APOE ε4 allele modifies the associations of toxic metals and their mixture with cognitive impairment among older adults.

BACKGROUND: The evidence of interactive effect of the toxic metal (TM) mixture and apolipoprotein E (APOE) ε4 gene on cognitive impairment in older adults is scarce. We aimed to explore whether the associations of single TMs and their mixture with cognitive impairment depend on APOE ε4 in Chinese community-dwelling older people. METHODS: A total of 1148 older adults from a subset of the baseline survey of a cohort study were included. Blood arsenic (As), cadmium (Cd), lead (Pb), strontium (Sr), and vanadium (V) were detected by inductively coupled plasma mass spectrometry. APOE gene (rs429358, rs7412) polymorphisms were analyzed by the Polymerase Chain Reaction instrument. Mixed effects logistic regression was applied to estimate the relationships of single TMs and APOE genotype with cognitive impairment. Weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were performed to examine joint impacts of the TM mixture, as well as the interaction of the TM mixture with APOE ε4 genotype on cognitive impairment. RESULTS: Pb displayed a significant linear association with an increased odds of cognitive impairment after adjustment for covariates (Ptrend = 0.045). While APOE genotype did not show a significant correlation with cognitive impairment. WQS showed that the TM mixture was associated with an increased risk of cognitive impairment by 31.0% (OR=1.31, 95% CI: 0.92, 1.87) while no significance was found. BKMR exhibited a significant linear association between the TM mixture and cognitive impairment. Moreover, both WQS and BKMR indicated that Pb contributed the most to cognitive impairment within the mixture. Significant interactions of Pb or the TM mixture and APOE genotype on cognitive impairment were observed, contributing to 38.1% and 38.2% of total effects, respectively. CONCLUSIONS: APOE ε4 allele amplifies the associations of single Pb or the TM mixture with cognitive impairment. These findings may help to develop precision prevention.

Effect of APOE ε4 genotype on amyloid-ß, glucose metabolism, and gray matter volume in cognitively normal individuals and amnestic mild cognitive impairment.

BACKGROUND AND PURPOSE: The presence of apolipoprotein E ε4 (APOE ε4) is associated with an increased risk of developing Alzheimer disease (AD). The aim of this study was to assess the effects of APOE ε4 on amyloid-ß (Aß) pathology, glucose metabolism, and gray matter (GM) volume and their longitudinal changes in healthy control (HC) and amnestic mild cognitive impairment (aMCI). METHODS: We included 50 HCs and 109 aMCI patients from the Alzheimer's Disease Neuroimaging Initiative phase 2/GO based on availability of baseline T1-weighted magnetic resonance imaging, 18 F-florbetapir positron emission tomography (PET), and 18 F-fluorodeoxyglucose (FDG) PET. Of these, 35 HCs and 67 aMCI patients who underwent 24-month scans were included for follow-up study. RESULTS: Voxelwise analysis revealed that APOE ε4 carriers exhibited greater baseline Aß deposition than APOE ε4 noncarriers in both diagnostic groups. However, there was no significant difference between APOE ε4 noncarriers and APOE ε4 carriers in terms of 18 F-FDG PET standardized uptake value ratio and GM volume. Region of interest-based analysis showed statistically significant greater Aß deposition in APOE ε4 carriers than APOE ε4 noncarriers only in aMCI patients. Furthermore, APOE ε4 carriers generally exhibited a greater magnitude and spatial extent of longitudinal changes in Aß deposition than APOE ε4 noncarriers in both diagnostic groups. CONCLUSIONS: Our findings suggest a differential effect of APOE ε4 on Aß pathology, glucose metabolism, and GM volume. Studying APOE ε4-related brain changes with neuroimaging biomarkers in preclinical AD offers an opportunity to further our understanding of the pathophysiology of AD at an early stage.

APOE ε4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD.

BACKGROUND: We studied the effect of apolipoprotein E (APOE) ε4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD). METHOD: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE ε4, sex, and their interaction on AO in EOAD and LOAD, separately. RESULTS: APOE ε4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE ε4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE ε4 carriers had younger AO relative to non-carriers (P < 0.0001). CONCLUSION: The observed earlier AO in EOAD APOE ε4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort.

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.

High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: Findings from a population-based cohort.

