Mild cognitive impairment in the oldest old.

BACKGROUND: No data exist on whether the syndrome of amnestic mild cognitive impairment occurs in the oldest old, or if the relationships for functional status and neuropsychometric performance based on clinical diagnosis hold true in this age group. DESIGN/METHODS: The authors performed comprehensive neurologic evaluations, neuropsychometric testing, and functional assessments on a sample of 90- to 100-year-old residents of Rochester, MN. Subjects were diagnosed as normal or with amnestic mild cognitive impairment (MCI) or dementia according to well-accepted criteria. Data on the following measures were collected and analyzed: Record of Independent Living (ROIL), Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), Trailmaking Test (TMT), and modified version of the Free and Cued Selective Reminding Test (FCSRT). RESULTS: Data on 111 subjects (56 normal, 13 MCI, and 42 dementia) were analyzed. On the ROIL, functional capacity to carry out activities of daily living was worse for patients with dementia compared to patients with MCI and normal subjects, but did not differ between MCI and normal subjects. Scores on the MMSE, DRS, and TMT-A were worse in the dementia group compared to the normal group, and in the dementia group compared to MCI, but scores on these measures for normal subjects compared to patients with MCI were not different. Scores on the FCSRT and memory subtest of the DRS showed differences among all three groups. CONCLUSION: In spite of the advanced age of the cohort, the relationship between cognitive and functional performance and clinical diagnosis follows patterns previously described in younger samples of normal subjects, subjects with amnestic mild cognitive impairment, and subjects with dementia.

Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia.

OBJECTIVES: To assess the diagnostic specificity of MRI-defined hippocampal atrophy for AD among individuals with a variety of pathologically confirmed conditions associated with dementia as well as changes attributable to typical aging, and to measure correlations among premortem MRI measurements of hippocampal atrophy, mental status examination performance, and the pathologic stage of AD. METHODS: An unselected series of 67 individuals participating in the Mayo Alzheimer's Disease Research Center/Alzheimer's Disease Patient Registry who had undergone a standardized antemortem MRI study and also postmortem examination were identified. Hippocampal volumes were measured from antemortem MRI. Each postmortem specimen was assigned a pathologic diagnosis and in addition, the severity of AD pathology was staged using the method of Braak and Braak. RESULTS: Individuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis, frontotemporal degeneration, and neurofibrillary tangle--only degeneration usually had substantial hippocampal atrophy, while those with changes of typical aging did not. Among all 67 subjects, correlations (all p < 0.001) were observed between hippocampal volume and Braak and Braak stage (r = -0.39), between hippocampal volume and Mini-Mental State Examination (MMSE) score (r = 0.60), and between MMSE score and Braak and Braak stage (r = -0.41). CONCLUSIONS: Hippocampal atrophy, while not specific for AD, was a fairly sensitive marker of the pathologic AD stage (particularly among subjects with isolated AD pathology [r = -0.63, p = 0.001]) and consequent cognitive status.

Prospective analysis of risk factors for nursing home placement of dementia patients.

OBJECTIVE: To examine risk factors for nursing home placement in a community-based dementia cohort. METHODS: Cognitively normal participants and cognitively impaired patients from a large AD Patient Registry were followed from diagnosis to placement, death, or last follow-up. This included over 3,600 person-years of surveillance. The normal group included 473 participants who did not, at any point, meet Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R) criteria for dementia. The patient group included 512 patients who met DSM-III-R criteria for dementia or criteria for mild cognitive impairment at diagnosis. Demographic, medical, social, cognitive, behavioral, and functional predictors of time to placement were examined using Cox modeling. RESULTS: In the normal group, only 21 people (4%) required nursing home placement. With subjects, enrollment year, age at initial evaluation, being widowed, and living in a retirement community were associated with time to placement in separate univariate analyses. Of 512 cognitively impaired patients, 203 (39.6%) were placed in nursing homes. Median time from diagnosis to placement was 5.3 years. Within the patient sample, four predictors were determined to be associated with time to nursing home placement. These included gender, enrollment year, functional status, and cognitive score. Interactions were present for functional status with cognitive score and enrollment year. CONCLUSION: In patients with dementia who are within 5 years of diagnosis, placement rates of approximately 10% per year can be expected. Disease severity indices including degree of cognitive and functional impairment are primary risk factors for placement.

Mild cognitive impairment and Alzheimer disease: regional diffusivity of water.

