James Schmeidler - Academia.edu (original) (raw)
Papers by James Schmeidler
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018
Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at... more Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at cognitive assessment-increases. The Framingham Heart Study provided 1897 participants with intact cognition at entry. Cox regression analysis for incident marked cognitive decline included "time-dependent" coefficients, with associations between total cholesterol and covariates changing by outcome age. Decline within age categories of 75-84 and 85-94 years was also examined. Significant associations of rising total cholesterol linear slope, low entry age, low education, and statin nonuse with risk diminished significantly by outcome age. At 85-94 years, falling linear slope was significant. The protected survival model posits a minority subpopulation with protection against mortality and cognitive decline associated with total cholesterol risk factors. It predicts the observed diminished or reversed cholesterol associations with increasing age. Protection is particularly likel...
Diabetes Care, 2017
OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) o... more OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account ...
Evidence-Based Practice in Child and Adolescent Mental Health, 2016
We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in he... more We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in help-seeking urban children (N=157) presenting for care in community mental health clinics. Children and their parents completed a standard intake assessment conducted by a community clinician followed by a structured trauma-focused assessment conducted by a study clinician. Clinicians provided ratings of child functional impairment, parents reported on internalizing/ externalizing problems, and children provided self-reports of PTSD symptom severity. Although community clinicians were mandated by clinic policy to ask about exposure to physical abuse, sexual abuse, and witnessed domestic violence, they identified exposure to these at significantly lower rates than study clinicians. Rates of PTSD based on community clinician diagnosis (1.9%) were also much lower than rates obtained by study clinicians (19.1%). A review of clinical charts one year after intake revealed no change in PTSD diagnosis rate following additional clinical contacts. Clinician-rated impairment, parent-rated emotional/behavioral problems, and child-rated PTSD symptom severity measures provided support for the validity of trauma exposure and PTSD as identified by study clinicians. Trauma exposure and PTSD diagnosis among help-seeking urban youth appear to be under-identified by community clinicians, which may compromise clinicians' ability to respond to environmental risks and provide appropriate evidence-based treatments.
Human molecular genetics, Oct 11, 2016
Recent studies have indicated that innate immune signaling molecules are involved in late-onset A... more Recent studies have indicated that innate immune signaling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mouse manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the etiology of AD, we have now analyzed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1 and MS4A4A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region specific manner, including hippocampus, an...
Aging cell, Jan 19, 2016
There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pat... more There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its tr...
European Neuropsychopharmacology, 2016
In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) we... more In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE *
Journal of Alzheimer's disease : JAD, 2009
APOE epsilon4 is a major risk factor for Alzheimer's disease. It has also been associated wit... more APOE epsilon4 is a major risk factor for Alzheimer's disease. It has also been associated with cognitive impairment and cognitive decline in young-olds, but the impact of the epsilon4 allele on cognitive function in very late life is still unclear. The object of this study was to evaluate the association of the epsilon4 allele of APOE with the cognitive performance of a sample of non-demented oldest-olds. Eighty-seven Spanish-speaking Puerto Rican non-demented nonagenarians were administered a complete neuropsychological assessment and provided a blood sample used for APOE genotyping. A factor analysis generated two factors: 1) verbal memory; and 2) visuo-spatial, naming and attention tasks, accounting for 43.6% of the overall variance in the 13 original neuropsychological variables. The multivariate analysis reflected, after controlling for gender, education, and age, the APOE epsilon4 carriers performed better in overall cognition (both factors analyzed together) than non-carr...
Journal of Alzheimer's disease : JAD, 2011
Systematic studies on Alzheimer's disease (AD)-related pathology that complement clinical and... more Systematic studies on Alzheimer's disease (AD)-related pathology that complement clinical and epidemiological data on dementia from low and middle income countries are rare. We report the first large study on AD-related pathology in autopsy service-derived brains from an urban center in India, a low/middle income country, and compare findings with a similar sample from New York. Amyloid-β plaques and neurofibrillary tangles were assessed in 91 brain specimens derived from hospital autopsy cases from Mumbai, India (age 60+ years; mean age 71.1 years, ± 8.3 SD; range 60-107 years) and compared with identically examined age-matched sample obtained in New York. These cases had no known clinical history of dementia. Our study showed that in comparison with the New York sample, the mean brain weight of the Mumbai sample was lower (p = 0.013) and mean diffuse plaque density was higher (p = 0.019), while differences in mean density and counts of neurofibrillary tangles and neuritic plaq...
