Predicting Progression from Normal to MCI and from MCI to AD Using Clinical Variables in the National Alzheimer's Coordinating Center Uniform Data Set Version 3: Application of Machine Learning Models and a Probability Calculator.

Clinical trials are increasingly focused on pre-manifest and early Alzheimer's disease (AD). Accurately predicting clinical progressions from normal to MCI or from MCI to dementia/AD versus non-progression is challenging. Accurate identification of symptomatic progressors is important to avoid unnecessary treatment and improve trial efficiency. Due to large inter-individual variability, biomarker positivity and comorbidity information are often insufficient to identify those destined to have symptomatic progressions. Using only clinical variables, we aimed to predict clinical progressions, estimating probabilities of progressions with a small set of variables selected by machine learning approaches. This work updates our previous work that was applied to the National Alzheimer's Coordinating Center (NACC) Uniform Data Set Version 2 (V2), by using the most recent version (V3) with additional analyses. We generated a user-friendly conversion probability calculator which can be used for effectively pre-screening trial participants.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

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.

Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer's Disease Database.

BACKGROUND: Brain tissue analysis is necessary to confirm prion diseases. Clinically unsuspected cases may be identified through neuropathologic testing. METHODS: National Alzheimer's Coordinating Center (NACC) Minimum and Neuropathologic Data Set for 1984 to 2005 were reviewed. Eligible patients had dementia, underwent autopsy, had available neuropathologic data, belonged to a currently funded Alzheimer's Disease Center (ADC), and were coded as having an Alzheimer's disease clinical diagnosis or a nonprion disease etiology. For the eligible patients with neuropathology indicating prion disease, further clinical information, collected from the reporting ADC, determined whether prion disease was considered before autopsy. RESULTS: Of 6000 eligible patients in the NACC database, 7 (0.12%) were clinically unsuspected but autopsy-confirmed prion disease cases. CONCLUSION: The proportion of patients with dementia with clinically unrecognized but autopsy-confirmed prion disease was small. Besides confirming clinically suspected cases, neuropathology is useful to identify unsuspected clinically atypical cases of prion disease.

A Novel Study Paradigm for Long-term Prevention Trials in Alzheimer Disease: The Placebo Group Simulation Approach (PGSA): Application to MCI data from the NACC database.

INTRODUCTION: The PGSA (Placebo Group Simulation Approach) aims at avoiding problems of sample representativeness and ethical issues typical of placebo-controlled secondary prevention trials with MCI patients. The PGSA uses mathematical modeling to forecast the distribution of quantified outcomes of MCI patient groups based on their own baseline data established at the outset of clinical trials. These forecasted distributions are then compared with the distribution of actual outcomes observed on candidate treatments, thus substituting for a concomitant placebo group. Here we investigate whether a PGSA algorithm that was developed from the MCI population of ADNI 1*, can reliably simulate the distribution of composite neuropsychological outcomes from a larger, independently selected MCI subject sample. METHODS: Data available from the National Alzheimer's Coordinating Center (NACC) were used. We included 1523 patients with single or multiple domain amnestic mild cognitive impairment (aMCI) and at least two follow-ups after baseline. In order to strengthen the analysis and to verify whether there was a drift over time in the neuropsychological outcomes, the NACC subject sample was split into 3 subsamples of similar size. The previously described PGSA algorithm for the trajectory of a composite neuropsychological test battery (NTB) score was adapted to the test battery used in NACC. Nine demographic, clinical, biological and neuropsychological candidate predictors were included in a mixed model; this model and its error terms were used to simulate trajectories of the adapted NTB. RESULTS: The distributions of empirically observed and simulated data after 1, 2 and 3 years were very similar, with some over-estimation of decline in all 3 subgroups. The by far most important predictor of the NTB trajectories is the baseline NTB score. Other significant predictors are the MMSE baseline score and the interactions of time with ApoE4 and FAQ (functional abilities). These are essentially the same predictors as determined for the original NTB score. CONCLUSION: An algorithm comprising a small number of baseline variables, notably cognitive performance at baseline, forecasts the group trajectory of cognitive decline in subsequent years with high accuracy. The current analysis of 3 independent subgroups of aMCI patients from the NACC database supports the validity of the PGSA longitudinal algorithm for a NTB. Use of the PGSA in long-term secondary AD prevention trials deserves consideration.

Education, cognitive function, and severity of neuropathology in Alzheimer disease.

