Maximizing utility of neuropsychological measures in sex-specific predictive models of incident Alzheimer's disease in the Framingham Heart Study.

INTRODUCTION: Sex differences in neuropsychological (NP) test performance might have important implications for the diagnosis of Alzheimer's disease (AD). This study investigates sex differences in neuropsychological performance among individuals without dementia at baseline. METHODS: Neuropsychological assessment data, both standard test scores and process coded responses, from Framingham Heart Study participants were analyzed for sex differences using regression model and Cox proportional hazards model. Optimal NP profiles were identified by machine learning methods for men and women. RESULTS: Sex differences were observed in both summary scores and composite process scores of NP tests in terms of adjusted means and their associations with AD incidence. The optimal NP profiles for men and women have 10 and 8 measures, respectively, and achieve 0.76 mean area under the curve for AD prediction. DISCUSSION: These results suggest that NP tests can be leveraged for developing more sensitive, sex-specific indices for the diagnosis of AD.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

BMI decline patterns and relation to dementia risk across four decades of follow-up in the Framingham Study.

BACKGROUND: Obesity has been associated with increased risk of dementia with several studies reporting a reverse causality, with weight loss preceding the onset of dementia. METHODS: Two thousand forty-five non-demented Framingham Offspring participants, aged 30 to 50 years, were included to determine effect of body mass index (BMI) decline patterns from mid- to late life over a 39-year follow-up. Group-based trajectory models were used to create BMI trajectories. RESULTS: Decreasing BMI trends were associated with higher risk of developing dementia in late life. Decliners with first early mid-life increasing and then later mid-life declining patterns of BMI were at greater increased risk of dementia compared to non-decliners (hazard ratio 3.84, 95% confidence interval 1.39-10.60). CONCLUSION: While patterns of decline in BMI were associated with dementia, a subgroup with a pattern of initial increasing BMI followed by declining BMI, both occurring within mid-life, appeared to be central to declining BMI-dementia association. Further validations are needed to provide robust conclusions.

Long-term blood pressure patterns in midlife and dementia in later life: Findings from the Framingham Heart Study.

INTRODUCTION: Long-term blood pressure (BP) measures, such as visit-to-visit BP variability (BPV) and cumulative BP, are strong indicators of cardiovascular risks. This study modeled up to 20 years of BP patterns representative of midlife by using BPV and cumulative BP, then examined their associations with development of dementia in later life. METHODS: For 3201 individuals from the Framingham Heart Study, multivariate logistic regression analyses were performed to examine the association between long-term BP patterns during midlife and the development of dementia (ages ≥ 65). RESULTS: After adjusting for covariates, every quartile increase in midlife cumulative BP was associated with a sequential increase in the risk of developing dementia (e.g., highest quartile of cumulative systolic blood pressure had approximately 2.5-fold increased risk of all-cause dementia). BPV was not significantly associated with dementia. DISCUSSION: Findings suggest that cumulative BP over the course of midlife predicts risk of dementia in later life. HIGHLIGHTS Long-term blood pressure (BP) patterns are strong indicators of vascular risks. Cumulative BP and BP variability (BPV) were used to reflect BP patterns across midlife. High cumulative BP in midlife is associated with increased dementia risk. Visit-to-visit BPV was not associated with the onset of dementia.

Midlife lipid and glucose levels are associated with Alzheimer's disease.

INTRODUCTION: It is unknown whether vascular and metabolic diseases assessed in early adulthood are associated with Alzheimer's disease (AD) later in life. METHODS: Association of AD with lipid fractions, glucose, blood pressure, body mass index (BMI), and smoking obtained prospectively from 4932 Framingham Heart Study (FHS) participants across nine quadrennial examinations was evaluated using Cox proportional hazard and Kaplan-Meier models. Age-, sex-, and education-adjusted models were tested for each factor measured at each exam and within three adult age groups (early = 35-50, middle = 51-60, and late = 61-70). RESULTS: A 15 mg/dL increase in high density lipoprotein (HDL) cholesterol was associated with decreased AD risk during early (15.4%, P = 0.041) and middle (17.9%, P = 0.014) adulthood. A 15 mg/dL increase in glucose measured during middle adulthood was associated with 14.5% increased AD risk (P = 0.00029). These findings remained significant after adjusting for treatment. DISCUSSION: Our findings suggest that careful management of cholesterol and glucose beginning in early adulthood can lower AD risk.

Blood levels of MCP-1 modulate the genetic risks of Alzheimer's disease mediated by HLA-DRB1 and APOE for Alzheimer's disease.