PURPOSE: To compare the regional diffusivity of water in the brains of normally aging elderly people and patients with mild cognitive impairment (MCI) or Alzheimer disease. MATERIALS AND METHODS: Magnetic resonance images were obtained in 21 patients with Alzheimer disease, 19 patients with MCI, and 55 normally aging elderly control subjects without evidence of cognitive impairment. Regions of interest were drawn to compare the apparent diffusion coefficient (ADC) and the anisotropy index (AI) in frontal, parietal, temporal, occipital, anterior, and posterior cingulate white matter (WM), and the thalami and hippocampi. RESULTS: Hippocampal ADC was higher in MCI and Alzheimer disease patients than in control subjects. ADC of the temporal stem and posterior cingulate, occipital, and parietal WM was higher in Alzheimer disease patients than in control subjects. Except for occipital AI, which was lower in MCI patients than in control subjects, there were no differences in AI among the three groups for any of the regions. CONCLUSION: Hippocampal ADC was significantly different between control subjects and MCI patients, many of whom likely have preclinical Alzheimer disease. Elevation in hippocampal ADC may reflect early ultrastructural changes in the progression of Alzheimer disease.

Rates of hippocampal atrophy correlate with change in clinical status in aging and AD.

BACKGROUND: The cognitive continuum in the elderly population can be conceptually divided into those who are functioning normally (control subjects), those with a mild cognitive impairment (MCI), and those with probable AD. OBJECTIVES: To test the hypothesis that the annualized rates of hippocampal atrophy differ as a function of both baseline and change in clinical group membership (control, MCI, or AD). METHODS: The authors identified 129 subjects from the Mayo Clinic AD Research Center/AD Patient Registry who met established criteria for normal control subjects, MCI, or probable AD, both at entry and at the time of a subsequent clinical follow-up evaluation 3 +/- 1 years later. Each subject underwent an MRI examination of the head at the time of the initial assessment and at follow-up clinical assessment; the annualized percentage change in hippocampal volume was computed. Subjects who were classified as controls or patients with MCI at baseline could either remain cognitively stable or could decline to a lower functioning group over the period of observation. RESULTS: The annualized rates of hippocampal volume loss for each of the three initial clinical groups decreased progressively in the following order: AD > MC > control. Within the control and MCI groups, those who declined had a significantly greater rate of volume loss than those who remained clinically stable. The mean annualized rates of hippocampal atrophy by follow-up clinical group were: control-stable 1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%, AD 3. 5%. CONCLUSION: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the cognitive continuum from normal to MCI to AD.

Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study.

BACKGROUND: Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. METHODS: The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. RESULTS: The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. CONCLUSION: These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.

Usefulness of MRI measures of entorhinal cortex versus hippocampus in AD.

OBJECTIVE: MRI-based measurements of hippocampal atrophy are a sensitive indicator of the early pathologic degeneration of the medial temporal lobe in AD. However, AD pathology appears first in the transentorhinal/entorhinal cortex, not the hippocampus. The authors tested the hypothesis that MRI-based measurements of the entorhinal cortex are more sensitive than measurements of hippocampal volume in discriminating among three clinical groups; controls, patients with a mild cognitive impairment (MCI), and patients with mild probable AD. METHODS: The authors studied 30 controls, 30 patients with MCI, and 30 patients with AD who were matched among clinical groups on age, gender, and education. All underwent a standardized MRI protocol from which the authors made measurements of hippocampal volume, entorhinal cortex volume, and the cumulative length of the medial border of the entorhinal cortex. RESULTS: Pairwise intergroup differences (p < 0.01) were found for all MRI measurements with the exception of the cumulative length of the entorhinal cortex, which did not differentiate controls from MCI patients. Whereas the hippocampal and entorhinal cortex volume measurements provided slightly better intergroup discrimination than the entorhinal distance measurement, overall differences in discriminating ability among the three MRI measurements were minor. CONCLUSIONS: Despite the theoretical rationale for the superiority of entorhinal measurements in early AD, the authors found MRI measurements of the hippocampus and entorhinal cortex were approximately equivalent at intergroup discrimination. Measurements of the hippocampus may be preferable because MRI depiction of the boundaries of the entorhinal cortex can be obscured by anatomic ambiguity, image artifact, or both.

Risk factors for nursing home placement in a population-based dementia cohort.

