Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment to Alzheimer’s disease (AD) dementia in elderly patients. In this analysis we compared the rates of decline to dementia estimated from three common global measures of cognition: Mini Mental Status Examination (MMSE) score, Clinical Dementia Rating sum of boxes score (CDR-SB), and a neuropsychological tests composite score (CS).
A total of 2,899 subjects in the National Alzheimer’s Coordinating Center Uniform Data Set age 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates were estimated and compared for standardized MMSE, CDR-SB, and Composite scores using Generalized Estimating Equations (GEE). Associations between rate of decline and several potential correlates of decline were also calculated and compared across measures.
The CDR-SB had the steepest estimated slope, with a decline of .49 standard deviations (SD) per year, followed by the MMSE with .22 SD/year, and finally the CS with .07 SD/year. The rate of decline of the three measures differed significantly in a global test for differences (p<.0001). Age at visit, BMI at visit, APOE ε4 allele status, and race (black vs. white) had significantly different relationships with rate of decline in a global test for difference among the three measures.
These results suggest that both the rate of decline and the effects of AD risk factors on decline to dementia can vary depending on the evaluative measure used.
neuropsychological testing; Alzheimer’s Disease; cognitive assessment; aging
The neuropathological examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently employed clinical diagnostic methods, clinical and neuropathological data from the National Alzheimer's Coordinating Center (NACC), which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer's Disease Centers (ADCs), were collected as part of the NACC Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on “probable” and “possible” AD levels of clinical confidence and 4 levels of neuropathological confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathological criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in demented subjects than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiological studies.
Alzheimer disease; Autopsy; Clinical trials; Diagnosis; Histopathology; Neuropathology; Non-Alzheimer dementia
Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.
Aging; Alzheimer disease; Amyloid; Dementia; Epidemiology; Neuropathology; MAPT; Neurofibrillary tangles
Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
Evidence suggests that patients with dementia with Lewy bodies (DLB) may have more nocturnal sleep disturbance than patients with Alzheimer's disease (AD). We sought to confirm such observations using a large, prospectively collected, standardized, multicenter-derived database, i.e. the National Alzheimer's Coordinating Center Uniform Data Set.
Nocturnal sleep disturbance (NSD) data, as characterized by the Neuropsychiatric Inventory Questionnaire (NPI-Q), were derived from 4,531 patients collected between September 2005 and November 2008 from 32 National Institute on Aging participating AD centers. Patient and informant characteristics were compared between those with and without NSD by dementia diagnosis (DLB and probable AD). Finally, a logistic regression model was created to quantify the association between NSD status and diagnosis while adjusting for these patient/informant characteristics, as well as center.
NSD was more frequent in clinically diagnosed DLB relative to clinically diagnosed AD (odds ratio = 2.93, 95% confidence interval = 2.22–3.86). These results were independent from the gender of the patient or informant, whether the informant lived with the patient, and other patient characteristics, such as dementia severity, depressive symptoms, and NPI-Q-derived measures of hallucinations, delusions, agitation and apathy. In AD, but not DLB, patients, NSD was associated with more advanced disease. Comorbidity of NSD with hallucinations, agitation and apathy was higher in DLB than in AD. There was also evidence that the percentage of DLB cases with NSD showed wide variation across centers.
As defined by the NPI-Q, endorsement of the nocturnal behavior item by informants is more likely in patients with DLB when compared to AD, even after the adjustment of key patient/informant characteristics.
Dementia with Lewy bodies; Alzheimer's disease; Sleep; Neuropsychiatric Inventory Questionnaire
Several methods of estimating prevalence of dementia are presented. For both Brookmeyer and the Chicago Health and Aging project (CHAP), the estimates of prevalence are derived statistically, forward calculating from incidence and survival figures. Here, the choice of incidence rates upon which to build the estimates may be critical. Brookmeyer used incidence rates from a number of published studies, whereas the CHAP investigators applied the incidence rates observed in their own cohort. The Aging, Demographics, and Memory Study (ADAMS) and the East Boston Senior Health Project (EBSHP) were sample surveys designed to ascertain the prevalence of AD and dementia. ADAMS obtained direct estimates by relying on probability sampling nationwide. EBSHP relied on projection of localized prevalence estimates to the national population. The sampling techniques of ADAMS and EBSHP were rather similar while their disease definitions were not. By contrast, EBSPH and CHAP have similar disease definitions internally, but use different calculation techniques, and yet arrive at similar prevalence estimates, which are considerably greater than those obtained by either Brookmeyer or ADAMS. Choice of disease definition may play the larger role in explaining differences in observed prevalence between these studies.