BACKGROUND: Education may modulate the degree to which the neuropathology of Alzheimer disease (AD) is expressed as impaired cognitive performance. METHODS: We studied 2,051 participants age 65+ years at 27 AD Centers who died and underwent autopsy. All took the Mini-Mental State Examination (MMSE) within 2 years before death. Braak & Braak stage, neuritic plaque density, and Consortium to Establish a Registry for Alzheimer's Disease and National Institute on Aging (NIA)/Reagan diagnostic classifications quantified AD neuropathologic severity. Multivariate analyses modeled MMSE in relation to education and neuropathologic severity, adjusting for age at death, Lewy body pathology, and vascular dementia. RESULTS: Higher education was associated with higher MMSE scores when AD neuropathology was absent or mild. But with more advanced neuropathology, differences in MMSE scores among education levels were attenuated. For example, among patients without AD by NIA/Reagan criteria, fitted MMSE scores ranged from 19.6 for patients with less than high school education to 25.9 with education beyond high school. But among patients with neuropathologically advanced AD, the range of scores by education was only 7.1 to 8.6. CONCLUSIONS: We found no evidence of larger education-related differences in cognitive function when Alzheimer disease (AD) neuropathology was more advanced. Higher Mini-Mental State Examination scores among more educated persons with mild or no AD may reflect better test-taking skills or cognitive reserve, but these advantages may ultimately be overwhelmed by AD neuropathology.

An alternative method for estimating efficacy of the AN1792 vaccine for Alzheimer disease.

BACKGROUND: In a randomized trial of AN1792 vaccine against A beta in Alzheimer disease (AD), only 20% of vaccine recipients had an anti-AN1792 antibody response. The trialists sought to estimate the efficacy of the vaccine among antibody responders by comparing outcomes among antibody responders in the vaccine group with outcomes among all placebo recipients. METHODS: We describe why the method used may be biased. An alternative approach to estimating efficacy is described that compares outcomes between responders in the vaccine group and potential responders in the placebo group. Although potential responders cannot be identified individually, the distribution of outcomes among them can be inferred indirectly, under certain assumptions. Three methods for assessing vaccine effects are compared using data on the ventricular volume boundary shift integral (BSI) from the AN1792 trial and in simulations. RESULTS: Mean (+/- standard error) increase in BSI relative to controls was 0.16 (+/-0.065) by intent-to-treat, 0.61 (+/-0.116) in the published comparison, and 0.81 (+/-0.320) in the proposed approach. Simulations show that the published method can often yield biased estimates, while the proposed method does not. CONCLUSIONS: Published results from the AN1792 trial may have underestimated the effect of vaccine on progression of cerebral atrophy among patients with an antibody response to the vaccine. For this and future similar trials, we suggest that intent-to-treat results always be reported, and that efficacy estimates be based on the proposed potential-outcomes method.

The North American Multiple System Atrophy Study Group.

The North American Multiple System Atrophy Study Group involves investigators in 12 US medical centers funded by a grant from the National Institutes of Health. The objectives are to examine the environmental and genetic risk factors for MSA; elucidate pathogenic mechanisms underlying the disorder; and refine evaluations used for assessment. During its first year, the group enrolled 87 patients, implemented four cores, and initiated four scientific projects. Most patients among the 87 had parkinsonian features, which frequently began asymmetrically and remained asymmetrical; one-third responded to levodopa and many developed levodopa complications; almost two-thirds of the patients had cerebellar dysfunction, of these 90% had ataxia; urinary incontinence occurred commonly, and sleep disorders affected most. The investigators studied the effects of oxidative and nitrative stress upon the formation of alpha-synuclein inclusions; generated transgenic models of alpha-synuclein accumulation that recapitulate several behavioral and neuropathological features of MSA; and compared the severity of the autonomic features of MSA, Parkinson's disease and dementia with Lewy bodies.

Serum cholesterol and risk of Alzheimer disease: a community-based cohort study.

OBJECTIVES: To examine the association of serum total cholesterol (TC) and high density lipoprotein (HDL) levels and subsequent incidence of dementia and Alzheimer disease (AD) in a population-based cohort study. METHODS: A cohort of cognitively intact persons, aged 65 and older, was randomly selected from Group Health Cooperative (GHC), a large health maintenance organization, and was assessed biennially for dementia. Premorbid levels of TC and HDL were obtained from a computerized clinical laboratory database at GHC. Cox proportional hazards regression was used to calculate hazard ratios (HR, 95% CI) for dementia and AD associated with quartiles of TC and HDL levels. RESULTS: Of the 2,356 eligible participants, 2,141 had at least one serum TC measure prior to the initial enrollment. Using the lowest TC quartiles as the reference group, the HR in the highest TC quartiles was not significantly elevated for dementia (1.16, 0.81 to 1.67) or for AD (1.00, 0.61 to 1.62) after adjusting for age, sex, education, baseline cognition, vascular comorbidities, body mass index, and lipid-lowering agent use. Serum HDL showed a similar lack of significant association with risk of dementia or AD. Models that included the presence of one or more APOE-epsilon4 alleles showed a typical association of epsilon4 with AD risk. This association was not materially modified by inclusion of TC level. CONCLUSION: The data do not support an association between serum total cholesterol or high density lipoprotein in late life and subsequent risk of dementia or Alzheimer disease (AD). The increased risk of AD with APOE-epsilon4 is probably not mediated by serum total cholesterol levels.

Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both.

OBJECTIVE: To examine the neuropsychological profile of dementia patients from a community-based autopsy sample of dementia, comparing Alzheimer disease (AD), Lewy body pathology (LBP) alone, and LBP with coexistent AD (AD/LBP). METHODS: The authors reviewed 135 subjects from a community-based study of dementia for whom autopsy and brain tissue was available. Diagnostic groups were determined according to standard neuropathologic methods and criteria, and the presence of LBs was determined using alpha-synuclein immunostaining. Neuropathologically defined diagnostic groups of AD, AD/LBP, and LBP were examined for differences on neuropsychological test performance at the time of initial study enrollment. RESULTS: There were 48 patients with AD alone, 65 with LB and AD pathology (AD/LBP), and 22 with LBP alone (LBP alone). There were no significant differences between groups demographically or on performance of enrollment Mini-Mental State Examination (MMSE) or Dementia Rating Scale (DRS). AD patients performed worse than the LBP patients on memory measures (Fuld Object Memory Evaluation Delayed Recall, Wechsler Memory Scale Logical Memory Immediate and Delayed Recall; p < 0.05) and a naming task (Consortium to Establish a Registry for Alzheimer's Disease Naming; p < 0.05). LBP patients were more impaired than AD patients on executive function (Trail Making Test Part B; p < 0.05) and attention tasks (Wechsler Adult Intelligence Scale-Revised Digit Span; p < 0.05). Decline in MMSE and DRS scores over time were greatest in the patients with AD/LBP. CONCLUSIONS: In a community-based sample of older, medically complicated patients with dementia, there are neuropsychological differences between dementia subtypes at the time of diagnosis. In particular, patients with Alzheimer disease (AD) alone and AD/Lewy body pathology (LBP) had more severe memory impairment than patients with LBP. LBP alone was associated with more severe executive dysfunction. Patients with AD/LBP had the most rapid rate of cognitive decline.

Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study.

OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

History of head trauma and risk of intracranial meningioma: population-based case-control study.

A population-based case-control study in western Washington state was performed to assess the relation between head trauma and meningioma. Based on 200 case and 400 control subjects, head trauma was associated with an increased risk of meningioma (odds ratio = 1.83; 95% CI = 1.28, 2.62), especially head traumas occurring 10 to 19 years before reference date (odds ratio = 4.33; 95% CI = 2.06, 9.10). A dose-response relationship was present for number, but not severity, of head traumas. Whether the associations observed in this study are causal remains unclear.

Healthcare utilization and costs in managed care patients with Alzheimer's disease during the last few years of life.

OBJECTIVES: To learn whether managed care patients with Alzheimer's disease (AD) are more or less costly to care for than patients with other forms of dementia or patients without dementia during the last few years of life. DESIGN: Case control study. SETTING: A health maintenance organization base population. PARTICIPANTS: Three groups of subjects (mean age 85) who were deceased members of a dementia registry obtained from a health maintenance organization base population: 263 subjects with clinically diagnosed probable AD, 133 subjects with other forms of dementia, and 100 cognitively intact controls. MEASUREMENTS: Utilization records were examined for the 3 years preceding death. RESULTS: In all subcategories and in aggregate, utilization and costs of care were either similar or lower for patients with AD than for the other groups, even after controlling for age, gender, and comorbidity. CONCLUSIONS: Persons with AD do not incur higher costs than persons with other types of dementia or age-matched persons without dementia in a mature health maintenance organization during the last few years of life, when utilization is likely to be highest.

Using census data and birth certificates to reconstruct the early-life socioeconomic environment and the relation to the development of Alzheimer's disease.