Diabetologia, 2015
Aims/hypothesis The purpose of this study was to investigate whether the association of glycaemic... more Aims/hypothesis The purpose of this study was to investigate whether the association of glycaemic control with cognitive function is modulated by the haptoglobin 1-1 (Hp 1-1) genotype in cognitively normal elderly individuals with type 2 diabetes. Methods In this cross-sectional study, we examined 793 participants who were genotyped for Hp (80 Hp 1-1 carriers and 713 Hp 1-1 non-carriers) enrolled in the Israel Diabetes and Cognitive Decline (IDCD) study. Glycaemic control was operationally defined by HbA 1c level. The outcome measures were performance in four cognitive domains (episodic memory, attention/working memory, language/semantic categorisation, executive function) and overall cognition, a composite of the domains. Effect sizes were obtained from hierarchical linear regression analyses for each outcome measure, controlling for demographics, type 2 diabetes-related characteristics, cardiovascular risk factors, and their interactions with Hp genotype. Results Interaction analyses showed significantly stronger associations of HbA 1c with poorer cognitive function among Hp 1-1 carriers than non-carriers; attention/working memory (p<0.001) and overall cognition (p=0.003). For these two cognitive domains, associations were significant for Hp 1-1 carriers despite the small sample size (p<0.00001 and p= 0.001, respectively), but not for non-carriers. Conclusions/interpretation Our findings suggest that patients with type 2 diabetes and poor glycaemic control carrying the Hp 1-1 genotype may be at increased risk of cognitive impairment, particularly in the attention/working memory domain. The association of glycaemic control with this domain may indicate cerebrovascular mechanisms.
Schizophrenia Research, 2010
PLoS ONE, 2009
The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and ... more The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome.
Neurology, 2012
Objectives: Identifying phenotypes for successful cognitive aging, intact cognition into late-old... more Objectives: Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (Ͼage 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75ϩ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype. Methods: The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model. Results: Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR ϭ 0.55 [95% confidence interval (CI) 0.41, 0.74], p Ͻ 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR ϭ 0.15 [95% CI 0.06, 0.37], p Ͻ 0.0001). Conclusions: Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial-and thus possibly genetic-successful cognitive aging. Neurology ® 2012;79:1116-1123 GLOSSARY AD ϭ Alzheimer disease; CDR ϭ Clinical Dementia Rating; CI ϭ confidence interval; CPRS ϭ Computerized Patient Record System; CRP ϭ C-reactive protein; CVRF ϭ cardiovascular risk factor; HR ϭ hazard ratio; JJP-VAMC ϭ James J. Peters Veterans Affairs Medical Center; MMSE ϭ Mini-Mental State Examination. Most studies supporting associations of cardiovascular risk factors (CVRFs) with increased risk of subsequent cognitive decline, dementia, and Alzheimer disease (AD) 1 derive from youngelderly (Ͻ75 years) cohorts. Longitudinal studies at older ages are inconsistent, with some associations in the opposite direction. 2-5 Focusing on successful cognitive aging, remaining cognitively intact into late-old age (Ͼage 75), might help explain these discrepancies. A CVRF associated with subsequent poor cognitive outcome based on young-elderly samples may be called a "putative" risk factor for those in late-old age because generalization would be plausible. Conversely, prevalent successful cognitive aging in those with this putative risk factor may be attributable to countervailing factors-perhaps familial-promoting successful cognitive aging. The putative risk factor in individuals with successful cognitive aging would be testable From the Department of Psychiatry (J.M.
Neurobiology of Aging, 2004
were retained if significant. Results: In the final modal, MCI (OR = 28.9, p < 0.001), LLD (OR = ... more were retained if significant. Results: In the final modal, MCI (OR = 28.9, p < 0.001), LLD (OR = 5.2, p = 0.010), APOE (OR = 3.1, p = 0.002), and age (OR = 1.1, p = 0.004 for each additional year) were significant main effects, with a trend for MCI by LLD interaction (p = 0.084). CVD (p = 0.357), education (p = 0.365), and gender (p = 0.407) were not significant. LLD by APOE interaction was significant (p = 0.045) with effect of LLD greater among NC (OR = 5.2) than among MCI (OR = 1.52). Analyses were repeated using only the sub-sample with CA at follow-up with comparable results. Conclusions: These results suggest that risk for development of dementia may be an interaction of presence of MCI, LLD, and the APOE gene, suggesting the incremental effect of LLD is greatest among those with no e4 allele.
