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.

Relationship of age to incidence of breast cancer in young women.

The rate of increase with age in the incidence of breast cancer in women was at a maximum at the lowest age that it could reasonably be estimated (in these data, 25 yr). It then declined linearly with age to about 50 years. The rate of increase with age, and its changes with age, were similar in many Western populations and in Japan. The decline with age in the rate of increase in the incidence of breast cancer was arrested at the age of 50 and replaced by rates of change that altered little with age. The premenopausal changes could be reproduced by a breast cancer precursor model with exponential decay of precursor prevalence with time. There was evidence for the existence of such a precursor.

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.

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.

Rapid eye movement sleep measures of Alzheimer's-type dementia patients and optimally healthy aged individuals.

It has been suggested that rapid eye movement (REM) sleep measures may be useful in the differential diagnosis of affective disorders. To determine what changes, if any, of REM measures occur in Alzheimer's dementia we examined the REM sleep of nine control and nine mild, nine moderate, and nine severe dementia subjects with probable Alzheimer's disease (AD). Control and mild and moderate AD groups were screened to exclude major depression. REM latency, REM time, REM activity, and REM density were examined. Results indicated that REM sleep measures are minimally affected by mild dementia. None of the REM sleep variables reported here successfully discriminated mild AD subjects from controls. However, REM time and REM latency were significantly affected in later stages of dementia. Total time in REM and REM latency successfully classified control and moderate-severe AD patients. In addition, the pattern of REM density across the night was also affected by severity of dementia. The results of this study, when compared to published REM measure findings in major depression, indicate that with proper cautions REM sleep measures may prove useful in the differential diagnosis of dementia and depression in geriatric patient populations.

Intracellular calcium response is reduced in CD4+ lymphocytes in Alzheimer's disease and in older persons with Down's syndrome.

Abnormalities in intracellular free calcium ([Ca2+]i) regulation are likely to play a role in brain aging and have been described in cells from patients with Alzheimer's disease (AD). [Ca2+]i acts as a second messenger in transmembrane signaling and regulates diverse functions in many cell types. Therefore, abnormalities in [Ca2+]i response may have far-ranging effects. Using flow cytometric assay for [Ca2+]i, we examined whether mitogen-induced increases in [Ca2+]i are abnormal in CD4+ T-lymphocytes from patients with familial AD (FAD), other AD, and Down's syndrome (DS) compared to age-matched controls. We observed that the peak [Ca2+]i responses were significantly decreased in CD4+ cells from 6 FAD patients (59% of control), 34 other AD patients (69% of age-matched control), and 6 older persons with DS (> 25 years old, 47% of control), after stimulation with 10 micrograms/ml anti-CD3 monoclonal antibody (mAb). The number of CD3 receptors on T lymphocytes of the AD patients was not decreased. In contrast, lymphocytes from subjects with FAD, other AD and older DS patients had no decrease in response to phytohemagglutinin (30 micrograms/ml). CD3 and related classes of membrane receptors are present on many cells of the central nervous system. Therefore, receptor signaling defects via this receptor in T lymphocytes of AD patients may be relevant to the central nervous system pathology seen in AD and DS.

Relationship between serum alpha 1-antichymotrypsin and Alzheimer's disease.

We obtained serum samples and measured alpha 1-antichymotrypsin (ACT) levels in 36 pairs of consecutive probable Alzheimer's disease (AD) patients and age- and sex-matched, cognitively intact control subjects. Serum ACT was measured by radial immunodiffusion. Unique to this study, we found that ACT levels rose significantly with age within controls (but not within AD cases), thus ACT may be related to the aging process. Consistent with other reports, we found that AD cases had greater serum ACT in 27 of 36 pairs [mean difference = 135.5 (SE = 50.8) mg/l (p < 0.05)]. Severity and duration of AD were not significantly associated with the observed difference. The ACT increase observed in AD is not sufficient to recommend ACT's use as a diagnostic marker for AD. Because adult Down's syndrome (DS) persons are known to have pathologic features of AD, we also measured serum ACT levels in 11 adult, noninstitutionalized, DS persons paired with 11 age- and sex-matched, volunteer control subjects; we found no statistically significant difference. The unexpected age-associated increase in ACT among normal controls could be an indicator of early amyloid plaque formation. Future studies comparing ACT levels in both serum and cerebrospinal fluid should help to clarify the origin of ACT found in amyloid plaques and its value as a diagnostic marker for AD.

Increased platelet membrane fluidity as a diagnostic marker for Alzheimer's disease: a test in population-based cases and controls.

To test whether increased platelet membrane fluidity as measured by decreased steady state fluorescence anisotropy (rs) of diphenylhexatriene is a biologic/diagnostic marker for Alzheimer's disease (AD), we enrolled 95 clinically diagnosed, probable AD cases from our Alzheimer's Disease Patient Registry and 133 control subjects of similar age and sex randomly selected from the same population base as the cases. We measured rs in platelet membranes following published assay procedures. Laboratory personnel and investigators were blind to the identity of the samples; cases and controls were assayed in random order. Our analyses showed that the distributions of rs values were unimodal and similar for cases and controls. The overall mean differences (control mean-case mean) for the two established assay methods tested were 0.0011 and 0.0003. A nonparametric Wilcoxon rank sum test also showed no difference between cases and controls. Multivariate analysis adjusted for the significant effects of the processing date and analysis platelet recovery led to a final model with the adjusted mean difference of 0.0007 for the principal method. Increased platelet membrane fluidity is not an antemortem diagnostic or biologic marker for AD in our population.