The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer's disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer's disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer's disease associated with father's occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer's disease (odds ratio = 1.80, 95% confidence interval = 1.19--2.73). The risk of Alzheimer's disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein epsilon 4 allele (APOE epsilon 4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer's disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE epsilon 4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer's disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07--5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78--2.52). Subjects carrying the APOE epsilon 4 allele alone have a threefold increased risk of Alzheimer's disease (odds ratio = 3.17, 95% confidence interval = 1.99--5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father's occupation being manual) had a relatively high risk of Alzheimer's disease (odds ratio = 14.8, 95% confidence interval = 4.9--46). The data suggest that APOE epsilon 4 may modify the associations between father's occupation, other early-life environmental factors, and development of Alzheimer's disease in late life.

The association between smoking and Alzheimer's disease: effects of study design and bias.

In epidemiologic studies, unrecognized bias can contribute to observed results, causing them to be inaccurate. Analytic study designs, such as the case-control and cohort designs, each carry potential for specific forms of bias. The cohort design is not susceptible to many forms of bias that are experienced by case-control studies. A consistent "protective" effect of smoking on Alzheimer's disease was documented by many case-control studies. However, the potential effect of biases cannot be separated from the results. Cohort studies now show that smoking may either be unrelated to Alzheimer's disease onset or possibly generate a modest increased risk. In this review the results and comparisons of various studies and potential biases are discussed.

Epidemiology of dementia: concepts and overview.

This article reviews current knowledge about the prevalence and incidence of dementia and the risk and protective factors for dementia. Relevant epidemiologic concepts and methodological issues are reviewed, focusing on the implications of designing and interpreting epidemiologic studies of dementia and illustrating the integrative role of epidemiology.

Physical activity and subarachnoid haemorrhage: a population based case-control study.

OBJECTIVE: To evaluate physical activity as a risk factor for subarachnoid haemorrhage. METHODS: A population based case-control study in King County, Washington. A standardised, personal interview was used to determine physical activity during the past year and at the onset of the bleed for case patients and a similar reference time for control subjects. Conditional logistic regression and a case cross over analysis were performed in which each case patient served as his or her own control. Subjects were 149 men and women with incident, spontaneous subarachnoid haemorrhage and two control subjects per case patient. Control subjects were identified through random digit dialing and matched on age, sex, and respondent type. RESULTS: Four of the 149 (2.7%) case patients were engaged in vigorous physical activity at the time of their subarachnoid haemorrhage. With those who were engaged in non-vigorous or no physical activity serving as the reference group, the relative risk of sustaining a subarachnoid haemorrhage for those engaged in vigorous physical activity was 11.6 (95% confidence interval (95% CI) 1.2-113.2). In the case cross over analysis, the relative risk was 15.0 (95% CI 4.3-52.2). Higher levels of long term regular physical activity over the past year were associated with a lower, but not statistically significant, risk of subarachnoid haemorrhage (test for trend, p=0.3). CONCLUSION: The risk of subarachnoid haemorrhage is increased during vigorous physical activity, although only a few result from this mechanism.

Head injury and the risk of AD in the MIRAGE study.

OBJECTIVES: It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-epsilon4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study. SUBJECTS: A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study. METHODS: Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses. RESULTS: Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking epsilon4 (OR = 3.3) than among epsilon4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3). CONCLUSION: Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-epsilon4 compared with those having one or two epsilon4 alleles, suggesting that these risk factors may have a common biologic underpinning.

Early-life risk factors and the development of Alzheimer's disease.

OBJECTIVE: To investigate the association of early-life factors with AD. BACKGROUND: The early-life environment and its effect on growth and maturation of children and adolescents are linked to many adult chronic diseases (heart disease, stroke, hypertension, and diabetes mellitus), and these effects are also linked to maternal reproduction. AD may have an early-life link. The areas of the brain that show the earliest signs of AD are the same areas of the brain that take the longest to mature during childhood and adolescence. A poor-quality childhood or adolescent environment could prevent the brain from reaching complete levels of maturation. Lower levels of brain maturation may put people at higher risk for AD. METHODS: In a community-based case-control study (393 cases, 377 controls), we investigated the association of early-life factors and AD. Early-life variables include mother's age at patient's birth, birth order, number of siblings, and area of residence before age 18 years. Patient education level and apolipoprotein E (APOE) genotypes were also included in the analysis. RESULTS: Area of residence before age 18 years and number of siblings are associated with subsequent development of AD. For each additional child in the family the risk of AD increases by 8% (OR = 1.08, 95% CI = 1.01 to 1.15). More controls compared with cases grew up in the suburbs (OR = 0.45, 95% CI = 0.25 to 0.82). APOE epsilon 4 and the patient's education level did not confound or modify the associations. CONCLUSIONS: The early-life childhood and adolescent environment is associated with the risk of AD.

The utility of apolipoprotein E genotyping in the diagnosis of Alzheimer disease in a community-based case series.

CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.