - March 2024. Data were previously collected across multiple US locations from 1994 to 2023. Older adults aged 55+ with whole-genome sequencing and dementia-free at baseline. An additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score. The risk of progression to all-cause dementia was evaluated using Cox-proportional hazard models (hazard ratios with 95% confidence intervals [OR 9%CI]). A total of 3,429 older adults were included (aged 75 ± 7 years; 59% female; 75% non-Latino White, 15% Black, 5.2% Latino, 3.6% other, and 0.4% Asian; 27% MCI), with 751 participants progressing to dementia. The most common high-risk indicator was a family history of dementia (56%), followed by APOE*ε4 genotype (36%), high mCAIDE score (34%), and high AD-PRS (11%). Most participants had at least one high-risk indicator, with 39% having one, 32% two, 9.8% three, and 1% four. The presence of 1, 2, 3, or 4 risk indicators was associated with a doubling (HR = 1.72, CI: 1.34-2.22, p = 2.5e-05), tripling (HR = 3.09, CI: 2.41-3.95, p = 4.4e-19), quadrupling (HR = 4.46, CI: 3.34-5.94, p = 2.2e-24), and a twelvefold increase (HR = 12.15, CI: 7.33-20.14, p = 3.2e-22) in dementia risk. We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

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

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

The Effects of Psychosocial and Traumatic Stressors on MCI Diagnosis

Background and Objective: Toxic stress exposure can have effects across the lifespan. Studies of civilians and veterans suggest a connection between psychosocial and traumatic stressor exposure in adulthood and a diagnosis of dementia later in life. The objective of this study was to investigate the impact of psychosocial and traumatic stressors on rates of MCI (Mild Cognitive Impairment) diagnosis in Vietnam Era Twin Study of Aging participants. Methods: 1,237 twin participants from the VETSA study were aged 61.72 ± 2.44 years at the time of data collection. Traumatic stress was measured by clinical interviewing, with psychosocial stressors quantified by self-report measures. Neuropsychological assessment determined MCI diagnosis. Previously conducted genotyping determined ApoE genotype. Mixed model analysis was used to determine effects on MCI diagnosis. Results: Our results from the mixed model analysis did not find a significant relationship between psychosocial and traumatic stress exposure and MCI diagnosis. PTSD diagnosis, measured by the DIS-III-R, collected for the Harvard Drug Study in 1996 (F = 0.249, p = 0.618) does not have a significant effect on MCI diagnosis. Life stress exposure, measured by the Holmes and Rahe (1967), (F = 0.249, p = 0.618) does not have a significant effect on MCI diagnosis. Significant associations were determined using the Type III fixed effects. Associations were considered statistically significant at p < 0.05, two-tailed. Implications: Few subjects in Wave 2 of VETSA had MCI (n = 147), due in part to the age of the participants at the time (Mean 61.72 ± (2.44 years)). This led to a lack of power in our analysis. Future studies should examine all available VETSA data.

Towards early diagnosis of Alzheimer's disease: advances in immune-related blood biomarkers and computational approaches.

Alzheimer's disease has an increasing prevalence in the population world-wide, yet current diagnostic methods based on recommended biomarkers are only available in specialized clinics. Due to these circumstances, Alzheimer's disease is usually diagnosed late, which contrasts with the currently available treatment options that are only effective for patients at an early stage. Blood-based biomarkers could fill in the gap of easily accessible and low-cost methods for early diagnosis of the disease. In particular, immune-based blood-biomarkers might be a promising option, given the recently discovered cross-talk of immune cells of the central nervous system with those in the peripheral immune system. Here, we give a background on recent advances in research on brain-immune system cross-talk in Alzheimer's disease and review machine learning approaches, which can combine multiple biomarkers with further information (e.g. age, sex, APOE genotype) into predictive models supporting an earlier diagnosis. In addition, mechanistic modeling approaches, such as agent-based modeling open the possibility to model and analyze cell dynamics over time. This review aims to provide an overview of the current state of immune-system related blood-based biomarkers and their potential for the early diagnosis of Alzheimer's disease.

Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype

ABSTRACT Objective Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status – particularly possession of the apolipoprotein E (APOE) ε4 allele – can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. Methods 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24–50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4−) on MIST scores. Results Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp 2 =.160), Time Cue (p = .003, ηp 2 =.157), and PM Total (p = .016, ηp 2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp 2 =.113) and PM Total (p = .048, ηp 2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4− Veterans on the MIST 15-min delay subscale (p = .031, ηp 2 = .150). Conclusions mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

APOE Genotype, ApoE Plasma Levels, Lipid Metabolism, and Cognition in Monozygotic Twins with, at Risk of, and without Affective Disorders.

Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed.

Impact of Short-Term Computerized Cognitive Training on Cognition in Older Adults With and Without Genetic Risk of Alzheimer's Disease: Outcomes From the START Randomized Controlled Trial

ObjectivesTo establish the impact of a 3-minute computerized cognitive training program (START) on cognition in older adults with and without genetic risk of Alzheimer's disease. DesignTwo-arm randomized controlled trial of the START program. Setting and ParticipantsRemote online trial in adults older than 50 taking part from home. MethodsThe trial compared the START program with placebo in 6544 people older than 50. Primary outcome was executive function measured through Trailmaking B, with other secondary cognitive measures. Genetic risk profile and ApoE4 status were determined by Illumina Array. ResultsSTART conferred benefit to executive function, attention, memory, and a composite measure, including in people with the ApoE4 genotype. Conclusions and ImplicationsThe 3-minute START task offers a means of supporting cognitive health in older adults and could be used at scale and within a precision medicine approach to reduce risk of cognitive decline in a targeted way.

