Expression Of Alzheimer's Disease Research Articles

Identification of miRNA-mRNA Pairs in the Alzheimer's Disease Expression Profile and Explore the Effect of miR-26a-5p/PTGS2 on Amyloid-β Induced Neurotoxicity in Alzheimer's Disease Cell Model.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common type of dementia. MicroRNAs (miRNAs) have been extensively studied in many diseases, including AD. To identify the AD-specific differentially expressed miRNAs and mRNAs, we used bioinformatics analysis to study candidate miRNA–mRNA pairs involved in the pathogenesis of AD. These miRNA–mRNAs may serve as promising biomarkers for early diagnosis or targeted therapy of AD patients. In this study, based on the AD mRNA and miRNA expression profile data in Gene Expression Omnibus (GEO), through differential expression analysis, functional annotation and enrichment analysis, weighted gene co-expression network analysis, miRNA–mRNA regulatory network, protein–protein interaction network, receiver operator characteristic and Least absolute shrinkage and selection operator (LASSO) regression and other analysis, we screened the key miRNA–mRNA in the progress of AD: miR-26a-5p/PTGS2. Dual-luciferase and qPCR experiments confirmed that PTGS2 is a direct target gene of miR-26a-5p. The expression of miR-26a-5p in the peripheral blood of AD patients and AD model cells (SH-SY5Y cells treated with Aβ25–35) was up-regulated, and the expression of PTGS2 was down-regulated. Functional gain -loss experiments confirmed that PTGS2 protects AD model cells from damage by inhibiting proliferation and migration. However, the expression of miR-26a-5p promotes the proliferation of AD model cells. It is further found that PTGS2 is involved in the regulation of miR-26a-5p and can reverse the effect of miR-26a-5p on the proliferation of AD model cells. In addition, through network pharmacology, qPCR and CCK-8, we found that baicalein may affect the progression of AD by regulating the expression of PTGS2. Therefore, PTGS2 can be used as a target for AD research, and miR-26a-5p/PTGS2 can be used as an axis of action to study the pathogenesis of AD.

Ovocystatin Induced Changes in Expression of Alzheimer's Disease Relevant Proteins in APP/PS1 Transgenic Mice.

Background: Ovocystatin is marked by structural and biological similarities to human cystatin C, which plays an important role in the course of neurodegenerative diseases. Recently, it has been shown that ovocystatin might prevent aging-related cognitive impairment in rats and reduce memory decline in an APP/PS1 mice model. Thus, this study aimed to assess the effect of ovocystatin on histopathological changes in APP/PS1 mice. Materials and methods: Ovocystatin was administered intraperitoneally for four weeks (40 μg/mouse) to 35-weeks-old transgenic (AD, n = 14) and wild type (NCAR, n = 15) mice (stock B6C3-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax). A histopathological evaluation comprised antibodies directed against β-amyloid (1:400, SIG-39320-1000, Covance) and Tau (1:4000, AHB0042, Invitrogen). Three regions of the hippocampus— the dentate gyrus (DG) and the cornu ammonis (CA1 and CA3)—were analyzed by immunohistochemistry in each animal. All differences are expressed as percentage relative to the control group. Results: The main results showed that the percentage of immunoreactive area of β-amyloid, tau protein deposits in APP/PS1+ovCYS was decreased in DG, CA1, and CA3 regions compared with the APP/PS1 control, respectively (p < 0.05). Conclusions: Ovocystatin caused significant changes in the expression pattern of all investigated proteins in hippocampal tissues both in APP/PS1 and NCAR mice.

Development of a Comprehensive Battery to Collect Social and Structural Determinants of Health (SSDOH) in Cognitively Normal or Very Mildly Impaired Persons.