INTRODUCTION: This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E (APOE) ε4 genotype. METHODS: Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case-control study embedded within an ongoing population-based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. RESULTS: The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p-tau181. DISCUSSION: In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p-tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS: Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community- and clinic-based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke.

Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk.

INTRODUCTION: European local ancestry (ELA) surrounding apolipoprotein E (APOE) ε4 confers higher risk for Alzheimer's disease (AD) compared to African local ancestry (ALA). We demonstrated significantly higher APOE ε4  expression in ELA versus ALA in AD brains from APOE ε4/ε4 carriers. Chromatin accessibility differences could contribute to these expression changes. METHODS: We performed single nuclei assays for transposase accessible chromatin sequencing from the frontal cortex of six ALA and six ELA AD brains, homozygous for local ancestry and APOE ε4. RESULTS: Our results showed an increased chromatin accessibility at the APOE ε4  promoter area in ELA versus ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility in ELA in astrocytes were enriched for synapsis, cholesterol processing, and astrocyte reactivity. DISCUSSION: Our results suggest that increased chromatin accessibility of APOE ε4  in ELA astrocytes contributes to the observed elevated APOE ε4  expression, corresponding to the increased AD risk in ELA versus ALA APOE ε4/ε4 carriers.

Predictive metabolic networks reveal sex- and APOE genotype-specific metabolic signatures and drivers for precision medicine in Alzheimer's disease.

INTRODUCTION: Late-onset Alzheimer's disease (LOAD) is a complex neurodegenerative disease characterized by multiple progressive stages, glucose metabolic dysregulation, Alzheimer's disease (AD) pathology, and inexorable cognitive decline. Discovery of metabolic profiles unique to sex, apolipoprotein E (APOE) genotype, and stage of disease progression could provide critical insights for personalized LOAD medicine. METHODS: Sex- and APOE-specific metabolic networks were constructed based on changes in 127 metabolites of 656 serum samples from the Alzheimer's Disease Neuroimaging Initiative cohort. RESULTS: Application of an advanced analytical platform identified metabolic drivers and signatures clustered with sex and/or APOE ɛ4, establishing patient-specific biomarkers predictive of disease state that significantly associated with cognitive function. Presence of the APOE ɛ4 shifts metabolic signatures to a phosphatidylcholine-focused profile overriding sex-specific differences in serum metabolites of AD patients. DISCUSSION: These findings provide an initial but critical step in developing a diagnostic platform for personalized medicine by integrating metabolomic profiling and cognitive assessments to identify targeted precision therapeutics for AD patient subgroups through computational network modeling.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

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.

Refined carbohydrate-rich diet is associated with long-term risk of dementia and Alzheimer's disease in apolipoprotein E ε4 allele carriers.

INTRODUCTION: In animal models, refined carbohydrates (RF) worsen Alzheimer's disease (AD). However, the long-term effects of high RF intake on the risk of dementia and AD are poorly described in epidemiological studies. Moreover, the interaction between RF and the apolipoprotein E ε4 allele (APOE-ε4) is unknown. Our study investigated whether RF-rich diets are associated with the risk of dementia and AD. METHODS: The glycemic load (GL) was quantified in 2777 elderly participants from the French Three-City Study to estimate RF intake. Then, the associations between GL and risk of dementia and AD, and the interaction with APOE-ε4 over a 12-year period were assessed using proportional hazards models. RESULTS: After adjustment for potential confounders, high afternoon-snack GL was associated with increased dementia and AD risk in APOE-ε4 carriers (hazard ratio = 1.27 [1.03-1.56]). DISCUSSION: This study highlights that RF-rich diets are a risk factor for dementia and AD in APOE-ε4 carriers.

Sex differences in the association of APOE ε4 genotype with longitudinal hippocampal atrophy in cognitively normal older people.

BACKGROUND AND PURPOSE: The aim of this study was to determine the effects of apolipoprotein E ε4 (APOE ε4) genotype and sex together on longitudinal change in adjusted hippocampal volume [hippocampal volume:intracranial volume ratio (HpVR)] across the Alzheimer's disease (AD) continuum. METHODS: At baseline, we included 372 individuals with normal cognition (NC), 738 individuals with mild cognitive impairment (MCI) and 271 patients with mild AD from the Alzheimer's Disease Neuroimaging Initiative database. We examined the effects of the APOE ε4 by sex interaction on longitudinal change in HpVR within the overall sample and within each diagnostic group. RESULTS: Female gender was found to be associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Similarly, APOE ε4 was associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Further, female APOE ε4 carriers showed a greater longitudinal reduction of HpVR than their male counterparts in the NC group, but not in the MCI or AD group. However, due to the relatively short duration of follow-up visits in patients with AD, further studies are needed to replicate these findings. CONCLUSION: Female APOE ε4 carriers show a greater longitudinal reduction of HpVR than their male counterparts in cognitively normal older adults.

Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

Surgery is associated with ventricular enlargement as well as cognitive and functional decline.

INTRODUCTION: In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear. METHODS: We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. RESULTS: The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. DISCUSSION: These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults.

Combining serum and urine biomarkers in the early diagnosis of mild cognitive impairment that evolves into Alzheimer's disease in patients with the apolipoprotein E ϵ4 genotype.

Possession of the apolipoprotein E (APOE) ϵ4 genotype is a major predictor of progression to Alzheimer's disease (AD), particularly in patients with mild cognitive impairment (MCI). However, the use of APOE genotyping in the diagnosis of MCI is limited due to its low sensitivity and specificity, which often results in a high false-positive rate. In this study, we found that there was a significant decrease in serum BDNF and notable increase in urine AD7c-NTP in MCI patients who harbored the APOE ϵ4 allele. Both serum BDNF and urine AD7c-NTP had higher positive predictive values and were more sensitive biomarkers of MCI. Additionally, a testing strategy employing serum BDNF and urine AD7c-NTP revealed increases in sensitivity, positive and negative predictive values, and predictive ability compared with the use of either biomarker alone, suggested that combinatorial detection might have great potential for translation to the clinic.

Effect of APOE genotype status on targeted clinical trials outcomes and efficiency in dementia and mild cognitive impairment resulting from Alzheimer's disease.

BACKGROUND: The apolipoprotein E (APOE) ε4 genotype has been recommended as a potential inclusion or exclusion criterion in targeted clinical trials for Alzheimer's disease (AD) and mild cognitive impairment (MCI) resulting from AD, and has been implemented in trials of immunotherapeutic agents. METHODS: We tested this recommendation with clinical trial simulations using participants from a meta-database of 19 studies to create trial samples with APOE ε4 proportions ranging from 0% (all noncarriers) to 100% (all carriers). For each percentage of APOE ε4 carriers, we resampled the database randomly for 1000 trials for each trial scenario, planning for 18- or 24-month trials with samples from 50 to 400 patients per treatment or placebo group, up to 40% dropouts, and outcomes on the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog) with effect sizes from 0.15 to 0.75, and calculated statistical power. RESULTS: Enrichment of clinical trial participants based on APOE ε4 carrier status resulted in minimal increases in power compared with enrolling participants with the APOE ε3 genotype only or enrolling patients without regard to APOE genotype. Increased screening requirements to enhance the sample would offset gains in power. CONCLUSIONS: Although samples enriched for APOE ε4 carriers in AD or MCI clinical trials showed slightly more cognitive impairment and greater decline using the number APOE ε4 alleles as an inclusion criterion most likely would not result in more efficient trials, and trials would take longer because fewer patients would be available. The APOE ε4/εX (where X = 2, 3 or 4) genotype could be useful, however, as an explanatory variable or covariate if warranted by a drug's action.

The critical need for defining preclinical biomarkers in Alzheimer's disease.

The increasing number of afflicted individuals with late-onset Alzheimer's disease (AD) poses significant emotional and financial burden on the world's population. Therapeutics designed to treat symptoms or alter the disease course have failed to make an impact, despite substantial investments by governments, pharmaceutical industry, and private donors. These failures in treatment efficacy have led many to believe that symptomatic disease, including both mild cognitive impairment (MCI) and AD, may be refractory to therapeutic intervention. The recent focus on biomarkers for defining the preclinical state of MCI/AD is in the hope of defining a therapeutic window in which the neural substrate remains responsive to treatment. The ability of biomarkers to adequately define the at-risk state may ultimately allow novel or repurposed therapeutic agents to finally achieve the disease-modifying status for AD. In this review, we examine current preclinical AD biomarkers and suggest how to generalize their use going forward.