We examined risk of one-year decline in four everyday activities in patients with dementia with Lewy bodies (DLB), relative to patients with Alzheimer disease (AD). Data were from the National Alzheimer’s Coordinating Center, gathered from 32 Alzheimer’s Disease Centers. Participants (n = 1,880) were: 60+ years, demented with a primary clinical diagnosis of probable AD or DLB, and had a global Clinical Dementia Rating of 0.5–2. The activities were measured with the Functional Activities Questionnaire. In modified Poisson regression models adjusted for demographics, baseline activity, years from symptom onset, cognitive impairment and co-morbidities, DLB participants 67–81 years had 1.5 to 2 times increased risk of decline in performing basic kitchen tasks, engaging in games/hobbies, and paying attention/understanding, relative to AD participants of the same age (p<0.05). There was no significant difference between AD and DLB participants outside of this age range. For decline in ability to go shopping alone, there was also no significant difference between AD and DLB participants. In summary, the functional course of DLB, relative to AD, may depend on the age of the patient. These findings may provide anticipatory guidance to families and health-care providers, which may be useful in the planning of care strategies.
Dementia with Lewy bodies; Alzheimer disease; Disease progression; Prognosis; Natural history studies; Activities of daily living
To determine whether genotypes at CLU,
PICALM, and CR1 confer risk for
Alzheimer’s disease (AD) and whether risk for AD associated with
these genes is influenced by APOE genotypes.
Association study of AD and CLU,
PICALM, CR1 and APOE
Academic research institutions in the United States, Canada, and
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively
normal controls, 1,092 with autopsies from 12 different studies, including
Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Unadjusted, CLU [odds ratio (OR) =
0.91, 95% confidence interval (CI) = 0.85 – 0.96 for
single nucleotide polymorphism (SNP) rs11136000],
CR1 (OR = 1.14, CI = 1.07 –
1.22, SNP rs3818361), and PICALM (OR = 0.89, CI
= 0.84 – 0.94, SNP rs3851179) were associated with AD in
Caucasians. None were significantly associated with AD in the other ethnic
groups. APOE ε4 was significantly associated with
AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the
Arab cohort. Adjusting for age, sex, and the presence of at least one
APOE ε4 allele greatly reduced evidence for
association with PICALM but not CR1 or
CLU. Models with the main SNP effect,
APOE ε4 (+/−), and an
interaction term showed significant interaction between
APOE ε4 (+/−) and
We confirm in a completely independent dataset that CR1,
CLU, and PICALM are AD susceptibility loci in
European ancestry populations. Genotypes at PICALM confer risk predominantly
in APOE ε4-positive subject. Thus, APOE and PICALM synergistically
Our earlier post hoc analysis suggested possible benefits of statins in reducing risk of Alzheimer’s disease (AD) in younger participants (< age 80 years) with the APOE ε4 allele. We further investigated these findings with more follow-up time and more recently enrolled participants.
A cohort of cognitively intact elderly was assessed biennially for dementia and AD.
3,392 non-demented member of a health maintenance organization (HMO) aged ≥ 65 years.
We identified statin use from the HMO pharmacy database and applied proportional hazards models with statin use as a time-dependent covariate to assess the statin-AD association and the modifying effects of age and the APOE ε4 allele.
Over an average of 6.1 years of follow-up of 3099 participants, 263 participants developed probable AD. The adjusted hazard ratio (aHR) for statin use was 0.62 (95% confidence interval [CI], 0.40 – 0.97) for AD in models including demographic characteristics and vascular risk factors as covariates. The strength of the statin-AD association diminished with age (statin × age-at-entry interaction p = 0.04); the aHR in those younger than 80 was 0.44 (CI 0.25 – 0.78) vs. 1.22 (CI 0.61 – 2.42) for those older than 80. The interaction term for statin use × APOE ε4 was not significant (p = 0.65).
This enlarged study confirms earlier findings that statin therapy in early old age, but not in late age, may be associated with reduced risk of AD. The relationship between statin use and AD was consistent across APOE genotypes.