OBJECTIVE: To examine risk factors for nursing home placement in a population-based dementia cohort. METHODS: The Mayo Clinic Medical Records linkage system was used to identify all patients with onset of dementia between 1980 and 1984. The patient group included 314 cases who met DSM-III-R criteria for dementia, including 220 cases who were community dwelling at onset. All dementia patients were followed until death. A control group included 323 patients who did not, at any point, meet DSM-III-R criterion for dementia. The groups were initially matched on age, gender, and year of initial registration. Demographic, medical, social, and functional predictors were examined as static and time-dependent risk factors for nursing home placement in the initial community-dwelling subgroups, using stepwise Cox regression modeling. RESULTS: Of the 314 dementia patients, 282 took residence in licensed skilled nursing homes for at least 6 weeks, suggestive of custodial care, at some point during the course of their illness. In the control group, 162 of the 323 people required nursing home placement. Within controls, the predictor variables of time to nursing home placement included initial age, being divorced, living in a townhome, apartment or assisted living apartment, change in Charlson comorbidity score, and change in amount of daily assistance required. Within the dementia sample, seven predictors were eventually determined to be associated with time to nursing home placement. These included total number of years of education, age at onset of dementia, being single, living in a retirement or supervised apartment at onset, change in Charlson comorbidity score, and a change in the amount of daily assistance required. CONCLUSIONS: Cumulative incidence of placement was 90% in the dementia cohort and 50% in the controls. Certain variables seem to impact time to nursing home placement in all older persons, whether they have dementia or not. Among these are age, living in assisted living settings, increasing comorbidity scores, and increasing need for functional assistance. Certain additional factors may have a specific impact in dementia. Among these is education, which seems to provide a protective effect. These predictors may be important covariates in clinical dementia studies that include time to nursing home placement as an outcome variable.

No association between TAU haplotype and Alzheimer's disease in population or clinic based series or in familial disease.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.

Diagnostic accuracy of four approaches to interpreting neuropsychological test data.

The diagnostic accuracy of 4 approaches to interpreting neuropsychological test results are evaluated in 672 cognitively normal and 407 cognitively impaired persons using the Mayo Cognitive Factor Scales (G. E. Smith et al., 1994). The interpretation approaches studied are absolute scores, difference scores, profile variability, and change scores at 1- to 2-year test-retest intervals. All dependent measures were "highly significant" when diagnostic groups were compared on null hypothesis significance testing analyses. In contrast, varied accuracy rates were obtained when each measure's ability to correctly classify individuals was evaluated relative to overall diagnostic accuracy. Odds ratios were also highly varied and ranged from < or = 1.0 (i.e., chance) to 34.9. The clinical usefulness of absolute scores and difference scores in data interpretation is supported. Neither profile variability measures nor measures of change over time were diagnostically useful.

Memory and MRI-based hippocampal volumes in aging and AD.

OBJECTIVE: To demonstrate structural-functional relationships between MRI-based volumetric measurements of medial temporal lobe structures and cognitive function. BACKGROUND: Previous work has documented the ability of MRI-based measurements of the hippocampus to discriminate between age-matched control subjects and patients with very mild AD. Relatively less is known about the correlation between medial temporal lobe structures and cognitive functions. METHOD: We evaluated structural-functional relationships among the hippocampal formation, parahippocampal gyrus, and amygdala, and measures of memory, language, and general cognitive performance in 220 probable AD patients and normal control subjects. Standardized instruments of memory and general cognitive function were used to assess subjects enrolled in a longitudinal study of aging and dementia. RESULTS: The volume of the hippocampal formation predicted performance on most acquisition and recall measures across the spectrum of normal aging and AD. If the groups were segregated, most of the expected associations between medial temporal lobe structures and memory measures were observed in the AD patients. CONCLUSION: MRI-based hippocampal volumetry accurately depicts the structural-functional relationships between memory loss and hippocampal damage across the spectrum from normal aging to dementia.

Frequency and distribution of vascular dementia.

It remains difficult to draw conclusions about the frequency and distribution of vascular dementia (VaD). The data from current studies cannot be compared and reconciled easily. Disagreement on diagnostic criteria and their field implementation remains the major problem. In particular, there is uncertainty about the classification of patients who show both vascular and degenerative features, about the advantages and disadvantages of using brief clinical scales (e.g., the Hachinski Ischemic Score), about the use of imaging findings in defining VaD, and about the minimal level of severity to be included in epidemiologic studies. Nevertheless, we can tentatively summarize current epidemiologic data in four points. (1) Both the prevalence and the incidence of VaD increase steeply with age. (2) The prevalence of VaD is generally higher among men than among women; the sex difference is more controversial for incidence. (3) There are sizeable differences in both incidence and prevalence across countries. (4) A declining trend in both the prevalence and the incidence of VaD was reported from one population; however, the decline was restricted to the age class 80-89 years. No trends data are available after the 1970s.