Neurobiology of Aging, 2012
Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk facto... more Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk factor for late onset AD. ApoE is also a key ligand for LRP, a major neuronal LDL receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by qPCR and Western blotting. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indices of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared to those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in Aβ and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.
Neurobiology of Aging, 2012
Background-Recent evidence shows that despite high incidence of dementia in the very old, they ex... more Background-Recent evidence shows that despite high incidence of dementia in the very old, they exhibit significantly lower levels of AD neuropathology relative to younger persons with dementia. The levels and distributions of some synaptic proteins have been found to be associated with dementia severity, even in the oldest-old, but the molecular and functional nature of these deficits have not been studied in detail. Objective-To assess the relationship of dementia with gene and protein expression of a panel of synaptic markers associated with different synaptic functions in young-, middle-, and oldest-old individuals. Design-The protein and mRNA levels of seven synaptic markers (complexin-1, complexin-2, synaptophysin, synaptobrevin, syntaxin, SNAP-25, and septin-5) were compared in the brains of non-demented and demented individuals ranging from 70 to 103 years of age. Participants-111 brains were selected to have either no significant neuropathology or only AD-associated pathology (neuritic plaques (NPs) and neurofibrillary tangles (NFTs)). The cohort was then stratified into tertiles as young-old (70-81 years-old), middle-old (82-88), and oldest-old (89-103). Results-The brains of persons with dementia evidenced significantly lower levels of gene and protein expression of synaptic markers regardless of age. Importantly, dementia was associated with reductions in all measured synaptic markers irrespective of their role(s) in synaptic function. Conclusions-Although other dementia-associated hallmarks of AD neuropathology (NPs and NFTs) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent an independent substrate of dementia spanning all ages.
Molecular Neurodegeneration, 2010
Background: Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanism... more Background: Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE. Results: In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions. Conclusions: These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.
Molecular Neurodegeneration, 2009
Objective Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central ... more Objective Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; ...
Journal of the American Society of Hypertension, 2012
There are very little data on the relationship between systolic blood pressure (SBP), diastolic b... more There are very little data on the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), arterial compliance and left ventricular structure and function, particularly left ventricular hypertrophy (LVH) in the very elderly (>75 years). SBP and arterial stiffness increase with age, and the question is: which of the two is the main stimulus to LV hypertrophy? This is a cross-sectional study to compare blood pressure and arterial stiffness measures with regard to their correlations with echocardiographic parameters of LV structure and function, controlling for age and cardiovascular risk factors, in a very elderly population. Arterial stiffness was determined by radial pulse waveform using pulse contour analysis. LV dimensions were measured by transthoracic M-mode echocardiography, and diastolic function by tissue Doppler measurements of diastolic mitral annular velocities. There were 179 subjects, all male, with a mean age of 81.8 years. Using age-adjusted partial correlations, SBP, DBP and mean arterial pressure (MAP) were correlated with parameters of LV structure and function. Correlation coefficients were: SBP v. left ventricular mass index (LVMI), r = 0.246; SBP v. early diastolic mitral annular velocity (MAV), r =-0.179; DBP v. LVMI, r = 0.199; DBP v. MAV, r =-0.199; MAP v. LVMI r = 0.276; and MAP v. MAV, r =-.206, all with p<0.05. However, neither capacitative nor reflective arterial compliance was significantly correlated with any parameter of LV structure and function. After controlling for age and ten cardiovascular and metabolic risk factors, the correlation between blood pressure and the measured LV parameters was substantially unchanged, as was the lack of correlation between indices of arterial compliance and the LV indices. Arterial blood pressure is correlated with LV structure and function in the very elderly, but arterial stiffness, as measured by diastolic pulse contour analysis, is not.
Journal of Neurochemistry, 2007
Epidemiological studies support an association between vascular risk factors, including hyperchol... more Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote b-amyloid (Ab) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Ab production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Ab production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Ab production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Ab40, Ab42, or APP, or the Ab42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR)/) mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Ab.
