Interleukin-1 and the immunogenetics of Alzheimer disease

Established genetic causes of familial Alzheimer disease (AD) involve genes for beta-amyloid precursor protein (betaAPP), presenilin-1, and presenilin-2. For the more common sporadic forms of AD, increased risk has been associated with a number of genes; the most important of which is the epsilon4 allele of apolipoprotein E. Two recent studies, one clinical and one using postmortem material, now show increased risk for AD associated with certain polymorphisms in the genes encoding the alpha and beta isoforms of interleukin-1 (IL-1). IL-1 levels are elevated in Alzheimer brain, and overexpression of IL-1 is associated with beta-amyloid plaque progression. IL-1 interacts with the gene products of several other known or suspected genetic risk factors for AD, including betaAPP, apolipoprotein E, alpha1-antichymotrypsin, and alpha2-macroglobulin. IL-1 overexpression is also associated with environmental risk factors for AD, including normal aging and head trauma. These observations suggest an important pathogenic role for IL-1, and for IL-1-driven cascades, in the pathogenesis of AD.     

Familial Alzheimer's disease: site of mutation influences clinical phenotype

Alzheimer's disease (AD) is caused by multiple genetic and/or environmental etiologies. Because differences in the genetically determined pathogenesis may cause differences in the phenotype, we examined age at onset and age at death in 90 subjects with dominantly inherited AD due to different mutations (amyloid precursor protein, presenilin-1, and presenilin-2 genes). We found that among patients with dominantly inherited AD, genetic factors influence both age at onset and age at death.     

Alzheimer's disease pathogenesis and therapeutic interventions.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system associated with progressive cognitive and memory loss. Molecular hallmarks of the disease are characterized by extracellular deposition of the amyloid beta peptide (Abeta) in senile plaques, the appearance of intracellular neurofibrillary tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus and other areas of brain essential for cognitive and memory functions. Abeta deposition causes neuronal death via a number of possible mechanisms including oxidative stress, excitotoxicity, energy depletion, inflammation and apoptosis. Despite their multifactorial etiopathogenesis, genetics plays a primary role in progression of disease. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). Plaques are formed mostly from the deposition of Abeta, a peptide derived from APP. The main factors responsible for Abeta formation are mutation of APP or PS1 and PS2 genes or ApoE gene. All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specifically the more amyloidogenic form, Abeta42. In addition to genetic influences on amyloid plaque and intracellular tangle formation, environmental factors (e.g., cytokines, neurotoxins, etc.) may also play important role in the development and progression of AD. A direct understanding of the molecular mechanism of protein aggregation and its effects on neuronal cell death could open new therapeutic approaches. Some of the therapeutic approaches that have progressed to the clinical arena are the use of acetylcholinesterase inhibitors, nerve growth factors, nonsteroidal inflammatory drugs, estrogen and the compounds such as antioxidants, neuronal calcium channel blockers or antiapoptotic agents. Inhibition of secretase activity and blocking the formation of beta-amyloid oligomers and fibrils which may inhibit fibrilization and fibrilization-dependent neurotoxicity are the most promising therapeutic strategy against the accumulation of beta-amyloid fibrils associated with AD. Furthermore, development of immunotherapy could be an evolving promising therapeutic approach for the treatment of AD.     

Interactions between Alzheimer's disease and cerebral ischemia—focus on inflammation

Progressive memory impairment, β-amyloid (Aβ) plaques associated with local inflammation, neurofibrillary tangles, and loss of neurons in selective brain areas are hallmarks of Alzheimer's disease (AD). Although β-amyloid precursor protein (APP) and Aβ have a central role in the etiology of AD, it is not clear which forms of APP or Aβ are responsible for the neuronal vulnerability in AD brain. Brain ischemia, another cause of dementia in the elderly, has recently been recognized to contribute to the pathogenesis of AD and individuals with severe cognitive decline and possibly underlying AD are at increased risk for ischemic events in the brain. Moreover, the ε4 allele of apolipoprotein E (ApoE) is a risk factor for both AD and poor outcome following brain ischemia and hemorrhage. Several factors and molecular mechanisms that lower the threshold of neuronal death in models of AD have recently been described. Among these neuroinflammation seems to play an important role. The development and maturation of both AD neuropathology and ischemic lesions in the central nervous system are characterized by activation of glial cells and upregulation of inflammatory mediators. Indeed, anti-inflammatory approaches have proven to be beneficial in the prevention and treatment of AD-like neuropathology and ischemic injuries in vivo. This review summarizes some of the findings suggesting that neuronal overexpression of human APP renders the brain more vulnerable to ischemic injury and describes the factors that are involved in increased neuronal susceptibility to ischemic stroke.     