Research addressing Alzheimer disease and related dementias must examine nonbiological factors influencing the risk for and expression of Alzheimer disease and related dementias. These factors address the interplay of cognition with lived experiences and social and structural determinants of health (SSDOH). However, coordinated measures of SSDOH are limited. The Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis developed and piloted a comprehensive battery to measure SSDOH. One hundred and twelve participants, very mildly cognitively impaired or unimpaired, enrolled in memory studies completed the electronic SSDOH battery. The Clinical Dementia Rating (CDR) determined the presence or absence of cognitive impairment. Four domains demonstrated above acceptable intraclass correlation scores for test-retest reliability (≥0.70), including adverse childhood events, discrimination, social status, and early education. Twenty very mildly impaired participants completed the electronic pilot study. Our findings indicate that participants with early-stage symptomatic Alzheimer disease are able to participate in electronic SSDOH data collection. In collaboration with the University of Pennsylvania ADRC, we replaced/modified certain assessments to increase intraclass correlation. The resulting battery, Social and Structural Life-courses Influencing Aging and Dementia (SS-DIAD), can serve as a SSDOH collection tool and is currently utilized in cognitively impaired and unimpaired research participants at both ADRCs.

Longitudinal associations between C-reactive protein and cognitive performance in normative cognitive ageing and dementia.

systemic inflammation appears to play an important role in the pathogenesis and expression of Alzheimer's disease and other dementias. Previous research has found that elevated levels of serum C-reactive protein (CRP) is associated with poorer cognitive functioning and increased risk for dementia. However, most studies are limited by single CRP measurements, which fail to capture long-term inflammatory exposures or dynamic changes in inflammation and cognition which may occur across repeated measurements. using data from 3,563 older adults aged 65-101 from the Health and Retirement Study, we examined bivariate changes in CRP and cognition measured repeatedly over a 10-year follow-up. Bivariate multilevel models estimated the effect of time-varying CRP on cognition among cognitively healthy older adults and in a subset of 427 participants who reported incident dementia onset during the follow-up period. in cognitively healthy participants, CRP was associated with lower level of cognitive functioning, but not rate of change over time. This effect was significant in participants under 80years of age (b = -0.09, standard error (SE) = 0.05, P = 0.04), but not in older participants. In participants with incident dementia, those with higher CRP experienced smaller rates of cognitive decline, leading up to dementia diagnosis. elevated levels of CRP predict poorer cognition and increased dementia risk in cognitively healthy adults under the age of 80. Conversely, increased CRP may confer protective effects on cognition in the prodromal stage of dementia.

PIP2 depletion and altered endocytosis caused by expression of Alzheimer's disease-protective variant PLCγ2 R522.

Variants identified in genome‐wide association studies have implicated immune pathways in the development of Alzheimer’s disease (AD). Here, we investigated the mechanistic basis for protection from AD associated with PLCγ2 R522, a rare coding variant of the PLCG2 gene. We studied the variant's role in macrophages and microglia of newly generated PLCG2‐R522‐expressing human induced pluripotent cell lines (hiPSC) and knockin mice, which exhibit normal endogenous PLCG2 expression. In all models, cells expressing the R522 mutation show a consistent non‐redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This manifests as enhanced release of cellular calcium ion stores in response to physiologically relevant stimuli like Fc‐receptor ligation or exposure to Aβ oligomers. Expression of the PLCγ2‐R522 variant resulted in increased stimulus‐dependent PIP2 depletion and reduced basal PIP2 levels in vivo. Furthermore, it was associated with impaired phagocytosis and enhanced endocytosis. PLCγ2 acts downstream of other AD‐related factors, such as TREM2 and CSF1R, and alterations in its activity directly impact cell function. The inherent druggability of enzymes such as PLCγ2 raises the prospect of PLCγ2 manipulation as a future therapeutic approach in AD.

