Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

BACKGROUND: A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5 Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. OBJECTIVE AND METHODS: In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4 Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200 subjects) and a replication data set (> 10 000 subjects) comprising European-descent individuals. RESULTS: Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10-8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10-9 ≤ meta p ≤ 4.88 × 10-8) and CTSB (meta p = 4.87 × 10-8) subregions that are located > 2 Mb upstream and ~ 0.3 Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. CONCLUSIONS: Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.

A replication study of 49 Type 2 diabetes risk variants in a Punjabi Pakistani population.

AIM: The burden of Type 2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number of loci predisposing to Type 2 diabetes risk, however, the relevance of such genetic loci in many South Asian sub-ethnicities remains elusive. The aim of this study was to replicate 49 single nucleotide polymorphisms (SNPs) previously identified through GWAS in Punjabis living in Pakistan. METHODS: We examined the association of 49 SNPs in 853 Type 2 diabetes cases and 1945 controls using additive logistic regression models after adjusting for age and gender. RESULTS: Of the 49 SNPs investigated, eight showed a nominal association (P < 0.05) that also remained significant after controlling for the false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit increase in the risk score comprising of all the 49 SNPs, the odds ratio in association with Type 2 diabetes risk was 1.16 (95% CI 1.13-1.19, P < 2.0E-16). CONCLUSION: These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan.

Genome-wide association analysis of age-at-onset in Alzheimer's disease.

The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ~2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.

Genome-wide association study of Alzheimer's disease with psychotic symptoms.

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.

APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism.

Genetic studies on Alzheimer's disease (AD), a devastating neurodegenerative disorder, have identified the apolipoprotein E (APOE) gene as a strong susceptibility marker for AD. The E*4 allele of APOE is a major risk factor for AD regardless of age of onset or family history. However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD emphasizes the involvement of other environmental or genetic elements that, either in conjunction with APOE*4 or alone, increase an individual's risk of developing AD. Among the candidate genes that may affect the risk of this multifactorial disease is the gene coding for alpha 1-antichymotrypsin (ACT). Like APOE protein, ACT binds to beta-amyloid peptide (A beta P) with high affinity in the filamentous deposits found in the AD brain and serves as a strong stimulatory factor in the polymerization of A beta P into amyloid filaments. In AD brains, ACT expression is enhanced, particularly in areas that develop amyloid plaques, suggesting that ACT may play an important role in the pathogenesis of AD. Here we show that a common polymorphism in the signal peptide of ACT confers a significant risk for AD. Furthermore, the APOE*4 gene dosage effect associated with AD risk is significantly modified by the ACT polymorphism. We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control. Our data show that ACT behaves as a modifier gene that alters the AD risk conventionally associated with the APOE*4 allele.

Amino acid position 11 of HLA-DRß1 is a major determinant of chromosome 6p association with ulcerative colitis.

The major histocompatibility complex (MHC) on chromosome 6p is an established risk locus for ulcerative colitis (UC) and Crohn's disease (CD). We aimed to better define MHC association signals in UC and CD by combining data from dense single-nucleotide polymorphism (SNP) genotyping and from imputation of classical human leukocyte antigen (HLA) types, their constituent SNPs and corresponding amino acids in 562 UC, 611 CD and 1428 control subjects. Univariate and multivariate association analyses were performed, controlling for ancestry. In univariate analyses, absence of the rs9269955 C allele was strongly associated with risk for UC (P = 2.67 × 10(-13)). rs9269955 is a SNP in the codon for amino acid position 11 of HLA-DRß1, located in the P6 pocket of the HLA-DR antigen binding cleft. This amino acid position was also the most significantly UC-associated amino acid in omnibus tests (P = 2.68 × 10(-13)). Multivariate modeling identified rs9269955-C and 13 other variants in best predicting UC vs control status. In contrast, there was only suggestive association evidence between the MHC and CD. Taken together, these data demonstrate that variation at HLA-DRß1, amino acid 11 in the P6 pocket of the HLA-DR complex antigen binding cleft is a major determinant of chromosome 6p association with UC.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance.

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Replication study of genome-wide associated SNPs with late-onset Alzheimer's disease.

Late-onset Alzheimer's disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Four recent genome-wide association studies (GWAS) have found variants showing significant association with LOAD on chromosomes 6, 10, 11, 12, 14, 18, 19, and on the X chromosome. We examined a total of 12 significant SNPs from these studies to determine if the results could be replicated in an independent large case-control sample. We genotyped these 12 SNPs as well the E2/E3/E4 APOE polymorphisms in up to 993 Caucasian Americans with LOAD and up to 976 age-matched healthy Caucasian Americans. We found no statistically significant associations between the 12 SNPs and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine potential associations between the 12 SNPs and age-at-onset (AAO) and disease duration among AD cases. Significant associations were observed between AAO and ZNF224/rs3746319 (P = 0.002) and KCNMA1/rs16934131 (P = 0.0066). KCNMA1/rs16934131 also demonstrated statistically significant association with disease duration (P = 0.0002). Although we have been unable to replicate the reported GWAS association with AD risk in our sample, we have identified two new associations with AAO and disease duration that need to be confirmed in additional studies.

Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.

The only recognized genetic determinant of the common forms of Alzheimer's disease (AD) is the epsilon 4 allele of the apolipoprotein E gene (APOE). To identify new candidate genes, we recently performed transcriptomic analysis of 2741 genes in chromosomal regions of interest using brain tissue of AD cases and controls. From 82 differentially expressed genes, 1156 polymorphisms were genotyped in two independent discovery subsamples (n=945). Seventeen genes exhibited at least one polymorphism associated with AD risk, and following correction for multiple testing, we retained the interleukin (IL)-33 gene. We first confirmed that the IL-33 expression was decreased in the brain of AD cases compared with that of controls. Further genetic analysis led us to select three polymorphisms within this gene, which we analyzed in three independent case-control studies. These polymorphisms and a resulting protective haplotype were systematically associated with AD risk in non-APOE epsilon 4 carriers. Using a large prospective study, these associations were also detected when analyzing the prevalent and incident AD cases together or the incident AD cases alone. These polymorphisms were also associated with less cerebral amyloid angiopathy (CAA) in the brain of non-APOE epsilon 4 AD cases. Immunohistochemistry experiments finally indicated that the IL-33 expression was consistently restricted to vascular capillaries in the brain. Moreover, IL-33 overexpression in cellular models led to a specific decrease in secretion of the A beta(40) peptides, the main CAA component. In conclusion, our data suggest that genetic variants in IL-33 gene may be associated with a decrease in AD risk potentially in modulating CAA formation.

Association of a common G6PC2 variant with fasting plasma glucose levels in non-diabetic individuals.

BACKGROUND/AIMS: Fasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples. METHODS: DNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination. RESULTS: While no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036). CONCLUSIONS: Our results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.

Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response.

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

ApoA-IV polymorphism associated with myocardial infarction in obese NIDDM patients. The San Luis Valley Diabetes Study.

Non-insulin-dependent diabetes mellitus (NIDDM) confers myocardial infarction (MI) risk unexplained by known factors. In 356 NIDDM patients and 1,087 people with normal glucose tolerance, we investigated the association between MI risk and polymorphism at codon 360 in the apolipoprotein A-IV (apoA-IV) gene. During 1984-1992, MI was diagnosed in 84 diabetic and in 106 nondiabetic people. The risk of MI did not differ by apoA-IV phenotype in nondiabetic people; however, in NIDDM patients, those with the apoA-IV 1-2 phenotype had 2.8 (95% confidence interval: 1.4-5.6) higher MI risk than those with the 1-1 phenotype, adjusting for age, gender, ethnicity, hypertension, smoking, body mass index, fat centrality, and low-density lipoprotein and high-density lipoprotein cholesterol. The risk of MI was particularly high in obese NIDDM patients with the apoA-IV 1-2 phenotype: 5.1 (2.4-11.2) times that in obese apoA-IV 1-1 NIDDM patients and 7.7 (3.6-16.7) times that in lean nondiabetic people. The effect of apoA-IV 1-2 did not appear to be a part of the insulin-resistance syndrome nor was it dependent on diabetes duration or control. One half of the excess MI risk in the diabetic population studied was explained by the apoA-IV 1-2 phenotype. These results indicate that approximately 17% of NIDDM patients have a high MI risk apoA-IV phenotype that is particularly deleterious in obese patients.

Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease.

Although possession of the epsilon 4 allele of the apolipoprotein E gene appears to be an important biological marker for Alzheimer's disease (AD) susceptibility, strong evidence indicates that at least one additional risk gene exists on chromosome 12. Here, we describe an association of the 3'-UTR +1073 C/T polymorphism of the OLR1 (oxidised LDL receptor 1) on chromosome 12 with AD in French sporadic (589 cases and 663 controls) and American familial (230 affected sibs and 143 unaffected sibs) populations. The age and sex adjusted odds ratio between the CC+CT genotypes versus the TT genotypes was 1.56 (p=0.001) in the French sample and 1.92 (p=0.02) in the American sample. Furthermore, we have discovered a new T/A polymorphism two bases upstream of the +1073 C/T polymorphism. This +1071 T/A polymorphism was not associated with the disease, although it may weakly modulate the impact of the +1073 C/T polymorphism. Using 3'-UTR sequence probes, we have observed specific DNA protein binding with nuclear proteins from lymphocyte, astrocytoma, and neuroblastoma cell lines, but not from the microglia cell line. This binding was modified by both the +1071 T/A and +1073 C/T polymorphisms. In addition, a trend was observed between the presence or absence of the +1073 C allele and the level of astrocytic activation in the brain of AD cases. However, Abeta(40), Abeta(42), Abeta total, and Tau loads or the level of microglial cell activation were not modulated by the 3'-UTR OLR1 polymorphisms. Finally, we assessed the impact of these polymorphisms on the level of OLR1 expression in lymphocytes from AD cases compared with controls. The OLR1 expression was significantly lower in AD cases bearing the CC and CT genotypes compared with controls with the same genotypes. In conclusion, our data suggest that genetic variation in the OLR1 gene may modify the risk of AD.