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.

Progression of Alzheimer's disease in black and white patients: the CERAD experience, part XVI. Consortium to Establish a Registry for Alzheimer's Disease.

We compared the progression of Alzheimer's disease (AD) in CERAD-enrolled black and white patients, as indicated by changes in selected clinical and neuropsychology measures, over a 1-year time interval. Of 225 black and 935 white AD patients who were enrolled, 148 (66%) black and 770 (82%) white patients remained in the study. Of these, 82 black and 532 white patients provided complete in-person information on first annual re-evaluation. Overall, with age, education, initial level of performance on each measure, and stage of disease at entry controlled, race had a very mild effect on change in disease (8 df multivariate analysis of variance [MANOVA], p < 0.047). Black patients showed less decline than white patients, most notably for the CERAD Boston Naming test (p < 0.02) and the third and final trial of the 10-item Word List Learning task (p < 0.003). Although unadjusted data indicate that black and white patients appear to differ notably at entry, our findings indicated that differences in progression of the dementing process are minor, suggesting that course of AD is comparable in these racial groups. Examination over a longer period is difficult because of the high attrition rate of black patients.

Interrater reliability of Alzheimer's disease diagnosis.

To determine interrater reliability of dementia diagnosis, 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients, based on a standardized set of medical record information. All patients had undergone similar examinations and follow-up to establish the initial clinical diagnosis (76% had autopsy). Raters were blind to the diagnosis and to follow-up information after the initial evaluation period. This paper presents interrater agreement (kappa values) for a diagnosis of Alzheimer's disease using the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for the clinical diagnosis of Alzheimer's disease, and the Eisdorfer and Cohen Research Diagnostic Criteria (ECRDC) for primary neuronal degeneration. The NINCDS showed somewhat higher average interrater reliability (kappa = 0.64) than the DSM-III (kappa = 0.55) and considerably higher interrater reliability than the ECRDC (kappa = 0.37). One rater displayed conspicuously lower levels of interrater reliability than the other 3, especially in DSM-III and ECRDC. This study indicates that interrater reliability of DSM-III and NINCDS criteria are comparable. Documentation of interrater reliability and, if necessary, training to improve reliability is an important consideration in research where different observers are diagnosing dementing illnesses.

Relationship between cigarette smoking and Alzheimer's disease in a population-based case-control study.

We investigated whether cigarette smoking is negatively associated with Alzheimer's disease (AD) in a population-based, frequency-matched, case-control study of 152 AD patients and 180 controls. Ever having smoked was associated with lower risk of AD (adjusted odds ratio = 0.61; 95% confidence interval: 0.37-0.99). Additional multivariate analyses demonstrated that education and history of hypertension modified this association. The direction of the modification was for higher education level and history of hypertension to further reduce the risk. The "dose-response" pattern showed the greatest risk reduction among those who smoked least and suggests a biologic mechanism of a dose-dependent up-regulation of nicotinic (cholinergic) brain receptors. These data, although consistent with current opinion about pathophysiology of AD, do not suggest smoking should be used as a preventive strategy for AD.

Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study.

OBJECTIVE: The joint effects of total cholesterol (TC) levels and the APOE genotype in Alzheimer's disease (AD) were evaluated because of previous reports that the APOE locus epsilon 4 allele was associated with both late-onset AD and elevated TC. DESIGN: Logistic regression was used to determine the effects of the APOE genotype, TC, age, and sex on prediction of AD in a community-based study of 206 cases and 276 controls. RESULTS: The relationship of the APOE genotype and AD was dependent on TC, age, and sex. However, current TC level does not fully explain the epsilon 4-Alzheimer's disease association. Affected men with higher TC and age under 80 years had the highest epsilon 4 allele frequencies. The epsilon 4 frequency declined significantly with age. SIGNIFICANCE: A pathologic role of higher TC or cholesterol-based differential survival of epsilon 4-carrying individuals may be involved in the relationship of the epsilon 4 allele with AD. The observed association of the APOE genotype and AD is expected to depend on the age, sex, and TC distributions of a given sample.

Predictors of mortality in patients diagnosed with probable Alzheimer's disease.

