A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Consortium to establish a registry for Alzheimer's disease: development, database structure, and selected findings.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded in 1986 by the National Institute on Aging to develop standardized assessments for patients with Alzheimer's disease (AD). Since that time, CERAD has developed and evaluated clinical and neuropsychological test batteries, a neuroimaging protocol, and an assessment of the neuropathological findings of the brains of these patients at autopsy. Approximately 1,200 carefully screened patients with AD and 450 control subjects were evaluated using these instruments at 24 major medical centers around the United States. Annual follow-up observations of these subjects were made for up to eight years. Autopsy examinations of the brain were done in over half of the deceased cases and the clinical diagnosis of AD was confirmed in 85 percent of them. This article outlines the procedures used for identifying the clinical sites, the entry and annual evaluations of patients and control subjects, the collection and analysis of data at a central Methodology and Data Management Center, and evaluation of the CERAD measures. We also present selected data from the 50 or so peer-reviewed papers published to date, with particular emphasis on findings from African-American patients with AD, and related policy implications.

Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV.

We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2) High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD.

The consortium to establish a registry for Alzheimer's Disease (CERAD). Part XIII. Obtaining autopsy in Alzheimer's disease.

Although autopsy rates in the United States have been decreasing steadily, the necessity for brain autopsy to confirm Alzheimer's disease (AD) remains. Of 308 consecutively deceased AD patients at 24 CERAD (Consortium to Establish a Registry for Alzheimer's Disease) sites, 167 (54%) were autopsied; 141 (46%) were not. The autopsied and nonautopsied groups were comparable in gender (men, 57.5% versus 49.7%), marital status (married, 69.3% versus 67.1%), age at entry (73 versus 74 years), age at death (76 versus 77 years), and stage of disease at entry (mild, 46% versus 43%). However, the autopsied patients were significantly more likely to be white (94.5% versus 82.1%), to be better educated (13.1 versus 11.3 years), to have been in the study longer (mean, 3.3 versus 2.6 years), and to have had longer total duration of AD (8.1 versus 6.7 years). Of the 24 CERAD sites, 13 stressed the importance of autopsy by dedicating a staff member to seek autopsy and by providing free autopsy and transportation; 11 did not. Logistic regression analysis showed that white race (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.10-6.83), increased education (OR = 1.12; 95% CI = 1.04-1.21), and emphasis on autopsy (OR = 4.69; 95% CI = 2.67-8.25) were the only significant factors. Although race and education were important, autopsy was more likely to be obtained when sites dedicated resources to this endeavor.

Neuropsychological test performance in African-American and white patients with Alzheimer's disease.

Little information exists on the performance of black versus white patients with Alzheimer's disease on neuropsychological tests for dementia. In this study, we compared performance on the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuropsychological battery between white (n = 830) and black (n = 158) patients with Alzheimer's disease enrolled in the CERAD study at 23 university medical centers in the United States. The black patients were older, had fewer years of formal education, and were more impaired in their activities of daily living than were the white patients. After controlling for these characteristics and for duration of the disease and severity of dementia, there were differences in the performance of black and white patients on several of the cognitive measures. Black patients scored lower than whites on tests of visual naming and constructional praxis and on the Mini-Mental State Examination. There were no statistical differences in performance on tests of fluency and word list memory. These findings suggest that cultural or experiential differences may modify performance on specific neuropsychological tests. These factors, in addition to age and educational background, should be considered when interpreting performance on neuropsychological tests in elderly black patients with dementia.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part V. A normative study of the neuropsychological battery.

The neuropsychological tests developed for the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are currently used to measure cognitive impairments of Alzheimer's disease (AD) in clinical investigations of this disorder. This report presents the normative information for the CERAD battery, obtained in a large sample (n = 413) of control subjects (ages 50 to 89) who were enrolled in 23 university medical centers in the United States participating in the CERAD study from 1987 to 1992. We compared separately the performance of subjects with high (> or = 12) and low (< 12) years of formal education. For many of the individual cognitive measures in the highly educated group, we observed significant age and gender effects. Only the praxis measure showed a significant age effect in the low-education group. Delayed recall, when adjusted for amount of material acquired (savings), was relatively unaffected by age, gender, and level of education. Our findings suggest that the savings scores, in particular, may be useful in distinguishing between AD and normal aging.