INTRODUCTION: C-Reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) are both implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption. Since the blood CRP level increases Alzheimer's disease (AD) risk depending on the apolipoprotein E (APOE) genotype, we hypothesized that the blood MCP-1 level exerts different effects on the AD risk depending on the genotypes. METHODS: Using multiple regression analyses, data from the Framingham Heart Study (n = 2884) and Alzheimer's Disease Neuroimaging Initiative study (n = 231) were analyzed. RESULTS: An elevated blood MCP-1 level was associated with AD risk in major histocompatibility complex, Class II, DR beta 1 (HLA-DRB1) rs9271192-AC/CC (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.50-6.28, p = 0.002) and in APOE ε4 carriers (HR = 3.22, 95% CI = 1.59-6.53, p = 0.001). In contrast, among HLA-DRB1 rs9271192-AA and APOE ε4 noncarriers, blood MCP-1 levels were not associated with these phenotypes. DISCUSSION: Since HLA-DRB1 and APOE are expressed in the BBB, blood MCP-1 released in the peripheral inflammatory cascade may function as a mediator of the effects of HLA-DRB1 rs9271192-AC/CC and APOE ε4 genotypes on AD pathogenesis in the brain via the BBB pathways.

Examination of potentially modifiable dementia risk factors across the adult life course: The Framingham Heart Study.

INTRODUCTION: We examined for associations between potentially modifiable risk factors across the adult life course and incident dementia. METHODS: Participants from the Framingham Heart Study were included (n = 4015). Potential modifiable risk factors included education, alcohol intake, smoking, body mass index (BMI), physical activity, social network, diabetes, and hypertension. Cox models were used to examine associations between each factor and incident dementia, stratified by early adult life (33-44 years), midlife (45-65 years), and late life (66-80 years). RESULTS: Increased dementia risk was associated with diabetes (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.07-2.46) and physical inactivity (HR = 1.57; 95% CI = 1.12-2.20) in midlife, and with obesity (HR = 1.76; 95% CI = 1.08-2.87) in late life. Having multiple potential modifiable risk factors in midlife and late life was associated with greater risk. DISCUSSION: Potentially modifiable risk factors individually have limited impact on dementia risk in this population across the adult life course, although in combination they may have a synergistic effect. HIGHLIGHTS: Diabetes and physical inactivity in midlife is associated with increased dementia risk. Obesity in late life is associated with increased dementia risk. Having more potentially modifiable risk factors in midlife and late life is associated with greater dementia risk.

Association Between Acoustic Features and Neuropsychological Test Performance in the Framingham Heart Study: Observational Study.

BACKGROUND: Human voice has increasingly been recognized as an effective indicator for the detection of cognitive disorders. However, the association of acoustic features with specific cognitive functions and mild cognitive impairment (MCI) has yet to be evaluated in a large community-based population. OBJECTIVE: This study aimed to investigate the association between acoustic features and neuropsychological (NP) tests across multiple cognitive domains and evaluate the added predictive power of acoustic composite scores for the classification of MCI. METHODS: This study included participants without dementia from the Framingham Heart Study, a large community-based cohort with longitudinal surveillance for incident dementia. For each participant, 65 low-level acoustic descriptors were derived from voice recordings of NP test administration. The associations between individual acoustic descriptors and 18 NP tests were assessed with linear mixed-effect models adjusted for age, sex, and education. Acoustic composite scores were then built by combining acoustic features significantly associated with NP tests. The added prediction power of acoustic composite scores for prevalent and incident MCI was also evaluated. RESULTS: The study included 7874 voice recordings from 4950 participants (age: mean 62, SD 14 years; 4336/7874, 55.07% women), of whom 453 were diagnosed with MCI. In all, 8 NP tests were associated with more than 15 acoustic features after adjusting for multiple testing. Additionally, 4 of the acoustic composite scores were significantly associated with prevalent MCI and 7 were associated with incident MCI. The acoustic composite scores can increase the area under the curve of the baseline model for MCI prediction from 0.712 to 0.755. CONCLUSIONS: Multiple acoustic features are significantly associated with NP test performance and MCI, which can potentially be used as digital biomarkers for early cognitive impairment monitoring.

Mid- to Late-Life Body Mass Index and Dementia Risk: 38 Years of Follow-up of the Framingham Study.

Growing evidence relates body mass index (BMI) to poorer health outcomes; however, results across studies associating BMI and dementia are conflicting. A total of 3,632 Framingham Offspring participants aged 20 to 60 years at their second health examination (1979-1983) were included in this study, with 190 cases of incident dementia identified by 2017. Cox proportional hazards regression models were fitted to investigate the association of BMI at each of their 8 exams as a baseline for dementia risk and the associations between obesity and dementia across age groups. Spline models were fitted to investigate nonlinear associations between BMI and dementia. Each 1-unit increase in BMI at ages 40-49 years was associated with higher risk of dementia, but with lower risk after age 70 years. Obesity at ages 40-49 years was associated with higher risk of dementia. Overall, the relationship between BMI and dementia risk was heterogeneous across the adult age range. Monitoring BMI at different ages might mediate risk for dementia across an individual's lifetime.