Pathologic heterogeneity in clinically diagnosed corticobasal degeneration.

BACKGROUND: Early reports suggested that corticobasal degeneration (CBD) is a distinct clinicopathologic entity. Because patients have had a fairly consistent constellation of clinical and laboratory findings, many have proposed that the pathologic diagnosis can be surmised with confidence during life. OBJECTIVE: To analyze the pathologic findings in a large series of cases with clinically diagnosed CBD. METHODS: Using the medical research linkage system of the Mayo Clinic for the period January 1990 to December 1997, we identified cases diagnosed during life with CBD who subsequently underwent autopsy. All patients had progressive asymmetric rigidity and apraxia (except one with rigidity but no apraxia) with other findings, suggesting additional cortical and basal ganglionic dysfunction. All cases underwent standardized neuropathologic examination with the distribution and severity of the pathologic changes determined for each case and the pathologic diagnoses based on currently accepted criteria. RESULTS: Thirteen cases were identified. The pathologic diagnoses were CBD in seven, AD in two, and one each for progressive supranuclear palsy, Pick's disease, nonspecific degenerative changes, and Creutzfeldt-Jakob disease. Two cases had negligible basal ganglia and nigral degeneration despite previously having obvious extrapyramidal signs. However, all patients had focal or asymmetric cortical atrophy with coexisting neuronal loss and gliosis with or without status spongiosis, which was maximal in the parietal and frontal cortical regions. CONCLUSIONS: The constellation of clinical features considered characteristic of CBD is associated with heterogeneous pathologies. Furthermore, this syndrome can occur in the absence of basal ganglia and nigral degeneration. The one invariable pathologic abnormality in patients with this syndrome, however, is asymmetric parietofrontal cortical degeneration. At present, accurate diagnosis of CBD requires tissue examination.

Use of physician and acute care services by persons with and without Alzheimer's disease: a population-based comparison.

OBJECTIVE: To estimate differences in use of acute care services between persons with and without Alzheimer's disease (AD). STUDY DESIGN: Population-based historical cohort study. SETTING/SUBJECTS: All Rochester, Minnesota, residents with AD onset between January 1, 1980, and December 31, 1984 (n = 301), plus one age- and sex-matched nondemented control per case, were identified with a retrospective review of community-based medical records. MEASUREMENTS: Cases and controls were followed in their medical records for number of acute care encounters in the year before January 1 of the index year (year of onset for AD case and their matched control) and in the 4 years following December 31 of the index year. Encounters included clinician visits (office or nursing home), emergency room (ER) visits, hospitalizations (inpatient and outpatient), and inpatient days. Multivariate regression analyses were adjusted for age, sex, pre-index level of illness, and follow-up time. RESULTS: In the pre-index period, cases and controls were similar with respect to level of illness, number of office visits, ER visits, and hospitalizations. In the year before AD onset, 17 cases (7%) had a clinician visit in the nursing home compared with no controls. In the 4 years after the index year, mean length of follow-up was 3.4 years for both cases and controls. The numbers of ER visits, hospitalizations, and inpatient days were similar for cases and controls. Sixty-four percent of AD cases had a clinician visit in a nursing home versus 1% of controls. Controls experienced more office visits than cases (median = 16 vs 10, P < .001). CONCLUSIONS: The onset of AD is not associated with greater use of acute care services. However, neither is the high use of nursing home care offset by fewer ER or hospital encounters.

Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment.

OBJECTIVE: To test the hypothesis that MRI-based measurements of hippocampal volume are related to the risk of future conversion to Alzheimer's disease (AD) in older patients with a mild cognitive impairment (MCI). BACKGROUND: Patients who develop AD pass through a transitional state, which can be characterized as MCI. In some patients, however, MCI is a more benign condition, which may not progress to AD or may do so slowly. PATIENTS: Eighty consecutive patients who met criteria for the diagnosis of MCI were recruited from the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry. METHODS: At entry into the study, each patient received an MRI examination of the head, from which the volumes of both hippocampi were measured. Patients were followed longitudinally with approximately annual clinical/cognitive assessments. The primary endpoint was the crossover of individual MCI patients to the clinical diagnosis of AD during longitudinal clinical follow-up. RESULTS: During the period of longitudinal observation, which averaged 32.6 months, 27 of the 80 MCI patients became demented. Hippocampal atrophy at baseline was associated with crossover from MCI to AD (relative risk [RR], 0.69, p = 0.015). When hippocampal volume was entered into bivariate models-using age, postmenopausal estrogen replacement, standard neuropsychological tests, apolipoprotein E (APOE) genotype, history of ischemic heart disease, and hypertension-the RRs were not substantially different from that found univariately, and the associations between hippocampal volume and crossover remained significant. CONCLUSION: In older patients with MCI, hippocampal atrophy determined by premorbid MRI-based volume measurements is predictive of subsequent conversion to AD.