The roles of apolipoprotein E ε4 on neuropathology and neuroinflammation in patients with Alzheimer's disease.

AIMS: To explore the roles of apolipoprotein E (APOE) ε4 on the neuropathology and neuroinflammation in Alzheimer's disease (AD) patients. METHODS: AD patients were divided into the APOE ε4 carrier and the APOE ε4 non-carrier groups according to APOE genotype. Demographic information, cognitive function, the levels of neuropathological proteins and neuroinflammatory factors in cerebrospinal fluid (CSF) were compared between the two groups, and their correlations were subsequently analyzed. RESULTS: ß amyloid protein (Aß)1-42 level from the APOE ε4 carrier group was significantly lower than that from the non-carrier group (p = 0.023), which was associated with worse cognitive function. The nitric oxide (NO) level was significantly elevated in the APOE ε4 carrier group compared to the non-carrier group (p = 0.016), which was significantly and positively correlated with the Trail Making Test (TMT)-A-time (r = 0.21, p = 0.026) and TMT-B-time (r = 0.38, p < 0.01). CONCLUSION: APOE ε4 is associated with poorer cognition, particularly the early symptoms of memory, language, and attention. APOE ε4 is associated with lower Aß1-42 level, and the more numbers of APOE ε4 are carried, the lower level of Aß1-42 is measured. APOE ε4 is associated with elevated NO level, which is linked to the impaired attention and executive function.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Predicting the apolipoprotein E ε4 allele carrier status based on gray matter volumes and cognitive function.

BACKGROUND: Apolipoprotein E (ApoE) ε4 carriers have a higher risk of developing Alzheimer's disease (AD) and show brain atrophy and cognitive decline even before diagnosis. OBJECTIVE: To predict ApoE ε4 status using gray matter volume (GMV) obtained from magnetic resonance imaging images and demographic data with machine learning (ML) methods. METHODS: We recruited 74 participants (25 probable AD, 24 amnestic mild cognitive impairment, and 25 cognitively normal older people) with known ApoE genotype (22 ApoE ε4 carriers and 52 noncarriers) and scanned them with three-dimensional (3D) T1-weighted (T1W) and 3D double inversion recovery (DIR) sequences. We extracted GMV from regions of interest related to AD pathology and used them as features along with age and mini-mental state examination (MMSE) scores to train different ML models. We performed both receiver operating characteristic curve analysis and the prediction analysis of the ApoE ε4 carrier with different ML models. RESULTS: The best model of ML analyses was a cubic support vector machine (SVM3) that used age, the MMSE score, and DIR GMVs at the amygdala, hippocampus, and precuneus as features (AUC = .88). This model outperformed models using T1W GMV or demographic data alone. CONCLUSION: Our results suggest that brain atrophy with DIR GMV and cognitive decline with aging can be useful biomarkers for predicting ApoE ε4 status and identifying individuals at risk of AD progression.

Role of nerve growth factor on cognitive impairment in patients with Alzheimer's disease carrying apolipoprotein E ε4.

AIMS: To investigate the roles of neurotrophic factors on cognition in patients with Alzheimer's disease (AD) carrying Apolipoprotein E (APOE) ε4. METHODS: Totals of 173 patients with AD were divided into APOE ε4 carrier and non-carrier groups, and their demographics, cognition, and neurotrophic factors in cerebrospinal fluid (CSF) were compared. Multiple linear regression analyses were performed to assess correlations among APOE ε4, neurotrophic factors and cognition. Mediation analyses were conducted to assess the sequential associations among APOE ε4, nerve growth factor (NGF), and cognition. RESULTS: Global cognition and multiple domains were impaired in the APOE ε4 carrier group (all p < 0.05). NGF level in the APOE ε4 carrier group was lower than that in the non-carrier group (p = 0.016). NGF level showed significant correlations with both global and multiple domains cognitions. Specifically, NGF mediated the association between APOE ε4 and Animal Fluency Test score (ß, -0.45; 95% CI [-0.96, -0.07]; p < 0.001) and Trail Making Test-A (time) (ß, 0.15; 95% CI [0.01, 0.33]; p < 0.001). CONCLUSION: APOE ε4 is associated with cognitive impairment, and those carrying APOE ε4 have decreased NGF level in CSF. Declined NGF level is correlated with compromised cognition. NGF mediates APOE ε4-associated cognitive impairment.