不同亚型精神分裂症患者的认知损害与精神症状及血清IL-2水平的关系

目的 探讨不同亚型精神分裂症患者认知功能损害与精神症状及血清白介素-2(IL-2)水平之间的关系。方法 对94例精神分裂症患者进行测验，评定其认知功能，即采用PANSS量表评定阴、阳性症状及分型，以数字划销测验(CT)、修订韦氏成人记忆量表(WMS-RC)、威斯康星卡片分类测验(WCST)，并用酶联免疫吸附法(ELISA)测定血清IL-2水平，比较认知功能损害与精神症状和血清IL-2水平之间的差异。结果 阴性亚型、混合型的认知损害程度较阳性亚型重；各亚型中认知损害主要与阴性症状相关，与阳性症状无关；各亚型间血清IL-2水平差异不显著；血清IL-2水平与认知损害有关，但各亚型不同。结论 认知损害与精神症状及血清IL-2水平之间的关系各亚型间存在差异。     

美满霉素抑制血管性认知功能损伤大鼠海马星型胶质细胞激活和神经炎症(英文)

目的观察美满霉素(minocycline)对血管性认知功能损伤大鼠海马组织GFAP、COX-2、NF-κB、IL-1β和TNF-α表达的影响,探讨美满霉素对血管性认知功能损伤脑保护作用的机制。方法Wistar大鼠随机分为假手术组(S组)、血管性认知功能损伤模型组(M组)和美满霉素治疗组(MT组)。免疫组织化学法检测大鼠海马组织COX-2和NF-κB的表达,蛋白质印迹和免疫组织化学法检测大鼠海马组织GFAP的表达,ELISA法检测大鼠海马组织IL-1β和TNF-α的表达。结果MT 组 GFAP、COX-2、NF-κB、IL-1β和 TNF-α表达较 M 组均降低(P<0.01) ;MT 和 M 组GFAP、COX-2、NF-κB、IL-1β和 TNF-α表达均显著高于 S 组(P<0.01)。结论美满霉素能降低血管性认知功能损伤大鼠海马组织中GFAP、COX-2、NF-κB、IL-1β和TNF-α的表达,抑制血管性认知功能损伤大鼠海马星型胶质细胞活化和神经炎症,发挥脑保护作用。     

阿尔茨海默病患者外周血IL-6、IL-8、TNF-α水平与认知功能的相关性

目的 探讨阿尔茨海默病(AD)患者外周血白细胞介素-6(IL-6)、IL-8及肿瘤坏死因子α(TNF-α)水平与认知功能的相关性.方法 选择2015年1月~2016年1月在济宁医学院附属医院兖州院区治疗的AD患者90例作为研究组,并选择同期在我院体检的90名健康人作为对照组,采用酶联免疫吸附法(ELISA)检测两组研究对象的外周血IL-6、IL-8及TNF-α水平,并采用简易精神状态量表(MMSE)和临床痴呆评定量表(CDR)对其认知功能和日常行为能力进行评估.比较各组间炎性因子水平的差异,分析炎性因子表达水平与认知功能的相关性.结果 研究组AD患者外周血的IL-6、IL-8及TNF-α水平均明显高于对照组[(128.64±10.28)pg/ml比(103.59±8.72)pg/ml,(134.32±9.67)pg/ml比(101.45±7.32)pg/ml,(221.39±23.54)pg/ml比(109.68±18.76)pg/ml],差异均有统计学意义(P<0.05).受教育年限为AD患者认知功能的保护因素,IL-6、IL-8及TNF-α水平为危险因素(P<0.05).整体人群中IL-6、TNF-α水平与MMSE得分呈负相关(r=-0.314,-0.079;P<0.05),IL-8与MMSE无相关性.结论 外周血IL-6及TNF-α水平与轻度AD患者的认知功能相关.     