Homocysteine,apolipoproteine E and methylenetetrahydrofolate reductase in Alzheimer's disease and mild cognitive impairment

BACKGROUND: Alzheimer's disease (AD) is the most common dementia disorder in elderly people. Currently, the only known genetic factor associated with the development of sporadic AD is the apolipoprotein E (ApoE) 4 allele. There is a need to identify other environmental and genetic risk factors that could modulate the risk of developing sporadic AD. OBJECTIVE: To analyse the correlation between the ApoE and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma homocysteine levels and vitamins (B(12) and folic acid) concentrations in serum from patients with AD and mild cognitive impairment (MCI) as compared with control group. METHODS: The study was carried out in 99 AD patients, 98 subjects with MCI and 100 healthy subjects. Diagnosis of probable AD was made according to the NINCDS-ADRDA and DSM-IV criteria. The following factors were analysed: age, gender, duration of disease, concentration of plasma total homocysteine, folic acid and vitamin B(12) in the serum and the polymorphism of MTHRF and ApoE genes. The results obtained were analysed by multivariate analysis of regression. RESULTS: We found that plasma total homocysteine is increased in AD patients (p < 0.0001) and depended on the MTHFR T/T genotype in the presence of low folate levels (p < 0.05). The increased frequency of ApoE4 allele in the AD population was independent of homocysteine, folic acid and vitamin B(12) levels and MTHFR status. CONCLUSIONS: We conclude that the concentration of plasma total homocysteine is increased in AD patients. This may be associated with the T/T genotype in the MTHFR gene; however, the distribution of the MTHRF C677T polymorphism in the Polish population does not differ in AD and controls.     

Genetic characteristics of dementia in Taiwan

The most common causes of dementia in Taiwan are Alzheimer's disease (AD) followed by vascular dementia (VaD). Several genetic studies have documented an increased risk of AD among apolipoprotein E gene allele 4 (ApoE4) carriers in Taiwanese (ethnic Chinese). Although ApoE4 is considered the most important risk factor for AD, the ApoE4 allele frequency is lower in Taiwanese (around 7%), than that in most Caucasian populations (over 10%). This phenomenon raises the hypothesis that low ApoE4 allele frequency contributes to the low prevalence of AD in Taiwanese. Other studies of the genetic impacts on modulation or regulation of manifestations, progression, and treatment response of AD in Taiwan have been inconclusive. Familial AD, which is conferred by PS1 gene mutation has been identified. There were very few studies of fronto-temporal dementia (FTD) or dementia with Lewy body (DLB) in Taiwan. Genetic studies of VaD remain limited and only NOTCH3 gene mutation has been detected in a Taiwanese cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) family. Limited data indicated that non- ApoE4-associated AD may represent a larger proportion of AD in Taiwanese, suggesting the existence of novel genetic factors which remain to be identified.     

Numb modifies neuronal vulnerability to amyloid beta-peptide in an isoform-specific manner by a mechanism involving altered calcium homeostasis: implications for neuronal death in Alzheimer's disease

Increased production of neurotoxic forms of amyloid beta-peptide (Abeta) and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch, a membrane receptor that controls cell-fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase enzyme activity that involves the presenilin-1 (PS1) protein in which mutations cause early-onset inherited AD. The actions of Notch can be antagonized by Numb, an evolutionarily conserved protein that exists in four isoforms that differ in two functional domains: a phosphotyrosine-binding (PTB) domain and a proline-rich region (PRR). We now report that Numb isoforms containing a short PTB domain increase the vulnerability of PC12 cells to death induced by Abeta1-42 and by 4-hydroxynonenal, a lipid peroxidation product previously shown to mediate neurotoxic effects of Abeta. Dysregulation of cellular calcium homeostasis occurs in cells expressing Numb isoforms with a short PTB domain, and the death-promoting effect of Numb is abolished by pharmacological inhibition of calcium release. The levels of Numb are increased in cultured primary hippocampal neurons exposed to Abeta, suggesting a role for endogenous Numb in the neuronal death process. Furthermore, higher levels of Numb were detected in the cortex of mice expressing mutant amyloid precursor protein (APP) relative to age-matched wild-type mice. Our data identify a novel isoform-specific effect of Numb on neuronal life and death cell fate decisions potentially relevant to the pathogenesis of AD. Our findings also suggest that the effects of Numb on cell fate decisions, both during development of the nervous system and in neurodegenertive disorders, are mediated by changes in cellular calcium homeostasis.     

Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications

Recent evidence indicates that different vascular risk factors are present in Alzheimer's disease (AD) and other prevalent dementia types probably contributing to deterioration of cerebrovascular function, thus enhancing neurodegeneration and premature neuronal death due to a reduction in brain perfusion. Brain blood flow shows a reduced velocity and increased pulsatility (PI) and resistance indices (RI) in different types of dementia and in diabetes and hypertension, as well. High levels of diastolic blood pressure correlate with diminished brain blood flow and elevated PI and RI, accompanied by cognitive deterioration. Nitric oxide (NO) levels are found increased in the sera and brain tissue of AD patients. Vascular risk factors (hyperglycemia, LDL-cholesterol, triglycerides, hypertension) and altered brain hemodynamic parameters correlate with APOE genotypes of which APOE-4/4 carriers represent the AD population with the highest cerebrovascular risk. In addition, the genomic profiles of patients with dementia integrating AD-related genes (APOE, PS1, PS2, cFOS) in a mini-tetragenic haplotype significantly differ from controls with an absolute genetic variation of about 50%-60%. Cerebrovascular dysfunction is a factor common to most types of dementia; however, genetic variation among different dementia types might be determinant for the activation of early vascular events inducing or accelerating neurodegeneration. In this regard, cerebrovascular dysfunction should be considered a potential therapeutic target in dementia.     

The genetic studies of dementias in Taiwan

In Taiwan, Alzheimer's disease (AD) followed by vascular dementia (VsD) is the most common cause of dementia among Taiwanese (ethnic Chinese). Several studies have documented the increase of risk for AD among the apolipoprotein E gene allele 4 (ApoE4) carriers in Taiwanese. It is a consensus that ApoE4 is the most important risk factor for AD at present. The researchers also found that ApoE4 allele frequency is lower in Taiwanese, around 7%, than it in the most Caucasian populations. This phenomenon raises the hypothesis that low ApoE4 allele frequency contributes to low prevalence of AD in Taiwanese. Besides, many genetic studies were involved in genetic impacts on modulation or regulation of the manifestation, progression, and treatment response of AD. But, these genetic studies are still inconclusive. Few familial AD attributed to PS1 gene mutation has been identified. The genetic studies of VsD are just beginning and NOTCH3 gene mutation has been detected in Taiwanese cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) families. Since there is a large proportion of non- ApoE4-associated AD in Taiwanese, it remains more researches to look for novel genetic factors in Taiwanese. Based on the Japanese experience of studies, the association between the polymorphisms of ApoE and familial AD, sporadic early-onset AD respectively warrants further investigation.     

Association of the mitochondrial tRNAA4336G mutation with Alzheimer's and Parkinson's diseases

Alzheimer's and Parkinson's diseases (AD, PD) are among the most common neurodegenerative disorders in adults. Both AD and PD have a complex aetiology, and it is widely considered that genetic factors, acting independently or in concert with other genetic and/or environmental factors, modify the risk of developing them. While the apolipoprotein E (ApoE) ε4 allele represents an established risk factor for familial and sporadic late‐onset AD, it has been suggested that a common polymorphism in the α1‐antichymotrypsin gene modifies the ApoE ε4 dosage effect in AD. Moreover, it has been proposed that a mitochondrial tRNA^Gln sequence variant (A4336G transition) confers an increased risk for both AD and PD. This finding is of particular interest as the A4336G mutation seems to predispose to two clinically and neuropathologically distinct neurodegenerative disorders. We have examined the allelic frequencies of these putative susceptibility genes in 28 neuropathologically confirmed cases of AD, 23 cases with Lewy‐body PD and 100 age‐matched controls without clinical or histological evidence of neurodegenerative disease. The ApoE ε4 allele frequency was significantly over‐represented in AD patients vs controls (0.35 vs 0.11) but we could not find evidence for an association between the α1‐antichymotrypsin AA genotype, the ApoE ε4 allele and AD. In contrast, the mtDNA^A4336G mutation was present in one of 28 AD cases and in two of 23 PD patients, whereas no mutation was found in 100 age‐matched controls ( P <0.05). Our data therefore support the hypothesis that the mitochondrial A4336G mutation represents a risk factor for AD and PD.     