Alteration in the Expression of Alzheimer's-Related Genes in Rat Hippocampus by Exercise and Morphine Treatments

Alteration in the Expression of Alzheimer's-Related Genes in Rat Hippocampus by Exercise and Morphine Treatments

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHNPCs) and in a non-cell autonomous manner. These findings were confirmed in PS1M146V/+ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1M146V/+ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1M146V/+ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.SIGNIFICANCE STATEMENT Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD). Mutant PS1 expression enhances the levels and assembly of toxic Aβ42 peptides and impairs the self-renewal and neuronal differentiation of adult hippocampal neural progenitor cells (AHNPCs) following environmental enrichment (EE) that is associated with heightened baseline anxiety. We now show that microglial depletion fully restores the EE-mediated impairments in AHNPC phenotypes and suppresses the heightened baseline anxiety observed in mice expressing FAD-linked PS1. Thus, we conclude that the memory deficits and anxiety-related behaviors in patients with PS1 mutations is a reflection not just of an increase in the levels of Aβ42 peptides, but to impairments in the self-renewal and neuronal differentiation of AHNPCs that modulate affective behaviors.

Race May Impact Expression of Alzheimer’s Biomarkers

Race May Impact Expression of Alzheimer’s Biomarkers

The protective effect of betulinic acid on microvascular responsivity and protein expression in alzheimer disease induced by cerebral micro-injection of beta-amyloid and streptozotocin.

Alzheimer's disease (AD) is mainly caused by accumulation of β-amyloid (Aβ) in vessels or parenchyma of the brain. Accordingly, natural compounds such as betulinic acid (BA) might improve the AD signs by increase in blood flow and through reduction in amyloid plaques. Intra-hippocampal injection of BA (0.2 and 0.4μmol/L /10μL DMSO /rat) was done at intervals of 180 and 10min before co-microinjection of 0.1μmol/L Aβ dissolved in PBS (5μL/rat, hippocampi) and 1.5mg/kg Streptozotocin dissolved in aCSF (10μL/rat, lateral ventricles). Cerebro-vascular responsivity tested by Laser Doppler, BBB leakage, Elisa assays of cytokines (TNF-α and IL-10), and Western blot analysis of proteins (BDNF and AchE) in the hippocampus were assessed 1month after the injections. Microvascular reaction and BBB function were significantly impaired in AD rats, which were improved via BA pretreatment. BA could increase BDNF expression and decrease cytokine levels in the hippocampus of AD rats (especially 0.1μmol/L Aβ: 0.4μmol/L BA); however, no significant changes were detected in the blotting of AchE among the groups. Betulinic acid could have a role in AD through protecting microcirculation, alleviating inflammation, and up-regulating BDNF expression which is clearer toward 1:4 molar ratios of Aβ to BA.

Glutamate Transporter GLT1 Expression in Alzheimer Disease and Dementia With Lewy Bodies.

Glutamate transporter solute carrier family 1, member 2 (GLT1/EAAT2), a major modulator of glutamate homeostasis in astrocytes, is assessed in post-mortem human brain samples of frontal cortex area 8 in advanced stages of Alzheimer disease (AD) and terminal stages of dementia with Lewy bodies (DLB) in order to gain understanding of astrogliopathy in diseases manifested by dementia. Glial fibrillary acidic protein (GFAP) mRNA expression is significantly increased in AD but not in DLB, whereas GLT1, vesicular glutamate transporter 1 (vGLUT1) and aldehyde dehydrogenase 1 family member 1 (ALDH1L1) are not modified in AD and DLB when compared with controls. GLT1 protein levels are not altered in AD and DLB but GFAP and ALDH1L1 are significantly increased in AD, and GFAP in DLB. As a result, a non-significant decrease in the ratio between GLT1 and GFAP, and between GLT1 and ALDH1L1, is found in both AD and DLB. Double-labeling immunofluorescence and confocal microscopy revealed no visible reduction of GLT1 immunoreactivity in relation to β-amyloid plaques in AD. These data suggest a subtle imbalance between GLT1, and GFAP and ALDH1L1 expression, with limited consequences in glutamate transport.

Effects of Herbal Compound (IMOD) on Behavior and Expression of Alzheimer's Disease Related Genes in Streptozotocin-Rat Model of Sporadic Alzheimer's Disease.

