Biomedical subjects

Julie A Schneider

Publications and source records attributed to Julie A Schneider.

At least 19 recordsLinked to original sources

PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗

PubMed2025

Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci. METHODS: By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined. RESULTS: First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). CONCLUSIONS: While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.

Humans↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2007

Estimation of the mediation effect with a binary mediator.

A mediator acts as a third variable in the causal pathway between a risk factor and an outcome. In this paper, we consider the estimation of the mediation effect when the mediator is a binary variable. We give a precise definition of the mediation effect and examine asymptotic properties of five different estimators of the mediation effect. Our theoretical developments, which are supported by a Monte Carlo study, show that the estimators that account for the binary nature of the mediator are consistent for the mediation effect defined in this paper while other estimators are inconsistent. We use these estimators to study the mediation effect of chronic cerebral infarction in the causal relationship between the apolipoprotein E epsilon4 allele and cognitive function among 233 deceased participants from the Religious Orders Study, a longitudinal, clinical-pathologic study of aging and Alzheimer's disease.

Aging↗

PubMed2006

Decision rules guiding the clinical diagnosis of Alzheimer's disease in two community-based cohort studies compared to standard practice in a clinic-based cohort study.

We developed prediction rules to guide the clinical diagnosis of Alzheimer's disease (AD) in two community-based cohort studies (the Religious Orders Study and the Rush Memory and Aging Project). The rules were implemented without informant interviews, neuroimaging, blood work or routine case conferencing. Autopsies were performed at death and the pathologic diagnosis of AD made with a modified version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. We compared the positive predictive value of the clinical diagnosis in the two community-based studies to the positive predictive value of the clinical diagnosis of AD made by standard clinical practice in a clinic-based cohort study using AD pathology as the gold standard. Of 306 clinic cases with probable AD, 286 (93.5%) met CERAD neuropathologic criteria for AD; the results were comparable for those with possible AD (51 of 54, 94.4%). Of 141 study subjects with probable AD, 130 (92.2%) met CERAD neuropathologic criteria for AD; the results were lower but acceptable for those with possible AD (26 of 37, 70.3%). The results were similar in secondary analyses using alternate neuropathologic criteria for AD. The clinical diagnosis of AD can be made in community-based studies without the use of informant interviews, neuroimaging, blood work or routine case conferencing. This approach holds promise for reducing the operational costs of epidemiologic studies of aging and AD.

Aged↗

PubMed2006

Chronic psychological distress and risk of Alzheimer's disease in old age.

Clinical and pathological data from the Rush Memory and Aging Project were used to test the hypothesis that distress proneness is associated with increased risk of Alzheimer's disease (AD). More than 600 older persons without dementia completed a 6-item measure of neuroticism, a stable indicator of proneness to psychological distress. At annual intervals thereafter, they underwent uniform evaluations that included clinical classification of AD and administration of 18 cognitive tests. Those who died underwent brain autopsy from which composite measures of AD pathology were derived. During a mean of about 3 years of follow-up, 55 people were clinically diagnosed with AD. In analyses that controlled for age, sex, and education, persons with a high level of distress proneness (score = 24, 90th percentile) were 2.7 times more likely to develop AD than those not prone to distress (score = 6, 10th percentile). Adjustment for depressive symptomatology or frequency of cognitive, social, and physical activity did not substantially change this effect. Distress proneness was also associated with more rapid cognitive decline. Among 45 participants who died and underwent brain autopsy, distress proneness was unrelated to diverse measures of AD pathology and was inversely related to cognition after controlling for AD pathology. The results support the hypothesis that distress proneness is associated with increased risk of dementia and suggest that neurobiologic mechanisms other than AD pathology may underlie the association.

Aged↗

PubMed2006

Early involvement of small inhibitory cortical interneurons in Alzheimer's disease.

Work on acute models of cortical injury has revealed a population of small GABAergic interneurons that are induced to increase their low constitutive expression of neuronal nitric oxide (NO) synthase (nNOS). In some cases, this activation may play a role in NO-mediated degeneration of pyramidal neurons. In this report, we explore the anatomy of various classes of cortical nNOS (+) (nitrergic) neurons, with emphasis on small interneurons, in the medial temporal lobe of subjects with Alzheimer's disease (AD) from two well-characterized cohorts, the Baltimore Longitudinal Study on Aging (BLSA) and the Religious Order Study (ROS). We find that small calbindin (+) cortical interneurons are induced to high levels of NADPHd/nNOS reactivity early in AD and abound in areas with emerging neurofibrillary pathology, that is, in entorhinal cortex in the beginning of the limbic stage of Braak, in hippocampal CA1 in the mature limbic stage and in temporal neocortex in the late limbic stage. This pattern was robust and significant in the younger of the two AD cohorts studied (BLSA), but persisted as a trend in the older cohort (ROS). In optimally prepared material, we find a significant correlation between numbers of these interneurons and markers of neuronal cell death, for example, caspase-3 activation. Our results show that small cortical inhibitory interneurons represent an extensive signaling system that is induced to higher levels of NADPHd/nNOS expression early in the paralimbic-limbic-neocortical sequence of AD progression. We propose that nNOS/NO signaling initiated in these interneurons can serve as a marker of early cortical injury in AD. The specific role played by inhibitory interneurons and NO in the elaboration of specific neuropathologies associated with AD, that is, Abeta and neurofibrillary deposits and cell death deserves further exploration in experimental animal models.