OBJECTIVE: We sought to identify factors associated with mortality in persons recently diagnosed with probable Alzheimer's disease (AD). BACKGROUND: Predicting mortality in AD in needed both in patient care and public health planning. Previous studies have identified several factors which contribute to mortality in AD, but few longitudinal studies of population-based cohorts exist. METHODS: In a longitudinal follow-up study 327 patients with newly diagnosed probable AD (mean Mini-Mental State Examination [MMSE] score of 20) from a large, stable health maintenance organization were identified. Demographic characteristics, dementia severity, and comorbid conditions were identified at enrollment. Patients were followed longitudinally (median 3.3 years, total 898 person-years). Baseline characteristics were used to predict survival in univariate and multivariate models. RESULTS: Increased mortality was seen in patients with probable AD (9.0 deaths per 100 person-years) compared with the community population adjusted for age and gender (4.3 deaths per 100 person-years). On univariate analysis we found increased age, male gender, impairment on MMSE or Blessed dementia rating scale (DRS), rate of MMSE decline, wandering or agitation, vascular disease, and sensory impairment affecting the ability to read or hear to be moderately associated with decreased survival. After adjusting for age and gender in a multivariate model, Blessed DRS score and sensory impairment affecting the ability to read were independently associated with decreased survival. CONCLUSIONS: Short-term mortality is increased in patients newly diagnosed with probable AD. Measures of dementia severity, measures of general debility, and vascular disease are associated with increased mortality. Of these, general debility and sensory impairment were more strongly associated with shortened survival.

Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease.

BACKGROUND: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 homozygotes have an earlier age at onset, increased amyloid burden, and decreased acetylcholine levels--findings that suggest differences in disease severity or rate of progression. Studies of genotype differences in rate of decline, however, have produced negative results that may be due to methodologic biases. The current study examined rate of decline in the largest sample of APOE-genotyped AD patients for whom longitudinal cognitive data have been reported. METHODS: Newly diagnosed patients with probable AD (n = 201) comprised four genotype groups: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (n = 30). The Dementia Rating Scale (DRS) was administered at baseline and then annually for 1 to 6 years (mean, 2.5 years). For each subject, a DRS slope was calculated reflecting annual rate of decline. Rate of decline as measured by DRS slope differed according to genotype, with the effect modified by DRS score (p < 0.014). At the mean DRS score observed in our sample (DRS = 105), the epsilon4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon2/3 (5.8 points per year; p < 0.003), epsilon3/3 (9.3 points per year; p < 0.076), and epsilon3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score (DRS = 80), even larger differences were observed among genotypes; the epsilon4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon2/3 (9.7 points per year; p < 0.0006), epsilon3/4 (15.8 points per year; p < 0.020), and epsilon3/3 (18.2 points per year; p < 0.173) groups. The epsilon2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105. CONCLUSIONS: APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 allele slows disease progression. These findings suggest that APOE plays a mechanistic role in the progression of AD, and is not simply related to disease onset.

The validity of 3 clinical diagnostic criteria for Alzheimer's disease.

To examine the validity of criteria-based (clinical) diagnosis of Alzheimer's disease (AD), 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients based on standardized medical record information. Diagnostic outcome was validated by neuropathologic examination (completed previously) for all (43) demented patients and 4 nondemented patients and by follow-up in the remainder (15) with no dementia. Raters were blind to the composition of the study group as well as to the clinical and pathologic diagnoses. We evaluated 3 diagnostic criteria sets for AD: the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the NINCDS-ADRDA Work Group criteria for the diagnosis of Alzheimer's disease (NINCDS), and the Eisdorfer and Cohen research diagnostic criteria for primary neuronal degeneration (ECRDC). ECRDC had the highest specificity (0.88) but also the greatest odds of false-negative diagnosis (LRneg = 0.61, sensitivity = 0.46). NINCDS had the best sensitivity (0.92, specificity = 0.65), and DSM-III showed intermediate values (sensitivity = 0.76, specificity = 0.80). We conclude that the investigator or clinician who wishes to ensure that patients classified as AD are more likely to be AD should choose DSM-III, whereas the investigator who wishes to include the greatest number of AD cases, seldom assigning a diagnosis of no AD to a true case, should choose NINCDS.

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.

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.

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

The Mini-Mental State Examination score and the clinical diagnosis of dementia.

To set a working cutoff score for the referral to diagnostic examination, we evaluated 150 consecutive patients with complaints potentially related to dementia, using the Mini-Mental State Examination (MMSE). All patients were later given a complete, standardized work-up and diagnosis as part of our Alzheimer's Disease Patient Registry protocol. Dementia diagnosis was made, consistent with accepted criteria, by consensus of the physicians and psychologist. Diagnosis was reaffirmed after 1-year follow-up exam; 133 of the 150 original patients completed follow-up (80 dementia, 53 no dementia). We evaluated the initial MMSE score compared with the follow-up diagnosis. Sensitivity, specificity, and predictive values were calculated for MMSE scores ranging from 22 through 29. The conventional cutoff score of < 24 shows a sensitivity of 0.63 and a specificity of 0.96; sensitivity increased at higher cutoff scores. Multivariate analysis showed that educational level added significant prediction only at scores of > or = 27. We conclude that an MMSE score of 26 or 27 should be used as a cutoff score in symptomatic populations with similar educational and socioeconomic backgrounds when the goal is to miss few true cases. Population surveys where the expected prevalence is low may require a different cutoff score to indicate the need for further diagnostic evaluation.