Associations of loneliness with risk of Alzheimer's disease dementia in the Framingham Heart Study.

INTRODUCTION: The relationship between persistent loneliness and Alzheimer's disease (AD) is unclear. We examined the relationship between different types of mid-life loneliness and the development of dementia and AD. METHODS: Loneliness was assessed in cognitively normal adults using one item from the Center for Epidemiologic Studies Depression Scale. We defined loneliness as no loneliness, transient loneliness, incident loneliness,or persistent loneliness, and applied Cox regression models and Kaplan-Meier plots with dementia and AD as outcomes (n = 2880). RESULTS: After adjusting for demographics, social network, physical health, and apolipoprotein E ε4, persistent loneliness was associated with higher (hazard ratio [HR], 1.91; 95% confidence interval [CI] 1.25-2.90; P < .01), and transient loneliness with lower (HR, 0.34; 95% CI 0.14-0.84; P < .05), risk of dementia onset, compared to no loneliness. Results were similar for AD risk. DISCUSSION: Persistent loneliness in mid-life is an independent risk factor for dementia and AD, whereas recovery from loneliness suggests resilience to dementia risk.

Rural-urban disparities in smoking patterns among Chinese adults: a social-ecological approach.

China has a long history of smoking behavior. Currently, nearly 26% of Chinese citizens smoke daily. This research used a nationally representative database to study the urban and rural disparities on smoking patterns applying the social-ecological model. Using the 2011 China Health and Nutrition Survey, the study sample included adult participants who were at least 18 years of age (n = 12,688). A subanalysis was carried out to investigate smoking cessation duration among smoking quitters (n = 519). Multinomial logistic regression was used to examine participants' smoking status. Zero-inflated negative binomial regression was applied to investigate participants' number of cigarettes smoked per day, and multivariable logistic regression was used to examine nondaily smoking behavior. Negative binomial regression was carried out to assess the duration of smoking cessation for individuals who quit smoking. Urban residents had lower odds of reporting current smoking status (AOR [adjusted odds ratio] = 0.83, 95% CI [0.74, 0.95]) as compared to rural residents. Urban residents also had higher odds of reporting nondaily smoking status (AOR = 1.17, 95% CI [1.04, 1.32]) and smoked fewer cigarettes per day (IRR [incidence rate ratio] = 0.93, 95% CI [0.89, 0.98]) as compared to rural participants. The disparity between urban and rural areas was not observed for smoking cessation duration. Further efforts should target the disparity between urban and rural regions regarding smoking prevention.

Growing concerns and controversies to Taiwan's National Health Insurance-what are the lessons from mainland China, South Korea and Singapore?

It has been over 20 years since Taiwan's implementation of its National Health Insurance (NHI) program. Under this program, the health insurance coverage rate has reached approximately 99% of the population. Despite guaranteeing the residents of Taiwan equal access regardless of socioeconomic status and background, critical problems and controversies persist, and they continue to challenge the NHI. We analyze the primary issues facing the NHI program with emphasis on financial and consumer behavioral aspects. Furthermore, we apply models from mainland China, South Korea and Singapore to discuss what Taiwan could learn from the systems employed by these countries to modify the NHI. Targeting the needs of the NHI, we have three policy recommendations: separating the NHI scheme into different target populations, strengthening the NHI referral system and regulating the access of overseas citizens to health services while in Taiwan. After two decades in existence, problems persist and there is a continuing need to improve Taiwan's NHI. Copyright © 2016 John Wiley & Sons, Ltd.

Sex-specific blood biomarkers linked to memory changes in middle-aged adults: The Framingham Heart Study.

The relationship between sex-specific blood biomarkers and memory changes in middle-aged adults remains unclear. We aimed to investigate this relationship using the data from the Framingham Heart Study (FHS). We conducted association analysis, partial correlation analysis, and causal dose-response curves using blood biomarkers and other data from 793 middle-aged participants (≤ 60 years) from the FHS Offspring Cohort. The results revealed associations of adiponectin and fasting blood glucose with midlife memory change, along with a U-shaped relationship of high-density lipoprotein cholesterol with memory change. No significant associations were found for the other blood biomarkers (e.g., amyloid beta protein 42) with memory change. To our knowledge, this is the first sex-specific network analysis of blood biomarkers related to midlife memory change in a prospective cohort study. Our findings highlight the importance of targeting cardiometabolic risks and the need to validate midlife-specific biomarkers that can accelerate the development of primary preventive strategies.

Comparison of Commonly Measured Plasma and Cerebrospinal Fluid Proteins and Their Significance for the Characterization of Cognitive Impairment Status.