Aged↗

PubMed2006

The relation of cigarette smoking to incident Alzheimer's disease in a biracial urban community population.

The relationship between smoking status and incident Alzheimer's disease (AD) was investigated in a random stratified sample of a biracial community in Chicago. Analyses are based on 1,064 persons (of 1,134 evaluated) who had data on smoking status, disease incidence, and key covariates such as apolipoprotein allele status. During a mean of about 4 years of follow-up, 170 persons met criteria for incident AD. Current smoking was associated with increased risk of incident AD (OR = 3.4, 95% CI = 1.4-8.0) compared to persons who never smoked. There was no apparent increase in risk of AD for former smokers compared to persons who never smoked (OR = 0.9, 95% CI = 0.5-1.7). Apolipoprotein E allele status modified this association in that former smokers with a upsilon4 allele were less likely to develop AD (p = 0.04) than those who never smoked. Former smokers also appeared to have a reduced risk of developing AD as their pack-years of smoking increased (p = 0.02)such that the odds of developing AD increased by 50% for every 10 years of smoking cessation (OR = 1.3, CI = 0.9-1.7). The results suggest that older people who currently smoke are more likely to develop AD compared to those who never smoked; the relation between those who used to smoke but quit and the risk of AD is complex and requires further research.

Black or African American↗

PubMed2006

Dietary copper and high saturated and trans fat intakes associated with cognitive decline.

BACKGROUND: Evidence from prospective epidemiologic studies and animal models suggests that intakes of dietary fats and copper may be associated with neurodegenerative diseases. OBJECTIVE: To examine whether high dietary copper intake is associated with increased cognitive decline among persons who also consume a diet high in saturated and trans fats. DESIGN: Community-based prospective study. SETTING: Chicago, Ill. Patients Chicago residents 65 years and older. MAIN OUTCOME MEASURES: Cognitive function was assessed using 4 cognitive tests administered during in-home interviews at 3-year intervals for 6 years. Dietary assessment was performed with a food frequency questionnaire. Dietary intakes of copper and fats were related to change in global cognitive score (the mean of the 4 tests) among 3718 participants. RESULTS: Among persons whose diets were high in saturated and trans fats, higher copper intake was associated with a faster rate of cognitive decline. In multiple-adjusted mixed models, the difference in rates for persons in the highest (median, 2.75 mg/d) vs lowest (median, 0.88 mg/d) quintiles of total copper intake was -6.14 standardized units per year (P<.001) or the equivalent of 19 more years of age. There was also a marginally statistically significant association (P = .07) with the highest quintile of food intake of copper (median, 1.51 mg/d) and a strong dose-response association with higher copper dose in vitamin supplements. Copper intake was not associated with cognitive change among persons whose diets were not high in these fats. CONCLUSION: These data suggest that high dietary intake of copper in conjunction with a diet high in saturated and trans fats may be associated with accelerated cognitive decline.

Aged↗

PubMed2006

Substantia nigra tangles are related to gait impairment in older persons.

OBJECTIVE: Parkinsonian signs, especially gait impairment, are common and associated with morbidity and mortality in older persons. Our objective was to test the hypothesis that substantia nigra neurofibrillary tangles (NFTs) are related to parkinsonian signs in older persons with and without dementia. METHODS: We studied 86 deceased older Catholic clergy without idiopathic Parkinson's disease from the Religious Order Study, a longitudinal clinical-pathological study. Mean age at death was 85.3 years. Signs of gait disturbance, bradykinesia, rigidity, and tremor were assessed proximate to death using a modified Unified Parkinson's Disease Rating Scale. Forty-micrometer paraffin-embedded sections of substantia nigra were bleached before tau immunohistochemistry and the optical disector was used to count NFTs. We used multivariable linear regression to examine parkinsonian signs as a function of nigra NFTs, controlling for age, sex, education, and cortical NFTs. RESULTS: Substantia nigra NFTs were present in 67 of 86 persons (77.9%). After controlling for age, sex, education, and cortical NFTs, nigra NFTs were related to gait impairment (p < 0.001), but not bradykinesia, rigidity, or tremor. Results were not confounded by dementia, Braak score, neuroleptic medication, cerebral infarcts, or Lewy bodies. INTERPRETATION: NFTs in the substantia nigra are associated with gait impairment in older persons with and without dementia.