Brain Research, 2010
To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role ... more To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role in AD pathology, we analyzed the expression of the cholesterol transporter ABCA1 in postmortem hippocampus from persons at different stages of dementia and AD associated neuropathology relative to cognitively intact normal donors by quantitative polymerase chain reaction (qPCR) and Western blot. In this study clinical dementia rating (CDR) scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as an index of the neuropathological progression of AD. Correlation analysis showed that ABCA1 mRNA expression was significantly elevated at the earliest recognizable stage of dementia compared to persons with intact cognition. ABCA1 mRNA was also positively correlated with Braak neuropathological stages and neuritic plaque density counts. Additionally, ABCA1 mRNA levels showed robust correlation with dementia severity even after controlling for the confounding contribution of accompanying neuropathological parameters to ABCA1 mRNA expression. Western blot analyses showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Thus, our study provides transcriptional and translational evidence that the expression of ABCA1, a key modulator of cholesterol transport across the plasma membrane, is dysregulated in the AD brain and that this dysregulation is associated with increasing severity of AD, whether measured functionally as dementia severity or neuropathologically as increased neuritic plaque and neurofibrillary tangle density.
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2018
Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at... more Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at cognitive assessment-increases. The Framingham Heart Study provided 1897 participants with intact cognition at entry. Cox regression analysis for incident marked cognitive decline included "time-dependent" coefficients, with associations between total cholesterol and covariates changing by outcome age. Decline within age categories of 75-84 and 85-94 years was also examined. Significant associations of rising total cholesterol linear slope, low entry age, low education, and statin nonuse with risk diminished significantly by outcome age. At 85-94 years, falling linear slope was significant. The protected survival model posits a minority subpopulation with protection against mortality and cognitive decline associated with total cholesterol risk factors. It predicts the observed diminished or reversed cholesterol associations with increasing age. Protection is particularly likel...
Diabetes Care, 2017
OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) o... more OBJECTIVE This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account ...
Evidence-Based Practice in Child and Adolescent Mental Health, 2016
We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in he... more We examined the identification of trauma exposure and post-traumatic stress disorder (PTSD) in help-seeking urban children (N=157) presenting for care in community mental health clinics. Children and their parents completed a standard intake assessment conducted by a community clinician followed by a structured trauma-focused assessment conducted by a study clinician. Clinicians provided ratings of child functional impairment, parents reported on internalizing/ externalizing problems, and children provided self-reports of PTSD symptom severity. Although community clinicians were mandated by clinic policy to ask about exposure to physical abuse, sexual abuse, and witnessed domestic violence, they identified exposure to these at significantly lower rates than study clinicians. Rates of PTSD based on community clinician diagnosis (1.9%) were also much lower than rates obtained by study clinicians (19.1%). A review of clinical charts one year after intake revealed no change in PTSD diagnosis rate following additional clinical contacts. Clinician-rated impairment, parent-rated emotional/behavioral problems, and child-rated PTSD symptom severity measures provided support for the validity of trauma exposure and PTSD as identified by study clinicians. Trauma exposure and PTSD diagnosis among help-seeking urban youth appear to be under-identified by community clinicians, which may compromise clinicians' ability to respond to environmental risks and provide appropriate evidence-based treatments.
Human molecular genetics, Oct 11, 2016
Recent studies have indicated that innate immune signaling molecules are involved in late-onset A... more Recent studies have indicated that innate immune signaling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mouse manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the etiology of AD, we have now analyzed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1 and MS4A4A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region specific manner, including hippocampus, an...
Aging cell, Jan 19, 2016
There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pat... more There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its tr...
European Neuropsychopharmacology, 2016
In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) we... more In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE *
Journal of Alzheimer's disease : JAD, 2009
APOE epsilon4 is a major risk factor for Alzheimer's disease. It has also been associated wit... more APOE epsilon4 is a major risk factor for Alzheimer's disease. It has also been associated with cognitive impairment and cognitive decline in young-olds, but the impact of the epsilon4 allele on cognitive function in very late life is still unclear. The object of this study was to evaluate the association of the epsilon4 allele of APOE with the cognitive performance of a sample of non-demented oldest-olds. Eighty-seven Spanish-speaking Puerto Rican non-demented nonagenarians were administered a complete neuropsychological assessment and provided a blood sample used for APOE genotyping. A factor analysis generated two factors: 1) verbal memory; and 2) visuo-spatial, naming and attention tasks, accounting for 43.6% of the overall variance in the 13 original neuropsychological variables. The multivariate analysis reflected, after controlling for gender, education, and age, the APOE epsilon4 carriers performed better in overall cognition (both factors analyzed together) than non-carr...