Influence of pharmacogenetic factors on Alzheimer's disease therapeutics

Alzheimer's disease (AD) is the result of the phenotypic expression of more than 200 genes which are potentially involved in neurodegeneration. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, might be responsible for AD pathogenesis leading to premature neuronal death. Drug metabolism, pharmacokinetics and pharmacodynamics are genetically regulated complex traits in which hundreds of genes may participate. Pharmacogenetics studies show that the therapeutic response in AD is genotype specific, with APOE-4/4 carriers as the worst responders to conventional treatments. In addition, about 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. With multifactorial therapies, combining different drugs, it is possible to slow down cognitive deterioration in parallel with improvement in noncognitive symptoms; however, the association of the APOE-4 allele with specific genetic variants of other genes negatively modulates the therapeutic response to multifactorial treatments affecting cognition, mood and behavior. Pharmacogenetic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic protocols into AD research and clinical practice can foster therapeutics optimization by improving drug efficacy and safety.     

Impact of aging: sporadic, and genetic risk factors on vulnerability to apoptosis in Alzheimer's disease

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer's disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell typespecific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4+ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4+ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4+ and CD8+ T cells.     

Impact of aging

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer’s disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymphocytes may serve as a cellular system in which to study risk factors of sporadic, as well as genetic AD in vivo. The aim of our present study was to clarify whether lymphocytes bearing genetic or sporadic risk factors of AD share an increased susceptibility to cell death. Additionally we examined whether a cell type-specific vulnerability pattern was present and how normal aging, the main risk factor of sporadic AD, contributes to changes in susceptibility to cell death. Here, we report that lymphocytes affected by sporadic or genetic APP and PS1 AD risk factors share an increased vulnerability to cell death and exhibit a similar cell type-specific pattern, given that enhanced vulnerability was most strongly developed in the CD4⁺ T-cell subtype. In this paradigm, sporadic risk factors revealed the highest impact on cell type-specific sensitivity of CD4⁺ T cells to apoptosis. In contrast, normal aging results in an increased susceptibility to apoptosis of both, CD4⁺ and CD8⁺ T cells.     

Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study

BACKGROUND: Lifestyle and vascular factors have been linked to dementia and Alzheimer's disease (AD), but the role of dietary fats in the development of dementia is less clear. METHODS: Participants were derived from random, population-based samples initially studied in midlife (1972, 1977, 1982, or 1987). Fat intake from spreads and milk products was assessed using a structured questionnaire and an interview. After an average follow-up of 21 years, a total of 1,449 (73%) individuals aged 65-80 years participated in the re-examination in 1998. Altogether 117 persons had dementia. RESULTS: Moderate intake of polyunsaturated fats at midlife decreased the risk of dementia even after adjustment for demographic variables, other subtypes of fats, vascular risk factors and disorders, and apolipoprotein E (ApoE) genotype (OR 0.40, CI 0.17-0.94 for the 2nd quartile vs. 1st quartile), whereas saturated fat intake was associated with an increased risk (OR 2.45, CI 1.10-5.47 for the 2nd quartile). The associations were seen only among the ApoE epsilon4 carriers. CONCLUSIONS: Moderate intake of unsaturated fats at midlife is protective, whereas a moderate intake of saturated fats may increase the risk of dementia and AD, especially among ApoE epsilon4 carriers. Thus, dietary interventions may potentially modify the risk of dementia, particularly among genetically susceptible individuals.     

Risk factors for dementia of Alzheimer type and aging-associated cognitive decline in a Spanish population based sample, and in brains with pathology confirmed Alzheimer's disease

We investigated the environmental and genetic factors for Alzheimer's disease (AD) in Spain and performed a door to door study of a cohort of more than 500 subjects, over 70 years old, from Leganés, a suburban area near Madrid. The cohort was followed for 6 years by neurologists and other health workers and was divided in three groups: normal controls, subjects with aging-associated cognitive decline (AACD) and probable AD or dementia of Alzheimer's type (DAT). Biological variables and polymorphisms of different genes, important in neurodegeneration or reported to be associated with AD, were investigated as putative risk modifiers. These polymorphisms have also been analyzed in 94 brains, 39 from patients with pathologically confirmed AD and 55 controls. The statistical investigation included the evaluation of different individual risks and a multinomial logistic regression analysis to detect predictive factors. The risk of AACD and AD increased with age, feminine gender and history of stroke and decreased with education. The allele ApoE4 increased the risk of AD but not of AACD. When the impact of ApoE4 was added to the model, the effect of education and stroke disappeared as risk modifiers.     