BACKGROUND: Although cerebrospinal fluid (CSF) amyloid-ß42 peptide (Aß42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer's disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). OBJECTIVE: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. METHODS: This cohort study included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. RESULTS: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aß42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aß42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aß42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aß42)]. These results were adjusted for age, sex, education, and APOEϵ4 genotype. CONCLUSIONS: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN.

The association between circulating CD34+CD133+ endothelial progenitor cells and reduced risk of Alzheimer's disease in the Framingham Heart Study.

Aim: Endothelial dysfunction has been associated with both cerebrovascular pathology and Alzheimer's disease (AD). However, the connection between circulating endothelial cells and the risk of AD remains uncertain. The objective was to leverage data from the Framingham Heart Study to investigate various circulating endothelial subtypes and their potential correlations with the risk of AD. Methods: The study conducted data analyses using Cox proportional hazard regression and linear regression methods. Additionally, genome-wide association study (GWAS) was carried out to further explore the data. Results: Among the eleven distinct circulating endothelial subtypes, only circulating endothelial progenitor cells (EPCs) expressing CD34+CD133+ were found to be negatively and dose-dependently associated with reduced AD risk. This association persisted even after adjusting for age, sex, years of education, apolipoprotein E (APOE) ε4 status, and various vascular diseases. Particularly noteworthy was the significant association observed in individuals with hypertension and cerebral microbleeds. Consistently, positive associations were identified between CD34+CD133+ EPCs and specific brain regions, such as higher proportions of circulating CD34+CD133+ cells correlating with increased volumes of white matter and the hippocampus. Additionally, a GWAS study unveiled that CD34+CD133+ cells influenced AD risk specifically in individuals with homozygous genotypes for variants in two stem cell-related genes: kirre like nephrin family adhesion molecule 3 (KIRREL3, rs580382 CC and rs4144611 TT) and exocyst complex component 6B (EXOC6B, rs61619102 CC). Conclusions: The findings suggest that circulating CD34+CD133+ EPCs possess a protective effect and may offer a new therapeutic avenue for AD, especially in individuals with vascular pathology and those carrying specific genotypes of KIRREL3 and EXOC6B genes.

Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS.

AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.

Establishing cognitive baseline in three generations: Framingham Heart Study.

Introduction: Generational changes warrant recalibrating normative cognitive measures to detect changes indicative of dementia risk within each generation. Methods: We performed linear regressions to compare eight neuropsychological (NP) tests among three-generation cohorts at baseline in Framingham Heart Study (FHS, n = 4787) and conducted Cox regressions to investigate the relationships of NP tests with generation-specific dementia risk. Results: The FHS second and third generations performed better than the first generation for seven NP tests (0.14-0.81 standard deviation improvement, P ≤ .001) while the second and third generations performed similarly for six of eight NP tests (P > .05). One standard deviation better performance was associated with a higher reduction in incident dementia risk in the second than the first generation (35% vs. 24%, P interaction = .02) for the similarities test. Discussion: Our findings suggest cohort-based norms are needed for cognitive assessment for the diagnosis of cognitive impairment and dementia.

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

The impact of blood MCP-1 levels on Alzheimer's disease with genetic variation of UNC5C and NAV3 loci.

Background: Previous study shows that monocyte chemoattractant protein-1 (MCP-1), which is implicated in the peripheral proinflammatory cascade and blood-brain barrier (BBB) disruption, modulates the genetic risks of AD in established AD loci. Methods: In this study, we hypothesized that blood MCP-1 impacts the AD risk of genetic variants beyond known AD loci. We thus performed a genome-wide association study (GWAS) using the logistic regression via generalized estimating equations (GEE) and the Cox proportional-hazards models to examine the interactive effects between single nucleotide polymorphisms (SNPs) and blood MCP-1 level on AD in three cohorts: the Framingham Heart Study (FHS), Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study/Memory and Aging Project (ROSMAP). Results: We identified SNPs in two genes, neuron navigator 3 (NAV3, also named Unc-53 Homolog 3, rs696468) (p < 7.55×10- 9) and Unc-5 Netrin Receptor C (UNC5C rs72659964) (p < 1.07×10- 8) that showed an association between increasing levels of blood MCP-1 and AD. Elevating blood MCP-1 concentrations increased AD risk and AD pathology in genotypes of NAV3 (rs696468-CC) and UNC5C (rs72659964-AT + TT), but did not influence the other counterpart genotypes of these variants. Conclusions: NAV3 and UNC5C are homologs and may increase AD risk through dysregulating the functions of neurite outgrowth and guidance. Overall, the association of risk alleles of NAV3 and UNC5C with AD is enhanced by peripheral MCP-1 level, suggesting that lowering the level of blood MCP-1 may reduce the risk of developing AD for people with these genotypes.