Journal of Alzheimer's disease : JAD, 2011
Systematic studies on Alzheimer's disease (AD)-related pathology that complement clinical and... more Systematic studies on Alzheimer's disease (AD)-related pathology that complement clinical and epidemiological data on dementia from low and middle income countries are rare. We report the first large study on AD-related pathology in autopsy service-derived brains from an urban center in India, a low/middle income country, and compare findings with a similar sample from New York. Amyloid-β plaques and neurofibrillary tangles were assessed in 91 brain specimens derived from hospital autopsy cases from Mumbai, India (age 60+ years; mean age 71.1 years, ± 8.3 SD; range 60-107 years) and compared with identically examined age-matched sample obtained in New York. These cases had no known clinical history of dementia. Our study showed that in comparison with the New York sample, the mean brain weight of the Mumbai sample was lower (p = 0.013) and mean diffuse plaque density was higher (p = 0.019), while differences in mean density and counts of neurofibrillary tangles and neuritic plaq...
Diabetologia, 2015
Aims/hypothesis The purpose of this study was to investigate whether the association of glycaemic... more Aims/hypothesis The purpose of this study was to investigate whether the association of glycaemic control with cognitive function is modulated by the haptoglobin 1-1 (Hp 1-1) genotype in cognitively normal elderly individuals with type 2 diabetes. Methods In this cross-sectional study, we examined 793 participants who were genotyped for Hp (80 Hp 1-1 carriers and 713 Hp 1-1 non-carriers) enrolled in the Israel Diabetes and Cognitive Decline (IDCD) study. Glycaemic control was operationally defined by HbA 1c level. The outcome measures were performance in four cognitive domains (episodic memory, attention/working memory, language/semantic categorisation, executive function) and overall cognition, a composite of the domains. Effect sizes were obtained from hierarchical linear regression analyses for each outcome measure, controlling for demographics, type 2 diabetes-related characteristics, cardiovascular risk factors, and their interactions with Hp genotype. Results Interaction analyses showed significantly stronger associations of HbA 1c with poorer cognitive function among Hp 1-1 carriers than non-carriers; attention/working memory (p<0.001) and overall cognition (p=0.003). For these two cognitive domains, associations were significant for Hp 1-1 carriers despite the small sample size (p<0.00001 and p= 0.001, respectively), but not for non-carriers. Conclusions/interpretation Our findings suggest that patients with type 2 diabetes and poor glycaemic control carrying the Hp 1-1 genotype may be at increased risk of cognitive impairment, particularly in the attention/working memory domain. The association of glycaemic control with this domain may indicate cerebrovascular mechanisms.
Schizophrenia Research, 2010
PLoS ONE, 2009
The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and ... more The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome.
Neurology, 2012
Objectives: Identifying phenotypes for successful cognitive aging, intact cognition into late-old... more Objectives: Identifying phenotypes for successful cognitive aging, intact cognition into late-old age (Ͼage 75), can help identify genes and neurobiological systems that may lead to interventions against and prevention of late-life cognitive impairment. The association of C-reactive protein (CRP) with cognitive impairment and dementia, observed primarily in young-elderly samples, appears diminished or reversed in late-old age (75ϩ years). A family history study determined if high CRP levels in late-old aged cognitively intact probands are associated with a reduced risk of dementia in their first-degree family members, suggesting a familial successful cognitive aging phenotype. Methods: The primary sample was 1,329 parents and siblings of 277 cognitively intact male veteran probands at least 75 years old. The replication sample was 202 relatives of 51 cognitively intact community-ascertained probands at least 85 years old. Relatives were assessed for dementia by proband informant interview. Their hazard ratio (HR) for dementia as a function of the proband's log-transformed CRP was calculated using the proportional hazards model. Results: Covarying for key demographics, higher CRP in probands was strongly associated with lower risk of dementia in relatives (HR ϭ 0.55 [95% confidence interval (CI) 0.41, 0.74], p Ͻ 0.02). The replication sample relationship was in the same direction, stronger in magnitude, and also significant (HR ϭ 0.15 [95% CI 0.06, 0.37], p Ͻ 0.0001). Conclusions: Relatives of successful cognitive aging individuals with high levels of CRP are relatively likely to remain free of dementia. High CRP in successful cognitive aging individuals may constitute a phenotype for familial-and thus possibly genetic-successful cognitive aging. Neurology ® 2012;79:1116-1123 GLOSSARY AD ϭ Alzheimer disease; CDR ϭ Clinical Dementia Rating; CI ϭ confidence interval; CPRS ϭ Computerized Patient Record System; CRP ϭ C-reactive protein; CVRF ϭ cardiovascular risk factor; HR ϭ hazard ratio; JJP-VAMC ϭ James J. Peters Veterans Affairs Medical Center; MMSE ϭ Mini-Mental State Examination. Most studies supporting associations of cardiovascular risk factors (CVRFs) with increased risk of subsequent cognitive decline, dementia, and Alzheimer disease (AD) 1 derive from youngelderly (Ͻ75 years) cohorts. Longitudinal studies at older ages are inconsistent, with some associations in the opposite direction. 2-5 Focusing on successful cognitive aging, remaining cognitively intact into late-old age (Ͼage 75), might help explain these discrepancies. A CVRF associated with subsequent poor cognitive outcome based on young-elderly samples may be called a "putative" risk factor for those in late-old age because generalization would be plausible. Conversely, prevalent successful cognitive aging in those with this putative risk factor may be attributable to countervailing factors-perhaps familial-promoting successful cognitive aging. The putative risk factor in individuals with successful cognitive aging would be testable From the Department of Psychiatry (J.M.