社区老年人群痴呆早期筛查和预测的生物指标研究

目的初步探索老年人群痴呆早期筛查的生化指标与易感基因,为早期诊断提供证据。方法采用随机整群抽样方法选取石家庄3个社区年龄≥60岁的老年人,采用统一问卷调查量表收集被调查者的人口学资料、蒙特利尔认知评估量表(MoCA)评分,并检测其血生化和炎性反应指标,采用MassArray法检测受试者46个阿尔茨海默病(AD)易感基因位点。根据MoCA结果将被调查者分为认知正常组、轻度认知障碍(MCI)组和痴呆组,比较各组生化指标、炎性反应指标以及易感基因分布的差异。结果与认知正常组相比,MCI组血糖(Glu)、载脂蛋白B(ApoB)、载脂蛋白E(ApoE)升高(P0.05),高密度脂蛋白(HDL)、载脂蛋白A-1(ApoA-1)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)显著降低(P0.05或P0.01);与认知正常组相比,痴呆组Glu、ApoB、ApoE、C反应蛋白(CRP)显著升高(P0.05或P0.01),ApoA-1、IL-6、TNF-α显著降低(P0.01)。MCI组与认知正常组相比较在FADS1、FADS2、ABCA7、ELOVL2、PICALM、MYRF、MS4A4A、MS4A6A等基因上具有统计学差异,痴呆组与认知正常组相比较在MS4A4A、MS4A6A等基因上具有统计学差异。结论Glu、HDL、ApoA-1、ApoB、ApoE、IL-6、TNF-α等生化指标和FADS1、FADS2、ABCA7、ELOVL2、PICALM、MYRF、MS4A4A、MS4A6A等基因在早期筛查MCI和痴呆中可能具有重要意义。     

阿尔茨海默病患者外周血白细胞介素23和白细胞介素17测定及意义

目的探讨阿尔茨海默病(Alzheimer’s disease,AD)患者外周血中炎症因子白细胞介素23(Interleukin-23,IL-23)和IL-17水平及其与认知功能损害的相关性。方法纳入AD患者102例(研究组),以及健康老年志愿者100例(对照组)。搜集受试者的一般资料和疾病信息。采用简易精神状态量表(MMSE)和临床痴呆评定量表(CDR)对受试者认知功能和日常行为能力进行评估。应用实时荧光定量逆转录-聚合酶链式反应(RTPCR)检测各组入选者外周血淋巴细胞中IL-23和IL-17的mRNA表达,应用酶联免疫吸附试验(ELISA)检测入选者血清IL-23和IL-17蛋白的表达。比较两组入选者血清炎症因子mRNA及蛋白水平的差异,分析外周血IL-23和IL-17表达的相关性。以全部入选者为研究对象,分析两组IL-17和IL-23表达差异与MMSE评分的相关性。以AD组为研究对象,分析患者IL-17和IL-23表达水平与CDR评分的相关性。结果 AD组外周血淋巴细胞中IL-23和IL-17的mRNA表达水平及血清IL-23和IL-17蛋白的表达水平均显著高于对照组,差异均有统计学意义(P<0.05),且两者具有显著正相关性(P<0.01)。整体人群中,IL-23和IL-17水平均与MMSE评分呈负相关(P<0.05)。AD患者血IL-23和IL-17水平与CDR评分均无相关性。结论外周血IL-23和IL-17水平与整体人群的认知功能相关,但与AD患者的痴呆严重度无明显相关性。     

一氧化碳中毒后迟发性脑病患者S100β、JNK通路蛋白及相关细胞因子水平变化及其临床意义

目的探讨急性一氧化碳中毒后迟发性脑病(delayed encephalopathy after acute carbon monoxide poisoning,DEACMP)患者脑脊液中S100β、Jun氨基末端激酶(jun amino-terminal kinase,JNK)通路蛋白、白细胞介素-4(interleukin-4,IL-4)、IL-10、转化生长因子β1(transforming growth factorβ1,TGF-β1)及干扰素γ(interferon-γ,IFN-γ)的变化及其临床意义。方法选取2010-01—2016-12作者医院收治的DEACMP患者20例(DEACMP组),另收集同期发生一氧化碳中毒但未发生迟发性脑病的患者37例作为对照组,检测两组患者入院后第2天脑脊液中S100β、JNK通路蛋白(JNK1、JNK2)及TNF-ɑ、IL-4、IL-10、TGF-β1、IFN-γ水平,并于治疗2周后对两组患者进行简易精神状态量表(mini-mental state examination,MMSE)评分,分析脑脊液S100β蛋白、JNK通路蛋白及相关细胞因子与MMSE评分的相关性。结果DEACMP组脑脊液中S100β、JNK1、JNK2、TNF-ɑ、IFN-γ水平均高于对照组(P0.05),而IL-4、IL-10、TGF-β1水平及MMSE评分均低于对照组(P0.05)。DEACMP组患者MMSE评分与患者脑脊液中S100β、JNK1、JNK2、TNF-ɑ、IFN-γ水平呈负相关(P0.05),与IL-4、IL-10、TGF-β1水平呈正相关(P0.05)。结论 DEACMP患者脑脊液中S100β、JNK通路蛋白及相关细胞因子发生明显改变,且其水平与患者恢复期认知功能损害有关。     