Purpose: Sporadic Alzheimer’s disease (AD) accounts for over 95% of cases. Possible mechanisms of AD such as inflammation and oxidative stresses in the brain motivate researchers to follow many therapies which would be effective, especially in the early stages of the disease. IMOD, the herbal extract of R. Canina, T. Vulgare and U. Dioica plant species enriched with selenium, has anti-inflammatory, immunoregulatory and protective effects against oxidative stress.Methods: In this study three AD-related genes, DAXX, NFκβ and VEGF, were chosen as candidate to investigate the neuroprotective effect of the extract by comparing their expression levels in the hippocampus of rat model of sporadic AD, using qPCR in the herbal-treated and control groups. The therapeutic effects on learning and memory levels were evaluated by Morris Water Maze (MWM) test.Results: Gene expression results were indicative of significant up-regulation of Vegf in rat’s hippocampus after treatment with the herbal extract comparing to model group (P-value= 0.001). The MWM results showed significant changes in path length and time for finding the hidden platform in all groups during test and the same change in the treated comparing to the control group in memory level.Conclusion: It could be concluded that the herbal extract may have significant effect on gene expression but not on behavioral level.

Neuroprotective effect of the Chinese medicine Tiantai No. 1 and its molecular mechanism in the senescence-accelerated mouse prone 8.

Tiantai No. 1, a Chinese medicine predominantly composed of powdered Rhizoma Gastrodiae, Radix Ginseng, and Ginkgo leaf at a ratio of 2:1:2 and dissolved in pure water, is neuroprotective in animal models of various cognitive disorders, but its molecular mechanism remains unclear. We administered Tiantai No. 1 intragastrically to senescence-accelerated mouse prone 8 (SAMP8) mice (a model of Alzheimer's disease) at doses of 50, 100 or 150 mg/kg per day for 8 weeks and evaluated their behavior in the Morris water maze and expression of Alzheimer's disease-related proteins in the brain. Tiantai No. 1 shortened the escape latency in the water maze training trials, and increased swimming time in the target quadrant during the spatial probe test, indicating that Tiantai No. 1 improved learning and memory in SAMP8 mice. Immunohistochemistry revealed that Tiantai No. 1 restored the proliferation potential of Ki67-positive cells in the hippocampus. In addition, mice that had received Tiantai No. 1 had fewer astrocytes, and less accumulation of amyloid-beta and phosphorylated tau. These results suggest that Tiantai No. 1 is neuroprotective in the SAMP8 mouse model of Alzheimer's disease and acts by restoring neuronal number and proliferation potential in the hippocampus, decreasing astrocyte infiltration, and reducing the accumulation of amyloid-beta and phosphorylated tau.

A methodological critique of the National Institute of Aging and Alzheimer’s Association Guidelines for Alzheimer’s disease, dementia, and mild cognitive impairments

In 2011, the U.S. National Institute on Aging published guidelines for clinical diagnostics for Alzheimer's disease dementia. These guidelines define a continuum with three stages-an early, pre-clinical stage with no symptoms, followed by mild cognitive impairment, and a final stage of Alzheimer's disease dementia. This methodological critique examines the validity of this continuum. No studies exist showing the progression of these biomarkers to Alzheimer's disease. There is also a lack of empirical evidence showing how biomarkers determine mild cognitive impairment, which has multiple etiologies. The guidelines fail to explain anomalies where there are biomarkers but no expression of Alzheimer's disease.

P3‐059: The impact of cholesterol intake on expression of Alzheimer's disease–related genes in the guinea pig brain

P3‐059: The impact of cholesterol intake on expression of Alzheimer's disease–related genes in the guinea pig brain