Neurobiology of Aging, 2004
were retained if significant. Results: In the final modal, MCI (OR = 28.9, p < 0.001), LLD (OR = ... more were retained if significant. Results: In the final modal, MCI (OR = 28.9, p < 0.001), LLD (OR = 5.2, p = 0.010), APOE (OR = 3.1, p = 0.002), and age (OR = 1.1, p = 0.004 for each additional year) were significant main effects, with a trend for MCI by LLD interaction (p = 0.084). CVD (p = 0.357), education (p = 0.365), and gender (p = 0.407) were not significant. LLD by APOE interaction was significant (p = 0.045) with effect of LLD greater among NC (OR = 5.2) than among MCI (OR = 1.52). Analyses were repeated using only the sub-sample with CA at follow-up with comparable results. Conclusions: These results suggest that risk for development of dementia may be an interaction of presence of MCI, LLD, and the APOE gene, suggesting the incremental effect of LLD is greatest among those with no e4 allele.
Neurobiology of Aging, 2012
Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk facto... more Inheritance of the ε4 allele of ApoE is the only confirmed and consistently replicated risk factor for late onset AD. ApoE is also a key ligand for LRP, a major neuronal LDL receptor. Despite the considerable converging evidence that implicates ApoE and LRP in the pathogenesis of AD, the precise mechanism by which ApoE and LRP modulate the risk for AD remains elusive. Moreover, studies investigating expression of ApoE and LRP in AD brain have reported variable and contradictory results. To overcome these inconsistencies, we studied the mRNA expression of ApoE and LRP in the postmortem brain of persons who died at different stages of dementia and AD-associated neuropathology relative to controls by qPCR and Western blotting. Clinical dementia rating scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as indices of the neuropathological progression of AD. ApoE and LRP mRNA expression was significantly elevated in the postmortem inferior temporal gyrus (area 20) and the hippocampus from individuals with dementia compared to those with intact cognition. In addition to their strong association with the progression of cognitive dysfunction, LRP and ApoE mRNA levels were also positively correlated with increasing neuropathological hallmarks of AD. Additionally, Western blot analysis of ApoE protein expression in the hippocampus showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Given the critical role played by LRP and ApoE in Aβ and cholesterol trafficking, increased expression of LRP and ApoE may not only disrupt cholesterol homeostasis but may also contribute to some of the neurobiological features of AD, including plaque deposition.
Neurobiology of Aging, 2012
Background-Recent evidence shows that despite high incidence of dementia in the very old, they ex... more Background-Recent evidence shows that despite high incidence of dementia in the very old, they exhibit significantly lower levels of AD neuropathology relative to younger persons with dementia. The levels and distributions of some synaptic proteins have been found to be associated with dementia severity, even in the oldest-old, but the molecular and functional nature of these deficits have not been studied in detail. Objective-To assess the relationship of dementia with gene and protein expression of a panel of synaptic markers associated with different synaptic functions in young-, middle-, and oldest-old individuals. Design-The protein and mRNA levels of seven synaptic markers (complexin-1, complexin-2, synaptophysin, synaptobrevin, syntaxin, SNAP-25, and septin-5) were compared in the brains of non-demented and demented individuals ranging from 70 to 103 years of age. Participants-111 brains were selected to have either no significant neuropathology or only AD-associated pathology (neuritic plaques (NPs) and neurofibrillary tangles (NFTs)). The cohort was then stratified into tertiles as young-old (70-81 years-old), middle-old (82-88), and oldest-old (89-103). Results-The brains of persons with dementia evidenced significantly lower levels of gene and protein expression of synaptic markers regardless of age. Importantly, dementia was associated with reductions in all measured synaptic markers irrespective of their role(s) in synaptic function. Conclusions-Although other dementia-associated hallmarks of AD neuropathology (NPs and NFTs) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent an independent substrate of dementia spanning all ages.