Statin; Old age; APOE genotype; Alzheimer disease
There is increasing emphasis on interdisciplinary “translation” in biomedical research.1 A major push towards prevention of Alzheimer's Disease is spawning translational research 2 that should span basic, clinical, and population investigations. Epidemiological studies, which address our understanding of risk and protective factors for disease at the population level, are contributing less than they could to translational research. In part, this is because the key concept of risk is being “lost in translation,” muddling interpretations and leading to interdisciplinary frustrations. Two epidemiologists offer a framework for resolving some of the confusion.
This study examines the clinical and neuropathologic characteristics of 37 participants in a community-based dementia series who had cognitive complaints at enrollment but did not meet dementia criteria. Participants had neuropsychological testing, were followed until death, and underwent autopsy. Twenty-four participants progressed to dementia, and their baseline characteristics were analyzed. Of the 24, 13 met criteria for neuropathologic Alzheimer disease (AD). The 13 participants who progressed to neuropathologic AD (mean intake age 78.5 ± 7.7, mean enrollment 6.4 ± 2.1 years) performed worse than 11 who progressed to neuropathologic non-AD dementias (mean intake age 79.0 ± 6.0, mean enrollment 6.0 ± 3.2 years) on baseline Wechsler Memory Scale (WMS) delayed logical memory (3.4 ± 2.9 vs 6.3 ± 3.9, P=.05) and delayed visual reproduction (1.4 ± 2.1 vs 3.1 ± 2.7, P=.02). These observations are consistent with the view that nondemented patients with underlying AD may be more likely to present with memory than nonmemory cognitive impairment.
autopsy; neuropathology; dementia; mild cognitive impairment
To determine the frequency and possible cognitive effect of histological Alzheimer’s disease (AD) in autopsied older nondemented individuals.
Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer’s Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions.
Washington University Alzheimer’s Disease Research Center.
Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years).
About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.
Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.
preclinical Alzheimer’s disease; nondemented aging; neuropathological Alzheimer’s disease
Many cognitively impaired patients’ brains fall into neuropathologic diagnostic categories that cannot be defined explicitly by the National Institute on Aging and Reagan Institute (NIA-RI) guidelines. Two specific case categories are considered: “tangle-intensive” patients with the highest density of neurofibrillary tangles (NFTs, as graded by the Braak staging system) but only moderate density of neuritic amyloid plaques (NPs, as graded by CERAD); and conversely “plaque-intensive” patients with intermediate severity NFTs and high density of NPs. To better understand these technically unclassifiable cases, we analyzed NACC Registry data, which includes both clinical and pathological information from the National Institute on Aging-funded Alzheimer Disease Centers (ADCs). 1,672 cases with antemortem diagnoses of dementia were included. To evaluate the diagnostic tendencies of ADC neuropathologists, we assessed how the plaque-intensive and tangle-intensive cases were diagnosed ultimately. Tangle-intensive cases were more likely to be designated “High likelihood” that the dementia was due to AD, whereas plaque-intensive cases were typically designated “Intermediate likelihood”. Only the Braak stage VI “tangle-intensive” cases had lower final MMSE scores than the “plaque-intensive” cases (P<0.02). We conclude that more explicit diagnostic categories, along with better understanding of pathology in earlier phases of the disease, may be helpful to better guide neuropathologists.
While the clinical and neuropathological characterization of Alzheimer’s Disease (AD) is well defined, our understanding of the progression of pathologic mechanisms in AD remains unclear. Post-mortem brains from individuals who did not fulfill clinical criteria for AD may still demonstrate measurable levels of AD pathologies to suggest that they may have presented with clinical symptoms had they lived longer or are able to stave off disease progression. Comparison between such individuals and those clinically diagnosed and pathologically confirmed to have AD will be key in delineating AD pathogenesis and neuroprotection. In this study, we expression profiled laser capture microdissected non-tangle bearing neurons in 6 post-mortem brain regions that are differentially affected in the AD brain from 10 non-demented individuals demonstrating intermediate AD neuropathologies (NDAD; Braak stage of II through IV and CERAD rating of moderate to frequent) and evaluated this data against that from individuals who have been diagnosed with late onset AD as well as healthy elderly controls. We identified common statistically significant expression changes in both NDAD and AD brains that may establish a degenerative link between the two cohorts, in addition to NDAD specific transcriptomic changes. These findings pinpoint novel targets for developing earlier diagnostics and preventative therapies for AD prior to diagnosis of probable AD. We also provide this high-quality, low post-mortem interval (PMI), cell-specific, and region-specific NDAD/AD reference data set to the community as a public resource.