Association of lipoprotein lipase gene variation with the physiological components of the insulin-resistance syndrome in the population of the San Luis Valley, Colorado.

OBJECTIVE: To cross-sectionally evaluate the presence of clustering of the insulin-resistance syndrome components. Tests were conducted for association of the HindIII restriction site polymorphism at the lipoprotein lipase locus with clustering of the physiological components of the insulin resistance syndrome. RESEARCH DESIGN AND METHODS: DNA samples of 370 normoglycemic Hispanics and 520 normoglycemic non-Hispanic whites from the San Luis Valley, Colorado, were amplified by the polymerase chain reaction. Lipids and glucose were determined by the standard procedures. Cross-tabulation and chi 2 analysis were used. RESULTS: The insulin-resistance syndrome components (elevated fasting insulin, reduced high-density lipoprotein cholesterol, and elevated triglycerides) appeared together in individuals of this population sample more often than expected by chance. Individuals in the population with the (+/+) lipoprotein lipase-HindIII restriction of fragment-length polymorphism genotype were more likely to have elevated fasting insulin and triglycerides and a reduced high-density lipoprotein-cholesterol level than subjects with the (+/-) genotype (odds ratio = 2.3, 95% confidence interval 1.38-3.98). CONCLUSIONS: As expected from the physiological function of lipoprotein lipase, the primary association of lipoprotein lipase genotypes is with triglyceride and high-density lipoprotein-cholesterol levels. This appears to be the first reported genetic association with the insulin-resistance syndrome and may reflect genotype specific differences in the regulation of lipoprotein lipase by insulin.

Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression.

OBJECTIVE: This study examined whether evidence of cerebrovascular disease in the form of magnetic resonance imaging (MRI) signal hyperintensities in white matter was associated with depressive symptoms in a high-functioning group of normal elderly volunteers. METHOD: Ninety-two community-dwelling elderly individuals participating in a study of white matter hyperintensities (WMHs) in normal aging whose apolipoprotein E (APOE) genotype had been determined completed the Geriatric Depression Scale and received an MRI scan. Univariate analyses of variance were used to examine the relationship between depressive symptoms and the location of WMHs (in deep white matter versus in periventricular white matter) and to determine whether WMHs were more likely to be associated with symptoms of impaired motivation and concentration or with mood symptoms. The effect on depressive symptoms of the interaction between severity of cerebrovascular disease as evidenced by WMHs and APOE genotype was also examined. RESULTS: Hyperintensities in the deep white matter, but not in the periventricular white matter, were associated with depressive symptoms, especially symptoms of impaired motivation, concentration, and decision making. The relationship between deep WMHs and depressive symptoms was especially strong in individuals carrying the APOE-4 allele. CONCLUSIONS: The pattern of depressive symptoms associated with WMHs in this study was similar to the pattern described in the literature as characterizing "vascular" depression in older persons with major depression. The results suggest that cerebrovascular disease may also underlie the depressive symptoms often found in older individuals who are not clinically depressed.

Expression of differential immune factors in temporal cortex and cerebellum: the role of alpha-1-antichymotrypsin, apolipoprotein E, and reactive glia in the progression of Alzheimer's disease.

A variety of factors and processes have been implicated in the development and progression of the pathology of Alzheimer's Disease (AD), including amyloid fragment deposition, reactive gliosis, alpha-1-antichymotrypsin (ACT), and apolipoprotein E (APOE). Carriers of the APOE 4 allele have been shown to have an enhanced risk of developing AD, and the ACT signal peptide A/A genotype may modify the APOEepsilon4 risk. The protein products of these genes have been shown to enhance conversion of diffuse beta amyloid (Abeta) fibrils, which are found in diffuse plaques, to the fibrillar form found in neuritic plaques. In affected regions of AD brain, ACT and APOE colocalize with Abeta deposits and reactive microglia and astrocytes. We examined the regional distribution of ACT, APOE, and reactive glia in temporal cortex, where neuritic plaques are abundant, and cerebellum (in areas where diffuse plaques but not neuritic plaques accumulate) to examine the relationship of these markers to the deposition of Abeta. In temporal cortex, ACT and APOE staining was localized to plaque-like profiles, reactive astrocytes, and blood vessels; human leukocyte antigen-DR (HLA-DR) and glial fibrillary acidic protein (GFAP) staining revealed focal clusters of reactive microglia and astrocytes. In cerebellum, ACT and APOE immunoreactivity was never localized to plaque-like profiles but was weakly localized to unreactive astrocytes; weak HLA-DR and GFAP immunoreactivity was present on quiescent microglia throughout the cerebellum. The lack of fibrillar amyloid deposits in cerebellum, despite the presence of well-characterized markers thought to mediate the production of Abeta, suggests that this brain region may be lacking certain factors necessary for fibril formation or that the cerebellum responds differently to stimuli that successfully mediate inflammation in affected cortex.