Molecular Neurodegeneration, 2010
Background: Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanism... more Background: Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE. Results: In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRα, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRα expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions. Conclusions: These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD.
Molecular Neurodegeneration, 2009
Objective Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central ... more Objective Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; ...
Journal of the American Society of Hypertension, 2012
There are very little data on the relationship between systolic blood pressure (SBP), diastolic b... more There are very little data on the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), arterial compliance and left ventricular structure and function, particularly left ventricular hypertrophy (LVH) in the very elderly (>75 years). SBP and arterial stiffness increase with age, and the question is: which of the two is the main stimulus to LV hypertrophy? This is a cross-sectional study to compare blood pressure and arterial stiffness measures with regard to their correlations with echocardiographic parameters of LV structure and function, controlling for age and cardiovascular risk factors, in a very elderly population. Arterial stiffness was determined by radial pulse waveform using pulse contour analysis. LV dimensions were measured by transthoracic M-mode echocardiography, and diastolic function by tissue Doppler measurements of diastolic mitral annular velocities. There were 179 subjects, all male, with a mean age of 81.8 years. Using age-adjusted partial correlations, SBP, DBP and mean arterial pressure (MAP) were correlated with parameters of LV structure and function. Correlation coefficients were: SBP v. left ventricular mass index (LVMI), r = 0.246; SBP v. early diastolic mitral annular velocity (MAV), r =-0.179; DBP v. LVMI, r = 0.199; DBP v. MAV, r =-0.199; MAP v. LVMI r = 0.276; and MAP v. MAV, r =-.206, all with p<0.05. However, neither capacitative nor reflective arterial compliance was significantly correlated with any parameter of LV structure and function. After controlling for age and ten cardiovascular and metabolic risk factors, the correlation between blood pressure and the measured LV parameters was substantially unchanged, as was the lack of correlation between indices of arterial compliance and the LV indices. Arterial blood pressure is correlated with LV structure and function in the very elderly, but arterial stiffness, as measured by diastolic pulse contour analysis, is not.
Journal of Neurochemistry, 2007
Epidemiological studies support an association between vascular risk factors, including hyperchol... more Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote b-amyloid (Ab) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Ab production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Ab production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Ab production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Ab40, Ab42, or APP, or the Ab42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR)/) mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Ab.
Brain Research, 2010
To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role ... more To gain insight into ATP-binding cassette transporter A1 (ABCA1) function and its potential role in AD pathology, we analyzed the expression of the cholesterol transporter ABCA1 in postmortem hippocampus from persons at different stages of dementia and AD associated neuropathology relative to cognitively intact normal donors by quantitative polymerase chain reaction (qPCR) and Western blot. In this study clinical dementia rating (CDR) scores were used as a measure of dementia severity, whereas, Braak neuropathological staging and neuritic plaque density were used as an index of the neuropathological progression of AD. Correlation analysis showed that ABCA1 mRNA expression was significantly elevated at the earliest recognizable stage of dementia compared to persons with intact cognition. ABCA1 mRNA was also positively correlated with Braak neuropathological stages and neuritic plaque density counts. Additionally, ABCA1 mRNA levels showed robust correlation with dementia severity even after controlling for the confounding contribution of accompanying neuropathological parameters to ABCA1 mRNA expression. Western blot analyses showed that the differential expression observed at the transcriptional level is also reflected at the protein level. Thus, our study provides transcriptional and translational evidence that the expression of ABCA1, a key modulator of cholesterol transport across the plasma membrane, is dysregulated in the AD brain and that this dysregulation is associated with increasing severity of AD, whether measured functionally as dementia severity or neuropathologically as increased neuritic plaque and neurofibrillary tangle density.