脑卒中患者认知功能情况及血管性认知障碍的影响因素

目的探讨脑卒中患者认知功能情况及血管性认知障碍(VCI)的影响因素。方法选取122例脑卒中患者,采用蒙特利尔认知评估(MoCA)量表评估患者认知功能并分组。MoCA评分24～30分的患者为认知功能正常组(正常组),20～23分的患者为非痴呆型血管性认知障碍组(VCIND组),0～19分的患者为血管性痴呆组(VaD组)。采集患者外周血进行同型半胱氨酸(Hcy)、超敏C反应蛋白(hsCRP)、IL-6、TNF-α检测。结果根据MoCA评分,122例患者分为正常组(30例)、VCIND组(30例)、VaD组(62例)。三组间文化程度、Hcy、IL-6、TNF-α的差异有统计学意义(均P0.05)。MoCA评分与hsCRP、Hcy、IL-6、TNF-α呈负相关(r=-0.179,P=0.049;r=-0.258,P=0.004;r=-0.644,P0.001;r=-0.723,P0.001)。Logistic回归分析结果显示,文化程度是VCI的保护因素(OR=0.270,P=0.006),IL-6、TNF-α是VCI的危险因素(OR=7.756,P=0.002;OR=10.020,P=0.042)。结论脑卒中患者hsCRP、Hcy、IL-6、TNF-α水平越高,MoCA评分越低。文化程度是VCI的保护因素,IL-6、TNF-α是VCI的危险因素。     

2型糖尿病认知功能障碍患者血清IL-6、TNF-α的水平

目的探讨2型糖尿病(DM)患者认知功能障碍与血清白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)水平之间的关系,并分析影响认知功能的其他因素。方法选取2型糖尿病患者(112例)的年龄、性别、受教育程度无明显差异(P>0.05)的正常对照组(100例)。根据蒙特利尔认知评估量表(MoCA)测评,将2型糖尿病患者分为糖尿病认知障碍组(32例)、糖尿病非认知障碍组(80例)。用ELISA法测定血清IL-6和TNF-α水平,并测定空腹血糖、糖化血红蛋白、血脂、体重指数、血压等指标。结果 2型糖尿病认知障碍组与非认知障碍组比较,糖尿病病程、空腹血糖、糖化血红蛋白、胰岛素治疗、体重指数差异有统计学意义(P<0.05);糖尿病认知障碍组血清IL-6和TNF-α水平高于糖尿病非认知障碍组(P<0.01)及正常对照组(P<0.01);2型糖尿病患者的MoCA评分与年龄、糖尿病病程、空腹血糖、HbA1c、LDL、TC、BMI及血清IL-6、TNF-α水平呈负相关(r分别=-0.349、-0.438、-0.415、-0.397、-0.193、-0.259、-0.221、-0.938、-0.881,P均<0.05),与受教育年限呈正相关(r=0.192,P<0.05)。结论血清IL-6和TNF-α水平升高是2型糖尿病患者认知功能下降的一个重要危险因素,提示炎症反应可能参与了糖尿病认知功能障碍的发病。     

脑外伤预后相关基因的研究

近年来发现了若干与脑外伤预后密切相关的基因,包括白介素-1(IL-1)家族的IL-1A、IL-1B及IL-1 RN基因、载脂蛋白E(APOE)基因、多巴胺D2受体(DRD2)基因、儿茶酚胺-o-甲基转移酶(COMT)基因、血管紧张素转换酶(ACE)基因及p53基因.它们分别从外伤后炎症反应的发牛和发展;中枢神经系统中脂质及淀粉样蛋白的转运和沉积;与多巴胺能系统有关的认知功能的改变;脑血管的自动调节功能及细胞凋亡等不同方面来影响脑外伤的进程和转归.充分认识这些基因多态性与脑外伤预后的关系,为该疾病的治疗提供了新思路、新方法.     