Aged, 80 and over↗

PubMed2006

The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study.

BACKGROUND: Few data are available about how social networks reduce the risk of cognitive impairment in old age. We aimed to measure this effect using data from a large, longitudinal, epidemiological clinicopathological study. METHODS: 89 elderly people without known dementia participating in the Rush Memory and Aging Project underwent annual clinical evaluation. Brain autopsy was done at the time of death. Social network data were obtained by structured interview. Cognitive function tests were Z scored and averaged to yield a global and specific measure of cognitive function. Alzheimer's disease pathology was quantified as a global measure based on modified Bielschowsky silver stain. Amyloid load and the density of paired helical filament tau tangles were also quantified with antibody-specific immunostains. We used linear regression to examine the relation of disease pathology scores and social networks to level of cognitive function. FINDINGS: Cognitive function was inversely related to all measures of disease pathology, indicating lower function at more severe levels of pathology. Social network size modified the association between pathology and cognitive function (parameter estimate 0.097, SE 0.039, p=0.016, R(2)=0.295). Even at more severe levels of global disease pathology, cognitive function remained higher for participants with larger network sizes. A similar modifying association was observed with tangles (parameter estimate 0.011, SE 0.003, p=0.001, R(2)=0.454). These modifying effects were most pronounced for semantic memory and working memory. Amyloid load did not modify the relation between pathology and network size. The results were unchanged after controlling for cognitive, physical, and social activities, depressive symptoms, or number of chronic diseases. INTERPRETATION: These findings suggest that social networks modify the relation of some measures of Alzheimer's disease pathology to level of cognitive function.

Aged↗

PubMed2006

Folic acid and cognition in older persons.

Folic acid supplementation has drawn much attention in recent years for the prevention of Alzheimer's disease and cognitive decline. In this review, the authors describe how current evidence does not support the use of folic acid supplements to protect against cognitive decline. Although a few studies suggest that folic acid supplementation may provide neuroprotection among persons who are folate deficient, there is also data to indicate that supplementation in persons without folate deficiency may pose a risk to neurological function. Vitamin B12 deficiency is common in old age and may not be easy to recognise. Folic acid supplementation may mask the anaemia associated with vitamin B12 deficiency and, therefore, may delay treatment while allowing progression of neurological symptoms. Whether or not folic acid supplementation exacerbates neurological symptoms of vitamin B12 deficiency is not clear. Further studies are needed to determine the possible risks and benefits of folic acid supplementation in older persons.

Aged↗

PubMed2006

Thoughts on B-vitamins and dementia.

The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer's disease. This commentary reviews the evidence to support protective relations of these vitamins, including consideration of known vitamin deficiency syndromes, theories of underlying biologic mechanisms, and the epidemiologic evidence. We also comment on the potential benefits and harms of vitamin supplementation as well as make recommendations for the direction of future studies.

Alzheimer Disease↗

PubMed2006

Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease.

CONTEXT: It is currently not known whether dietary intakes of folate and vitamins B12 and B6, co-factors in the methylation of homocysteine, protect against Alzheimer's disease. OBJECTIVE: To examine the association between risk of incident Alzheimer's disease and dietary intakes of folate, vitamin B-12, and vitamin B-6. DESIGN: Prospective cohort study. SETTING: Geographically defined biracial Chicago community. PARTICIPANTS: 1,041 residents, aged 65 years and older, initially free of Alzheimer's disease and followed a median 3.9 years for the development of incident disease. MAIN OUTCOME MEASURE: Probable Alzheimer's disease identified through structured clinical neurological evaluation using standardized criteria. RESULTS: A total of 162 persons developed incident Alzheimer's disease during follow-up. In logistic regression models adjusted for age, sex, race, education, cognitive activities, APOE-epsilon4, and dietary intakes of vitamin E in food and total niacin, there was no association between risk of developing Alzheimer's disease and quintiles of folate intake or of vitamin B-12 intake. The adjusted odds ratio was 1.6 (95% confidence interval: 0.5, 5.2) for persons in the highest quintile of total folate intake (median of 752.7 microg/d) compared with persons in the lowest quintile of intake (median, 202.8 microg/d). Compared with persons in the first quintile of total vitamin B-12 intake (median, 3.1 microg/d) the odds ratio was 0.6 (95% confidence interval: 0.2, 1.6) for persons in the fifth quintile of intake (median, 20.6 microg/d). Intake of vitamin B-6 was not associated with incident Alzheimer's disease after control for dietary intakes of vitamin E and total niacin. CONCLUSION: Dietary intakes of folate, vitamin B-12, or vitamin B-6 do not appear to be associated with the development of Alzheimer's disease.