Work-related physical activity and the risk of dementia and Alzheimer's disease

BACKGROUND: Leisure-time physical activity has been related with a reduced risk of dementia and Alzheimer's disease (AD). The effects of occupational and commuting physical activity (physical activity at work and on the way to work) on cognitive health are still unclear. This study aimed to clarify the association between work-related physical activity and dementia/AD. METHODS: Participants of the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study were derived from random, population-based samples previously studied in a survey carried out in 1972, 1977, 1982, or 1987. After an average follow-up of 21 years, 1449 individuals (73%) aged 65 to 79 years participated in the re-examination in 1998. RESULTS: Neither occupational [Odds Ratio (OR) 1.45; 95% Confidence Intervals (CI) 0.66-3.17] nor commuting physical activity (OR 0.46; 95% CI 0.10-2.17) were associated with the risk of dementia or AD after adjustments for age, sex, education, follow-up time, locomotor symptoms, main occupation during life, income at midlife, leisure-time physical activity, other subtype of work-related physical activity, ApoE genotype, vascular disorders and the smoking status. There were also no interactions between work-related physical activity and the ApoE epsilon4 genotype, leisure-time physical activity or sex. CONCLUSIONS: In this study, work-related physical activity was not found to be sufficient to protect against dementia and AD later in life. The lack of effect might be partly due to a residual confounding. Nevertheless, physical activity during leisure-time may be beneficial even for people who are physically active at work or when commuting.     

Genetic counseling and testing for families with Alzheimer's disease

With the identification of the genes responsible for autosomal dominant early-onset familial Alzheimer's disease (FAD genes), there is a considerable interest in the application of this genetic information in medical practice through genetic testing and counseling. Pathogenic mutations in the PSEN1 and PSEN2 genes encoding presenilin-1 and -2, and the APP gene encoding amyloid b precursor protein, account for 18-50% of familial EOAD cases with autosomal dominant pattern of inheritance. A clinical algorithm of genetic testing and counseling proposed for families with AD has been presented here. A screening for mutations in the APP, PSEN1, and PSEN2 genes is available to individuals with AD symptoms and at-risk children or siblings of patients with early-onset disease determined by a known mutation. In an early-onset family, a known mutation in an affected patient puts the siblings and children at a 50% risk of inheriting the same mutation. The goal of genetic testing is to identify at-risk individuals in order to facilitate early and effective treatments in the symptomatic person based on an individual's genotype and strategies to delay the onset of disease in the presymptomatic mutation carriers. However, there are several arguments against the use of genetic testing both presymptomatically (unpredictable psychological consequences of information about a genetic defect for family members) and as a diagnostic tool for the differential diagnosis of dementia in general practice (a risk of errors in an interpretation of mutation penetrance and its secondary effects on family members, especially for novel mutations; the possibility of coexistence of another form of dementia at the presence of a mutation). Currently, APOE genotyping for presymptomatic individuals with a family history of late-onset disease is not recommended. The APOE4 allele may only confer greater risk for disease, but its presence is not conclusive for the development of AD.     

Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer’s disease

There is no effective drug to treat Alzheimer’s disease (AD), a neurodegenerative disease affecting an estimated 30 million people around the world. Strongly supported by preclinical and clinical studies, amyloid-beta (Aβ) may be a target for developing drugs against AD. Meanwhile, the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered. Neuronal regeneration, which does not occur normally in the mammalian central nervous system, can be promoted by neurotrophic factors (NTFs). Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD, thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.     

Cortical neuritic plaques and hippocampal neurofibrillary tangles are related to dementia severity in elderly schizophrenia patients

Cognitive decline has been described in elderly patients with schizophrenia, but the underlying pathology remains unknown. Some studies report increases in plaques and neurofibrillary tangles, but there is no evidence for an increased risk for Alzheimer's disease (AD) in elderly schizophrenics. Models of a decreased cerebral reserve suggest that increases in AD-related neuropathology below the threshold for a neuropathological diagnosis could be related to dementia severity in elderly schizophrenia patients. We tested this hypothesis in 110 autopsy specimens of schizophrenia patients, without a neuropathological diagnosis of AD or other neurodegenerative disorders. Furthermore, we assessed the effects of apolipoprotein E (ApoE) status, a known genetic risk factor for AD. Measures of density of neuritic plaques were obtained in five cortical regions, and the degree of hippocampal neurofibrillary tangles was rated. Dementia severity was measured prior to postmortem using the Clinical Dementia Rating (CDR) scale. multivariate analyses of variance were conducted with the factors dementia severity, by ApoE4 carrier status. Hippocampal neurofibrillary tangles correlated with increased dementia severity (p < .05). Neuritic plaque density increased with greater dementia severity (p < .005), and ApoE4 carrier status (p < .005), and these differences were magnified by the ApoE4 carrier status (p < .01). Even below the threshold for a neuropathological diagnosis of AD, neuritic plaques and hippocampal neurofibrillary tangles are associated with dementia severity in schizophrenia patients, even more so in the presence of genetic risk factors, suggesting that a decreased cerebral reserve in elderly schizophrenics may increase susceptibility for dementia.