β-Amyloid 42/40 ratio and kalirin expression in Alzheimer disease with psychosis

Psychosis in Alzheimer disease differentiates a subgroup with more rapid decline, is heritable, and aggregates within families, suggesting a distinct neurobiology. Evidence indicates that greater impairments of cerebral cortical synapses, particularly in dorsolateral prefrontal cortex, may contribute to the pathogenesis of psychosis in Alzheimer disease (AD) phenotype. Soluble β-amyloid induces loss of dendritic spine synapses through impairment of long-term potentiation. In contrast, the Rho guanine nucleotide exchange factor (GEF) kalirin is an essential mediator of spine maintenance and growth in cerebral cortex. We therefore hypothesized that psychosis in AD would be associated with increased soluble β-amyloid and reduced expression of kalirin in the cortex. We tested this hypothesis in postmortem cortical gray matter extracts from 52 AD subjects with and without psychosis. In subjects with psychosis, the β-amyloid1–42/β-amyloid1–40 ratio was increased, due primarily to reduced soluble β-amyloid1–40, and kalirin-7, -9, and -12 were reduced. These findings suggest that increased cortical β-amyloid1–42/β-amyloid1–40 ratio and decreased kalirin expression may both contribute to the pathogenesis of psychosis in AD.

An Individualized Approach to Tracking and Treating Alzheimer’s Disease

There can be substantial variation in the expression of Alzheimer's disease. Patients vary in who is affected (e.g., education, age at onset), in how they are affected (e.g., neuropathological profile, comorbidities), and in when they present (i.e., stage of illness). Even people with similar starting profiles can have dramatically different courses. For these reasons, tracking disease progression in individuals and the effects of treatment on them can be challenging. This variability further complicates the difficulty of dementia's high dimensionality--Alzheimer's disease affects many aspects of cognition, function, and behavior.

Differential effects of simvastatin and pravastatin on expression of Alzheimer's disease-related genes in human astrocytes and neuronal cells

Inhibitors of HMG-CoA reductase (statins) are widely used medications for reduction of cholesterol levels. Statin use significantly reduces risk of cardiovascular disease but has also been associated with lower risk of other diseases and conditions, including dementia. However, some reports suggest that statins also have detrimental effects on the brain. We provide evidence that simvastatin and pravastatin have significantly different effects on expression of genes related to neurodegeneration in astrocytes and neuroblastoma (SK-N-SH) cells in culture. Simvastatin significantly reduced expression of ABCA1 in astrocytes and neuroblastoma cells (by 79% and 97%, respectively; both P < 0.001). Pravastatin had a similar but attenuated effect on ABCA1 in astrocytes (-54%, P < 0.001) and neuroblastoma cells (-70%, P < 0.001). Simvastatin reduced expression of apolipoprotein E in astrocytes (P < 0.01). Furthermore, both statins reduced expression of microtubule-associated protein tau in astrocytes (P < 0.01), while both statins increased its expression in neuroblastoma cells (P < 0.01). In SK-N-SH cells, simvastatin significantly increased cyclin-dependent kinase 5 and glycogen synthase kinase 3beta expression, while pravastatin increased amyloid precursor protein expression. Our data suggest that simvastatin and pravastatin differentially affect expression of genes involved in neurodegeneration and that statin-dependent gene expression regulation is cell type specific.

Dietary vitamin E, brain redox status and expression of Alzheimer's disease-relevant genes in rats

Oxidative stress is one of the major pathological features of Alzheimer's disease (AD). Here, we investigated whether dietary vitamin E (VE) depletion may induce adverse effects and supplementation with alpha-tocopherol (alphaT) may result in beneficial effects on redox status and the regulation of genes relevant in the pathogenesis of AD in healthy rats. Three groups of eight male rats each were fed diets with deficient ( < 1 mg alphaT equivalents/kg diet), marginal (9 mg alphaT equivalents/kg diet) or sufficient (18 mg alphaT equivalents/kg diet) concentrations of natural-source VE for 6 months; a fourth group was fed the VE-sufficient diet fortified with alphaT (total VE, 146 mg alphaT equivalents/kg diet). Feeding of the experimental diets dose dependently altered alphaT concentrations in the cortex and plasma. No significant changes in F2-isoprostane concentrations, activities of antioxidative enzymes (total superoxide dismutase, Se-dependent glutathione peroxidase) and concentrations of glutathione or the expression of AD-relevant genes were observed. In this non-AD model, depletion of VE did not induce adverse effects and supplementation of alphaT did not induce positive effects on the parameters related to the progression of AD.