Mild cognitive impairment: clinical characterization and outcome.

BACKGROUND: Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials. OBJECTIVE: To characterize clinically subjects with MCI cross-sectionally and longitudinally. DESIGN: A prospective, longitudinal inception cohort. SETTING: General community clinic. PARTICIPANTS: A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn. MAIN OUTCOME MEASURES: The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale-Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, respectively. RESULTS: The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD. CONCLUSIONS: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.

REM sleep behavior disorder and dementia: cognitive differences when compared with AD.

OBJECTIVE: To determine whether the dementia associated with REM sleep behavior disorder (RBD) differs from Alzheimer's disease (AD) and, if so, whether differences in cognitive performance between RBD/dementia and AD resemble reported differences between dementia with Lewy bodies (DLB) and AD. METHODS: This retrospective study compares neurocognitive performance between 31 patients with degenerative dementia and polysomnography-confirmed RBD and 31 patients without brainstem Lewy body pathology who met Consortium to Establish a Registry for Alzheimer's Disease (CERAD) clinical and neuropathologic criteria for AD. The patient groups did not differ in dementia severity (based on Global Deterioration Scale score) or duration. RESULTS: RBD preceded or coincided with the onset of cognitive decline in 94% of the patients. All but one patient with RBD/dementia had one or more of the following clinical features of DLB: visual hallucinations, extrapyramidal signs, or fluctuating cognition/alertness. The data revealed significantly worse performance on attention, perceptual organization, visual memory, and letter fluency for the RBD/dementia group, whereas the AD group showed significantly worse performance on confrontation naming and verbal memory. CONCLUSIONS: Patients with RBD and degenerative dementia demonstrate a significantly different pattern of cognitive performance from patients with AD. Most of the patients in the RBD/dementia sample also meet criteria for possible or probable DLB, and the pattern of cognitive differences from AD is similar to reported comparisons between DLB and AD. The cognitive and clinical data provide evidence to suggest that the dementia associated with RBD may represent DLB.

Postmenopausal estrogen replacement therapy and risk of AD: a population-based study.

OBJECTIVE: To study the association between estrogen replacement therapy in postmenopausal women and AD using a case-control design. BACKGROUND: Studies of the effect of estrogen therapy on the risk of AD have been limited and have yielded conflicting results. METHODS: Case patients were all postmenopausal women who developed AD in the quinquennium 1980 through 1984 in Rochester, MN (n = 222). One control subject from the same population and free of dementia was matched to each case patient by age (+/-3 years) and length of enrollment in the records-linkage system (n = 222). Estrogen exposure was defined as any form of estrogen (oral, parenteral, topical, suppository) used for at least 6 months after the onset of menopause and before the onset of AD (or corresponding year in the matched control subject). Information on dose and duration of use was abstracted. Consistent with the matched design, analyses entailed conditional logistic regression. RESULTS: AD patients and control subjects had identical age at menarche (median: 13.0 versus 13.0 years) and age at menopause (median: 50.0 versus 50.0 years). The frequency of estrogen use was higher among control subjects than AD patients (10% versus 5%; odds ratio = 0.42; 95% confidence interval 0.18 to 0.96; p = 0.04). There was a significant trend of decreasing odds ratios with increasing duration of use. The inverse association between estrogen therapy and AD remained significant after adjustment for education and age at menopause. CONCLUSION: These results from a population-based study suggest that estrogen replacement therapy is associated with a reduced risk of AD in postmenopausal women.

A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease.

Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missense mutation (T-->C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (>60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.

Testing normal older people three or four times at 1- to 2-year intervals: defining normal variance.

Normative data were presented that defined the upper and lower standards for deciding if cognitive abilities show reliable change over 2 or more testing occasions when retesting occurs at 1- to 2-year intervals. The Mayo Cognitive Factor Scores (MCFS; G. E. Smith et al., 1994) were analyzed because they permit the quantitation of overall functioning in 5 clinically important cognitive domains: established verbal knowledge, nonverbal reasoning, attention and concentration, new learning, and delayed memory. To the authors' knowledge, this is the first report of both group-level and individual-level data analyses derived from a respectably sized sample of normal persons who have been tested 3 or more times at clinically common test-retest intervals.