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

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

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

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

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

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

APOE Genotype, White Matter Hyperintensities, and Cerebral Microbleeds in a Cohort with Intact Cognition (P1-9.011)

APOE Genotype, White Matter Hyperintensities, and Cerebral Microbleeds in a Cohort with Intact Cognition (P1-9.011)

Generation of three isogenic, gene-edited iPSC lines carrying the APOE-Christchurch mutation into the three common APOE variants: APOE2Ch, APOE3Ch and APOE4Ch

Late-onset Alzheimer’s disease (AD) has become the paradigm of a non-mendelian complex neurodegenerative disease, for which a major genetic determinant is known, the APOE locus. A rare APOE variant named Christchurch (APOEch) yielding a missense mutation from Arginine to Serine at amino acid 136, has been suggested to exert a protective effect in an individual carrying the most penetrant form of Familial AD (Paisa mutation in PSEN1 gene, E280A). We describe here a new set of induced pluripotent stem cell (iPSC) lines, where the Christchurch mutation (Ch) has been introduced by gene editing into the APOE locus of three isogenic iPSC lines carrying the more common APOE variants (APOE 2/2, APOE 3/3, and an APOE 4/4) in homozygosity. Brain cells derived from these iPSC lines will enable a better understanding of APOE biology in general and facilitate the study of how the Christchurch variant affects the function of each APOE genotype. This set of iPSC lines are globally available via the European Bank of iPSCs, EBiSC.org.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

Human in vivo evidence of associations between herpes simplex virus and cerebral amyloid-beta load in normal aging

BackgroundMounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of AD, possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging, which may contribute to the elucidation of the role of HSV-1 infection as a potential AD risk factor.MethodsTo shed light into this question, serum anti-HSV IgG levels were correlated with 18F-Florbetaben-PET binding to Aβ deposits and blood markers of neurodegeneration (pTau181 and neurofilament light chain) in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers.ResultsWe showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration.ConclusionsAll together, these results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Alzheimer's disease prevention: Apolipoprotein e4 moderates the effect of physical activity on brain beta-amyloid deposition in healthy older adults

ObjectivesTo investigate if higher baseline physical activity levels are associated with less β-amyloid burden and whether the ApoE4 genotype moderates this association cross-sectionally and longitudinally. DesignProspective cohort study. Methods204 cognitively normal older adults (74.5 ± 6.6 years; 26 % ApoE4-carrier) were analyzed. Baseline physical activity was measured using the Minnesota Physical Activity Questionnaire. Brain β-amyloid burden was measured with positron emission tomography using 11C-labeled Pittsburgh compound. A subsample of 128 participants underwent longitudinal positron emission tomography (2.0 ± 0.9 scans over 5 ± 3 years). Statistical analysis was run according to physical activity (high/low group) and the ApoE4 genotype (carrier/noncarrier). ResultsThe ApoE4 genotype moderated the relationship between physical activity and β-amyloid, such that low physical activity had a greater impact on β-amyloid deposition in ApoE4-carriers than noncarriers. This ApoE4 × physical activity effect on brain β-amyloid deposition was also observed when all available β-amyloid scan timepoints were included in the model. β-amyloid deposition increased over time (p < 0.001), and ApoE4-carriers had disproportionately greater β-amyloid accumulation than ApoE4-noncarriers. The lower physical activity group had marginally greater β-amyloid accumulation than the higher physical activity group (p = 0.099), but there was no significant ApoE4 effect on β-amyloid accumulation. ConclusionsLow physical activity in combination with the ApoE4-carrier genotype is associated with increased β-amyloid burden, suggesting that ApoE4 moderates the effect of physical activity on β-amyloid load. However, this effect was insufficient for baseline physical activity to modulate the change in β-amyloid accumulation over time.

Vascular Heparan Sulfate and Amyloid-β in Alzheimer's Disease Patients.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease characterized by the accumulation of extracellular amyloid-β peptides (Aβ) within the cerebral parenchyma and vasculature, which is known as cerebral amyloid angiopathy (CAA). This study utilized confocal imaging to investigate heparan sulfate (HS) expression within the cerebrovasculature and its associations with Aβ, gender, and ApoE4 genotype in AD. Our investigation revealed elevated levels of HS in the cerebrovasculature of AD patients with severe CAA. Additionally, these patients exhibited higher HS colocalization with Aβ in the cerebrovasculature, including both endothelial and vascular smooth muscle cell compartments. Intriguingly, a reversal in the polarized expression of HS within the cerebrovasculature was detected in AD patients with severe CAA. Furthermore, male patients exhibited lower levels of both parenchymal and cerebrovascular HS. Additionally, ApoE4 carriers displayed heightened cerebrovascular Aβ expression and a tendency of elevated cerebrovascular HS levels in AD patients with severe CAA. Overall, these findings reveal potential intricate interplay between HS, Aβ, ApoE, and vascular pathology in AD, thereby underscoring the potential roles of cerebrovascular HS in CAA development and AD pathology. Further study of the underlying mechanisms may present novel therapeutic avenues for AD treatment.