Decreased drebrin mRNA expression in Alzheimer disease: Correlation with tau pathology

To investigate the mRNA expression of the dendritic spine protein drebrin in Alzheimer's disease (AD), we performed post-mortem in situ hybridization studies in brain sections from 20 AD patients and 21 controls. AD diagnosis was confirmed by decreased drebrin protein and increased Abeta(40) (+464%; P < 0.05), Abeta(42) (+369%; P < 0.0001), Abeta(42/40) ratio (+226%; P < 0.01), total tau (+2,725%; P < 0.0001), and paired helical filament tau (PHFtau; +867%; P < 0.001) compared with controls. We found significant decreases in drebrin mRNA in the parietal cortex (-27%; P < 0.01), the temporal cortex (-22%; P < 0.05), and the hippocampus (-25%; P < 0.05) of AD patients compared with controls. Cortical levels of drebrin mRNA correlated positively with soluble total tau (r(2) = +0.244) but negatively with duration of symptoms (r(2) = -0.357) and PHFtau (r(2) = -0.248). Drebrin mRNA levels were correlated to a lesser degree with the drebrin protein content (r(2) = +0.136) and with sim2 (r(2) = +0.176), a potential modulator of drebrin transcription. Our results suggest that the down-regulation of drebrin mRNA expression plays an important role in AD and is closely related to the progression of the disease.

Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia.

Survival of CLL cells requires sustained activation of the anti-apoptotic PI-3-kinase/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or anti-apoptotic. High density lipoprotein (HDL) particles are anti-apoptotic through sphingosine-1-phosphate receptor 3 (S1P3)-mediated activation of the PI-3-K/Akt pathway. We have noted that apoE4-very low density lipoprotein (VLDL) (but not apoE2- or apoE3-VLDL) particles increase apoptosis of endothelial cells by recruiting the phosphoinositol phosphatase SHIP-2 to the plasma membrane, thereby directly inhibiting the anti-apoptotic activity of HDL (DeKroon R, et al., Circ Res 99:829–836, 2006). Since apoE4-VLDL increases apoptosis of certain cells, and since increased leukemia cell apoptosis favors longer survival in CLL, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. Of the 193 CLL patients (50 women and 133 men) studied, 29% had an APOE4 genotype. In the entire group, survival of men and women was not statistically different. However, women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients (median >25 yr vs. 14.0 yr; p = 0.02) (Figure). [Display omitted] Men and women had the same time-to-treatment (treatment-free survival) irrespective of APOE genotype. VLDL is metabolized to LDL by the actions of LPL. Patients had shorter survival and time-to-treatment if their CLL cell lipoprotein lipase (LPL) mRNA levels were high (p = 0.002). In analyzing APOE genotype and LPL levels in the same patients, we demonstrated that APOE4 was a more important determinant of survival than was the LPL level (p = 0.0007). The beneficial effect of APOE4 in CLL survival is likely mediated through allele-specific influences of APOE4 on serum lipoproteins increasing leukemia cell apoptosis. The frequency of the APOE alleles in the CLL patient population was not significantly different than that of a control population (16 and 13%, respectively). APOE genotype therefore does not appear to affect susceptibility to CLL, but influences the clinical course of disease, particularly after therapy is initiated. In contrast, APOE genotype does influence susceptibility to other diseases, most notably Alzheimer's disease in which APOE4 markedly increases risk. The beneficial impact of APOE4 in CLL and its deleterious impact on Alzheimer's disease expression may relate to a common mechanism of APOE4 in enhancing apoptotic cell death. APOE genotyping of patients with CLL may provide important clinical prognostic information, particularly in women. Most importantly, the allele-specific influence of APOE on disease progression may provide important new insights into the mechanisms of disease and response to therapy, and lead to new agents for treatment.