Aged↗

PubMed2005

The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort.

The long-term objective of the Rush Memory and Aging Project is to identify the postmortem indices linking genetic and environmental risk factors to the development of Alzheimer's disease (AD). The overall study design involves a detailed assessment of risk factors for AD in older persons without known dementia who agree to annual clinical evaluation and organ donation at the time of death. In contrast to other clinical-pathologic studies which are conducted on special populations, the Rush Memory and Aging Project enrolled a cohort with much greater diversity in terms of educational attainment, in addition to gender, race, and ethnicity. From September of 1997 through April of 2005, more than 1,000 older persons without known dementia from more than 30 residential facilities across the Chicago metropolitan area agreed to participate. Their mean age was 81 years, about a third had 12 or fewer years of education, a third were men, and about 10% were members of a racial or ethnic minority group. More than 950 already have completed their baseline clinical evaluation.

Activities of Daily Living↗

PubMed2005

Implicit memory and Alzheimer's disease neuropathology.

Explicit memory failure is the defining cognitive feature of Alzheimer's disease and relates to the hallmark neuropathological features (plaques and tangles) of this illness. However, a pattern of preserved and impaired implicit memory has been found in Alzheimer's disease patients that may be explained by the association between the processing demands of certain implicit tests and the level of regional Alzheimer's disease neuropathology. In this study, we tested the hypothesis that these neuropathological features are related to implicit memory--measured by repetition priming--in a test that emphasized conceptual (or meaning-based) cognitive processing, and that the pathological changes are not related to implicit memory in a repetition priming test that emphasized perceptual (or sensory-based) cognitive processing. Subjects were older nuns, priests and brothers participating in the Religious Orders Study who agreed to annual neurological and neuropsychological evaluation for Alzheimer's disease and common neurological conditions of ageing, and brain autopsy at time of death. Explicit memory was measured by seven tests of episodic recall and recognition and converted to a previously established summary measure. Implicit memory was measured by four repetition priming tests. One test, category exemplar priming, emphasized conceptual, or meaning-based cognitive processing. A second test, word-identification priming, emphasized perceptual, or sensory-based cognitive processing. Two additional priming tests, picture-naming and word-stem completion, invoke both conceptual and perceptual processes. Neuritic and diffuse plaques, and neurofibrillary tangles identified by Bielschowsky silver stain, were quantified from five regions separately (frontal, parietal, temporal, entorhinal cortex and the hippocampus) and converted to a previously established summary measure. In linear regression analyses--controlling for age, sex and education--higher levels of Alzheimer's disease neuropathology were related to lower levels of explicit memory proximate to death. Higher levels of neuropathology were also related to lower levels of priming on the category-exemplar test, but were not related to levels of priming on the word-identification, picture-naming, or word-stem completion tests. The results suggest that hallmark indices of Alzheimer's disease neuropathology are associated with performance on priming tests to the extent that conceptual, but not perceptual, processing resources are required.

Aged↗

PubMed2005

Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment.

We determined whether oxidative stress is an early event in the pathogenesis of sporadic Alzheimer disease (AD), and correlated oxidative stress with neuropsychological functions and neurofibrillary pathology in AD and mild cognitive impairment (MCI). Oxidative stress was measured as the percentage of astrocytes expressing heme oxygenase-1 (HO-1) in post mortem temporal cortex and hippocampus after dual HO-1/glial fibrillary acidic protein (GFAP) immunohistochemistry. Glial HO-1 expression in the MCI temporal cortex and hippocampus was significantly greater than in the non-demented group and did not differ from AD values. Astroglial HO-1 expression in the temporal cortex was associated with decreased scores for global cognition, episodic memory, semantic memory and working memory. Hippocampal astroglial HO-1 expression was associated with lower scores for global cognition, semantic memory and perceptual speed. Glial HO-1 immunoreactivity in the temporal cortex, but not hippocampus, correlated with the burden of neurofibrillary pathology. Cortical and hippocampal oxidative stress is a very early event in the pathogenesis of sporadic AD and correlates with the development of specific cognitive deficits in this condition.

Aged↗