Laser capture microdissection; Affymetrix microarrays; Expression profiling; Neuron; Transcriptomics
The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer’s Disease Centers (ADC) program of the National Institute on Aging (NIA) consists of brief measures of attention, processing speed, executive function, episodic memory and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3,268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered “clinically cognitively normal” based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease (AD) in a relatively well-educated sample. Regression models investigating the impact of age, education, and gender on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: 1) determining the psychometric properties of the battery; 2) establishing normative data, including norms for different ethnic minority groups; and 3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with AD and other forms of dementia.
Alzheimer’s Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world’s population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regards to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.
expression profiling; neuron; Affymetrix microarrays; laser capture microdissection
Several studies have demonstrated that specific neuropathologic features may be associated with the presence of visual hallucinations in dementia patients, but the clinical usefulness of these studies has been limited because their subjects were selected on the basis of neuropathologic findings rather than clinical presentations. This study seeks to investigate the demographic, clinical, and neuropathologic features of community-based dementia subjects with and without visual hallucations.
A prospective examination of the clinical and neuropathologic correlates of visual hallucinations in community-based dementia subjects.
One hundred forty-eight subjects with sufficient clinical and neuropathologic data from a community-based incident dementia autopsy case series.
Subjects were classified according to the presence or absence of visual hallucinations and subjects with visual hallucinations (n = 27) were younger at intake and more likely to exhibit agitation, delusions, and apathy than subjects without visual hallucinations (n = 121). Subjects with visual hallucinations were also more likely than subjects without visual hallucinations to have Lewy-related pathology (LRP) (78% versus 45%). In addition, a higher frequency of visual hallucinations was observed in subjects with neocortical LRP than subjects with limbic-, amygdala-, or brainstem-predominant LRP. Although Alzheimer’s disease (AD) with concomitant LRP was the most common neuropathologic subtype in the VH-positive group (59%), the frequency of subjects with Alzheimer disease pathology did not differ significantly between those with and without visual hallucinations (74% versus 62%).
Subjects with visual hallucinations were more likely to have concomitant postural and gait disturbance, additional neuropsychiatric symptoms, and neocortical LRP than subjects without visual hallucinations. Visual hallucinations accompanying dementia have distinct clinical and neuropathologic characteristics that are important for prognosis and clinical management.
hallucinations; dementia; Lewy body disease; Alzheimer’s disease
Lewy related pathology (LRP) is a common pathologic finding at autopsy in dementia patients. Recently criteria for categorizing types of LRP in dementia patients were published, though these criteria have yet to be systematically applied to large dementia samples. We examined a large (N = 208) referral-based autopsy sample for LRP, and applied the published criteria for LRP categorization to these cases. We found almost half (49%) of LRP positive cases from this sample were not classifiable. However, modifying the published criteria by reducing the number of regions requiring examination, allowing more variability in LRP severity scores within specific brain regions, and adding an amygdala predominant category permitted classification of 97% of LRP positive cases from the referral-based sample. Application of the modified criteria to an unrelated community-based autopsy sample (N = 226) allowed classification of 96% of LRP positive cases. Modest modifications in the published criteria permit a significantly greater number of dementia cases with LRP to be classified. In addition, this modification allows for more limited sampling of brain regions for classification of LRP. We propose that these modified criteria for the categorization of LRP be utilized in patients with a history of dementia.
Lewy bodies; dementia; α-synuclein
The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for late-onset Alzheimer’s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE ε4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ε4 carriers and influences Alzheimer’s neuropathology.
We investigated the risk of PD associated with calcium channel blockers (CCBs) and β-blockers in a population-based case-control study of 206 men and women between ages 35 and 89 with a new diagnosis of idiopathic PD between 1992 and 2002, and 383 controls without PD or other neurodegenerative disorders who were frequency matched on age, sex, duration of GHC enrollment and clinic. The adjusted odds ratio associated with ever use was 0.85 (95% confidence interval [CI]: 0.43, 1.66) for CCBs, and 1.20 (95% CI: 0.71, 2.03) for β-blockers. We observed no association with PD risk for either class of medication in terms of duration, dose, number of prescriptions or pattern of use. The weakness of these associations and the absence of additional influence of dose or duration of use argue against any causal interpretation.
Parkinson’s disease; Calcium Channel Blockers; β-blockers; Epidemiology; Case-Control
In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer’s disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.
Alzheimer’s disease; laser capture microdissection; Affymetrix microarrays; expression profiling; neuron; transcriptomics