髓样细胞触发受体2对阿尔茨海默病的诊断意义

目的探讨髓样细胞触发受体2(TREM2)的表达水平对阿尔茨海默病痴呆的诊断意义。方法选取60例阿尔茨海默病(AD)患者作为研究组,20例健康体检者作为对照组。用酶联免疫吸附(ELISA)法测定血清中TREM2、C反应蛋白(CRP)和白细胞介素6(IL-6)的含量。比较两组TREM2、CRP和IL-6的表达差异及相关性。在简易精神状态检查量表(MMSE)、缺血指数量表(HIS)、汉密尔顿抑郁量表(HAMD)、CDR量表的基础上,用蒙特利尔认知评估量表(MoCA)作为主要认知评估工具,比较TREM2与MMSE和MoCA量表评分的相关性。通过受试者工作特征曲线(ROC)和曲线下面积(AUC)来判断TREM2在AD诊断中的应用价值。结果 AD患者血清中TREM2水平显著升高(P0. 05)。TREM2水平与MMSE和MoCA评分之间发生了负相关(均P0. 01)。AD患者的IL-6和CRP水平升高(均P0. 05)。TREM2水平与血清IL-6和CRP呈正相关(均P0. 05)。结论 TREM2在AD患者外周血中表达增高,与认知功能相关,可能是诊断AD的有前途的生物标志物。     

APOE and APOC1 gene polymorphisms are associated with cognitive impairment progression in Chinese patients with late-onset Alzheimer’s disease

Current evidence shows that apolipoprotein E(APOE), apolipoprotein CI(APOC1) and low density lipoprotein receptor-related protein(LRP) variations are related to late-onset Alzheimer's disease. However, it remains unclear if genetic polymorphisms in these genes are associated with cognitive decline in late-onset Alzheimer's disease patients. We performed a 30-month longitudinal cohort study to investigate the relationship between Alzheimer's disease and APOE, APOC1, and LRP. In this study, 78 Chinese Han patients with late-onset Alzheimer's disease were recruited form Guangxi Zhuang Autonomous Region in China. APOE, APOC1, and LRP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphisms. The Mini-Mental State Examination and Clinical Dementia Rating Scale were used to assess patients' cognitive function. After a 30-month follow-up period, we found a significant reduction in Mini-Mental State Examination total score, a higher proportion of patients fulfilling cognitive impairment progression criteria, and a higher proportion of APOC1 H2 carriers in APOE ε4 carriers compared with non-carriers. In addition, the APOE ε4 allele frequency was significantly higher in the cognitive impairment progression group compared with the non-cognitive impairment progression group. In conclusion, APOE ε4 plays an important role in augmenting cognitive decline, and APOC1 H2 may act synergistically with APOE ε4 in increasing the risk of cognitive decline in Chinese patients with late-onset Alzheimer's disease.     

Triggering receptor expressed on myeloid cells 2 activation downregulates toll-like receptor 4 expression and ameliorates cognitive impairment in the Aβ1-42-induced Alzheimer's disease mouse model

Increasing evidence suggests that changes in the triggering receptor expressed on myeloid cells 2 (TREM2) is closely correlated with the pathological development of Alzheimer's disease (AD). However, the biological function and related role of this change remain poorly understood. Higher TREM2 expression has been reported in the brain of AD patients than in normal controls. Here, levels of TREM2 gene and protein levels were observed to be higher in both cortex and hippocampus of the Aβ_1-42-induced AD mice than in those of the wild type mice. Together with in vitro experimental data, we found that the anti-inflammatory role of TREM2 was, to some extent, limited and potentially counteracted by the hyperactive toll-like receptor 4 (TLR4) in the AD mice. In this context, Interleukin 4 (IL-4), as an agonist of TREM2, was administered to the AD mice to persistently activate TREM2. Interestingly, TREM2 activation in IL-4-treated AD mice led to an elevation in lysosomes and microtubule-associated protein 1 light chain 3 (LC3) II/I expression, demonstrating that the level of microglia autophagy was increased. Increased autophagy significantly downregulated the expression levels of caspase recruitment domain-containing protein 9 (CARD9) and TLR4, potentially weakening the CARD9-TLR4 pathway and suppressing the TLR4-mediated pro-inflammatory effect in IL-4-treated AD mice. Furthermore, data acquired from Morris water maze testing indicated that IL-4 administration could ameliorate cognitive impairment in the AD mice. In conclusion, the findings from in vitro and in vivo experiments suggest that TREM2 might represent a potential drug target to treat neuroinflammation in AD.     

Prolonged visual fixation as a surrogate marker of cholinergic deficit in Parkinson's disease: A 2-year follow-up study

IntroductionThe search for biomarkers of cognitive impairment in Parkinson's disease is driven by the potential clinical applications in disease prognostication. Various eye tracking studies on cognitive functions in Parkinson's disease suggest a promising role of eye movement parameters as a biomarker for cognitive decline but the clinical utility has not been validated in longitudinal studies. The present study aims to investigate the longitudinal progression of eye fixation duration in a visual search task and its correlation with domain-specific cognitive impairment.MethodThis is a 2-year follow-up study on a group of non-demented Parkinson's disease patients, with baseline eye movement metrics and multi-domain cognitive functions measured, to assess the association between domain-specific cognitive impairment and progression of visual fixation duration.ResultsA total of 49 from the original 62 non-demented Parkinson's disease patients were re-examined at a 2-year follow-up. 15 cases (31%) were classified as having mild cognitive impairment. Visual fixation duration was significantly prolonged after 2 years. Using repeated measures ANOVA, impairment in semantic verbal fluency, visual and verbal recognition memory and orienting function of attention had a significant effect on prolonging visual fixation over time.ConclusionCorrelation between prolonged visual fixation and multiple domains of cognitive impairment related to cholinergic dysfunction in repeated measures over two years provides preliminary evidence for the eye tracking paradigm as a surrogate marker for cholinergic deficit in Parkinson's disease. The clinical utility in terms of disease prognostication is yet to be confirmed in prospective longitudinal studies with longer follow-up periods.     

多奈哌齐治疗老年性痴呆的临床研究

目的:探讨乙酰胆碱和促炎症细胞因子在AD发病机制中的相互关系。方法:采用对照研究,对36名阿尔茨海默病(Alzheimer’sdisease,AD)患者用MMSE量表测定其治疗前后认知功能;采用Elisa方法测定乙酰胆碱酯酶抑制剂治疗前后脑脊液中白介素-1、肿瘤坏死因子、白介素-6等细胞因子的变化。结果:多奈哌齐组治疗24周后认知功能与治疗前比较明显提高,认知功能改善比脑复康组明显,同时CSF中IL-1、TNF-α、IL-6和sIL-6R的水平与治疗前相比,均明显降低且有显著意义(P<0.01)。结论:胆碱酯酶抑制剂多奈哌齐治疗AD,改善认知功能的同时,可使脑内促炎症细胞因子有所降低。提示胆碱能功能与促炎症细胞因子在AD发病中相互影响,具有密切联系。     

Evidence for a cytokine model of cognitive function

Aiming at a formulation of a cytokine model of cognitive function under immunologically unchallenged physiological conditions, this article reviews the cytokine biology in the central nervous system (CNS) and recent developments in normal cytokine functions within the CNS that subserve cognitive processes. Currently available evidence shows that the cytokines IL-1beta, IL-6 and TNF-alpha play a role in complex cognitive processes at the molecular level, such as synaptic plasticity, neurogenesis, as well as neuromodulation. Such findings provide evidence for a cytokine model of cognitive function, which shows that cytokines play an intimate role in the molecular and cellular mechanisms subserving learning, memory and cognition under physiological conditions. These cytokine-mediated cognitive processes have implications in the long-term development and pathogenesis of specific neuropsychiatric disorders such as major depression and dementia. The identification of this central role of cytokines in various brain activities during health provides greater insight into normal brain functions, especially synaptic plasticity, memory and cognition, and facilitates the understanding of specific biological mechanisms involved in neuropsychiatric diseases, such as dementia and depression. In order to extend the suggested cytokine model of cognitive function onto other members of the cytokine family, future research is required to investigate the physiological effects of other cytokines such as interferon-gamma (IFNgamma), alpha(1)-antichymotrypsin and IL-2 on cognitive function at the molecular level under immunologically unchallenged conditions.     

Dimensions of Cognitive Ability in Dementia: Differential Sensitivity to Degree of Impairment in Alzheimer's Disease

The purpose of this study was to identify dimensions of cognitive functioning in demented elderly persons and examine sensitivity of these dimensions to different degrees of cognitive impairment in Alzheimer's disease. Participants included 210 demented elderly patients and 89 normal controls. Principal components analysis of neuropsychological test scores for the demented patients yielded the following six components: (1) Memory/Learning, (2) Spatial/Nonverbal, (3) Verbal/Lexical Knowledge, (4) Verbal Fluency, (5) Visual Paired Associates, and (6) Verbal Attention Span. All dimensions discriminated among normal controls and three groups of patients with probable Alzheimer's disease defined by decreasing Mini-Mental State Exam scores. Differential sensitivity of cognitive dimensions was observed as a function of level of cognitive impairment.     

Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice

It was recently shown that adaptive immunity plays a key role in cognitive function. T cells appear to be major players in learning and memory; thus, mice devoid of functional T cells are impaired in performance of cognitive tasks such as Morris water maze (MWM), Barnes maze and others. This is a reversible phenomenon; injection of immune deficient mice with T cells from wild type counterparts improves their cognitive function. Recently we described a critical role for T cell-derived IL-4 as having beneficial effects on learning and memory through regulation of meningeal myeloid cell phenotype. In the absence of IL-4, meningeal myeloid cells acquire a pro-inflammatory skew. Thus, the presence of IL-4 in the meningeal spaces maintains a delicate balance of pro- and anti-inflammatory myeloid cell phenotype. Here we show that macrophages alternatively activated in vitro (M2 cells) can circumvent the need for ‘pro-cognitive’ T cells when injected intravenously into immune deficient mice. These results show for the first time that M2 myeloid cells are new and unexpected players in cognitive function, conferring beneficial effects on learning and memory without adaptive immune influence. These results might lead to development of new therapeutic approaches for cognitive pathologies associated with malfunction of adaptive immunity, such as chemo-brain, age-related dementia, HIV-dementia, and others.     

The relationship between nicotinic receptors and cognitive functioning in healthy aging: An in vivo positron emission tomography (PET) study with 2‐[18F]fluoro‐A‐85380

Extensive experimental and neuropathological evidence supports the general hypothesis that decline in the basal forebrain cholinergic system contributes significantly to age‐related cognitive impairment. Postmortem studies suggest reductions in neuronal nicotinic acetylcholine receptors (nAChRs, particularly the α₄β₂ subtype) with aging. This study aimed to determine the distribution of α₄β₂‐subtype nAChRs in vivo by 2‐FA PET in healthy subjects (aged 21–83) and to establish whether there is an age‐related decline in nAChRs. Furthermore, the relationship between PET measures of 2‐FA binding and neurobehavioral measures of cognitive function was investigated. All participants were nonsmokers and underwent extensive cognitive testing and a PET scan after injection of 2‐FA (200 MBq). Brain regional 2‐FA binding was assessed through a simplified estimation of distribution volume (DV_S). As expected, increasing age was associated with poorer cognitive performance, particularly on tasks assessing episodic memory and attentional processes. No significant age‐related differences in regional nAChR DV_S were found. Furthermore, no significant correlations were found between cognitive measures and nAChR DV_S. These results are consistent with recent studies suggesting the stability of cholinergic markers during senescence. It is plausible that changes in α₄β₂ nAChRs do occur with advancing age, but are beyond detection by the clinical 2‐FA PET approach adopted here. However, this approach may be appropriate for use in pathologies considered to undergo extensive nAChR loss such as Alzheimer's disease and Parkinson's disease. Synapse 63:752–763, 2009. © 2009 Wiley‐Liss, Inc.     

Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper

Alzheimer disease (AD) includes inflammatory processes in the senile plaques and surrounding glia, with increased expression of acute phase proteins such as C-reactive protein (CRP) and IL-6. Increased IL-6 expression during normal brain aging suggests a link of age-related inflammation to the onset of AD during aging. Blood levels of CRP and IL-6 are also associated with higher risk of Alzheimer disease and cognitive decline during aging. Some infections are known to induce inflammation and amyloid deposits. For example, HIV induces the deposition of the same beta-amyloid as in Alzheimer disease. The ApoE4 allele may increase HIV-associated dementia, in addition to its well-known effect on accelerating the onset age of AD. Many other adverse effects of apoE4 are recognized, which suggested the hypothesis that apoE4 persists in human populations because of balancing selection (Charlesworth-Martin hypothesis). The apoE4 allele was acquired during human evolution and may have conferred initial advantages in pathogen resistance. As evidence for this hypothesis, apoE4 carriers have less severe liver damage during hepatitis C infections. As human lifespan lengthened and cognitive and cardiovascular health became more important, the apoE3 allele spread, while the E4 allele was maintained in all populations by balancing selection.