The incidence of MCI differs by subtype and is higher in men: the Mayo Clinic Study of Aging.

OBJECTIVE: Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. We estimated the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately. METHODS: A population-based prospective cohort of Olmsted County, MN, residents ages 70-89 years on October 1, 2004, underwent baseline and 15-month interval evaluations that included the Clinical Dementia Rating scale, a neurologic evaluation, and neuropsychological testing. A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria. RESULTS: Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI. The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7). The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5). The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2). CONCLUSIONS: The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.

Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.

OBJECTIVE: We investigated the prevalence of mild cognitive impairment (MCI) in Olmsted County, MN, using in-person evaluations and published criteria. METHODS: We evaluated an age- and sex-stratified random sample of Olmsted County residents who were 70-89 years old on October 1, 2004, using the Clinical Dementia Rating Scale, a neurologic evaluation, and neuropsychological testing to assess 4 cognitive domains: memory, executive function, language, and visuospatial skills. Information for each participant was reviewed by an adjudication panel and a diagnosis of normal cognition, MCI, or dementia was made using published criteria. RESULTS: Among 1,969 subjects without dementia, 329 subjects had MCI, with a prevalence of 16.0% (95% confidence interval [CI] 14.4-17.5) for any MCI, 11.1% (95% CI 9.8-12.3) for amnestic MCI, and 4.9% (95% CI 4.0-5.8) for nonamnestic MCI. The prevalence of MCI increased with age and was higher in men. The prevalence odds ratio (OR) in men was 1.54 (95% CI 1.21-1.96; adjusted for age, education, and nonparticipation). The prevalence was also higher in subjects who never married and in subjects with an APOE epsilon3epsilon4 or epsilon4epsilon4 genotype. MCI prevalence decreased with increasing number of years of education (p for linear trend <0.0001). CONCLUSIONS: Our study suggests that approximately 16% of elderly subjects free of dementia are affected by MCI, and amnestic MCI is the most common type. The higher prevalence of MCI in men may suggest that women transition from normal cognition directly to dementia at a later age but more abruptly.

White blood cell telomerase activity and incident respiratory illness among community-dwelling elderly vaccinated against seasonal influenza.

Immune cell telomerase activity may impact vaccine response in the elderly. Fifty persons aged 60-100 years were tested for post-influenza vaccination telomerase RNA expression (TERT) in peripheral blood mononuclear cells to assess for an association with influenza antibody levels and influenza-like illness or incident respiratory infection (IRI) in the year following vaccination. High rates of seroprotective influenza antibody (> or = 1:40 titers) were observed post-vaccination (86-92% to vaccine viral strains), with no association to TERT. No IRI occurred among persons in the top quartile of TERT expression, whereas the IRI rate was 33% in the lower three quartiles (Kaplan-Meier P=0.028). TERT expression was also IRI significantly higher in those who did not experience IRI than those who did in the follow-up period (0.845 vs. 0.301, P=0.024). These data suggest that telomerase expression may correlate with immune capacity for vaccine response in the elderly and could represent a target for recognizing risk for vaccine failure.

Mayo's Older Americans Normative Studies: Visual Form Discrimination and copy trial of the Rey-Osterrieth Complex Figure.

Age-adjusted normative data are presented for persons age 70-89 years for the Visual Form Discrimination Test and Rey-Osterrieth Complex Figure (copy trial only). Adjustment for the effect of education on test performance is also provided. These data were collected as part of Mayo's Older Americans Normative Studies (MOANS). The normative information provided here should prove useful for characterizing performance on these measures as well as comparing the person's performance against his or her functioning on any other test with MOANS norms. Limitations and unique features of the MOANS normative data are also discussed.

Mortality in amnestic mild cognitive impairment: a prospective community study.

OBJECTIVE: To assess the hazard of death in persons with and without amnestic mild cognitive impairment (aMCI). METHODS: From 1987 through 2003, persons with aMCI (n = 243) and an age- and gender-matched reference group of cognitively normal persons in Olmsted County, MN, were recruited through the Mayo Clinic Alzheimer's Disease Patient Registry and followed prospectively through 2004. Survival was estimated using Kaplan-Meier survival curves, and the hazard of death for the aMCI cohort vs the reference cohort was estimated using Cox proportional hazards models. RESULTS: Over a median follow-up of 5.7 years, persons with aMCI had increased mortality (hazard ratio [HR] = 1.7; 95% CI: 1.3 to 2.3) vs reference subjects. The hazard of death by aMCI subtype was 1.5 in persons with single-domain aMCI (95% CI: 1.1 to 2.1) and 2.9 in persons with multiple-domain aMCI (95% CI: 1.9 to 4.6) vs reference subjects. Analyses restricted to aMCI cases showed an interaction between aMCI subtype and APOE-epsilon4 allele status (p = 0.003). Among aMCI cases with an APOE-epsilon4 allele, there was no difference in mortality between single- and multiple-domain aMCI (HR = 1.2; 95% CI: 0.6 to 2.3). However, among aMCI cases with no APOE-epsilon4 allele, the hazard of death in multiple-domain aMCI was 4.6 (95% CI: 2.3 to 9.1) vs single-domain aMCI. CONCLUSIONS: Amnestic mild cognitive impairment is associated with increased mortality, which is greater in multiple-domain aMCI than in single-domain aMCI. Mortality in aMCI subtypes may vary by APOE-epsilon4 allele status.

Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI.

OBJECTIVE: To test the hypothesis that the atrophy rate measured from serial MRI studies is associated with time to subsequent clinical conversion to a more impaired state in both cognitively healthy elderly subjects and in subjects with amnestic mild cognitive impairment (MCI). METHODS: Ninety-one healthy elderly patients and 72 patients with amnestic MCI who met inclusion criteria were identified from the Mayo Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry. Atrophy rates of four different brain structures--hippocampus, entorhinal cortex, whole brain, and ventricle--were measured from a pair of MRI studies separated by 1 to 2 years. The time of the second scan marked the beginning of the clinical observation period. RESULTS: During follow-up, 13 healthy patients converted to MCI or Alzheimer disease (AD), whereas 39 MCI subjects converted to AD. Among those healthy at baseline, only larger ventricular annual percent volume change (APC) was associated with a higher risk of conversion (hazard ratio for a 1-SD increase 1.9, p = 0.03). Among MCI subjects, both greater ventricular volume APC (hazard ratio for a 1-SD increase 1.7, p < 0.001) and greater whole brain APC (hazard ratio for a 1-SD increase 1.4, p = 0.007) increased the risk of conversion to AD. Both ventricular APC (hazard ratio for a 1-SD increase 1.59, p = 0.001) and whole brain APC (hazard ratio for a 1-SD increase 1.32, p = 0.009) provided additional predictive information to covariate-adjusted cross-sectional hippocampal volume at baseline about the risk of converting from MCI to AD. DISCUSSION: Higher whole brain and ventricle atrophy rates 1 to 2 years before baseline are associated with an increased hazard of conversion to a more impaired state. Combining a measure of hippocampal volume at baseline with a measure of either whole brain or ventricle atrophy rates from serial MRI scans provides complimentary predictive information about the hazard of subsequent conversion from mild cognitive impairment to Alzheimer disease. However, overlap among those who did vs those who did not convert indicate that these measures are unlikely to provide absolute prognostic information for individual patients.

DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment.

The authors assessed whether measures of hippocampal water diffusivity at baseline can predict future progression to Alzheimer disease (AD) in amnestic mild cognitive impairment (aMCI). Higher baseline hippocampal diffusivity was associated with a greater risk of progression to AD in aMCI (p = 0.002). Magnetic resonance diffusion-weighted imaging may help identify patients with aMCI who will progress to AD as well as or better than structural MRI measures of hippocampal atrophy.

1H MR spectroscopy in common dementias.

OBJECTIVE: To determine the 1H MR spectroscopic (MRS) findings and intergroup differences among common dementias: Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). METHODS: The authors consecutively recruited 206 normal elderly subjects and 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. The 1H MRS metabolite ratio changes in common dementias were evaluated with respect to normal and also differences among the common dementias. RESULTS: N-acetylaspartate (NAA)/creatine (Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD or between patients with DLB and VaD. NAA/Cr was lower in patients with AD and FTLD than DLB. MI/Cr was higher in patients with AD and FTLD than VaD. MI/Cr was also higher in patients with FTLD than DLB. CONCLUSIONS: NAA/Cr levels are decreased in dementias that are characterized by neuron loss, such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis, such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit, such as AD and DLB.

Mild cognitive impairment: a cross-national comparison.

OBJECTIVE: The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). METHODS: Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. RESULTS: When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. CONCLUSIONS: Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.

Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD.

OBJECTIVE: To correlate different methods of measuring rates of brain atrophy from serial MRI with corresponding clinical change in normal elderly subjects, patients with mild cognitive impairment (MCI), and patients with probable Alzheimer disease (AD). METHODS: One hundred sixty subjects were recruited from the Mayo Clinic Alzheimer's Disease Research Center and Alzheimer's Disease Patient Registry Studies. At baseline, 55 subjects were cognitively normal, 41 met criteria for MCI, and 64 met criteria for AD. Each subject underwent an MRI examination of the brain at the time of the baseline clinical assessment and then again at the time of a follow-up clinical assessment, 1 to 5 years later. The annualized changes in volume of four structures were measured from the serial MRI studies: hippocampus, entorhinal cortex, whole brain, and ventricle. Rates of change on several cognitive tests/rating scales were also assessed. Subjects who were classified as normal or MCI at baseline could either remain stable or convert to a lower-functioning group. AD subjects were dichotomized into slow vs fast progressors. RESULTS: All four atrophy rates were greater among normal subjects who converted to MCI or AD than among those who remained stable, greater among MCI subjects who converted to AD than among those who remained stable, and greater among fast than slow AD progressors. In general, atrophy on MRI was detected more consistently than decline on specific cognitive tests/rating scales. With one exception, no differences were found among the four MRI rate measures in the strength of the correlation with clinical deterioration at different stages of the disease. CONCLUSIONS: These data support the use of rates of change from serial MRI studies in addition to standard clinical/psychometric measures as surrogate markers of disease progression in AD. Estimated sample sizes required to power a therapeutic trial in MCI were an order of magnitude less for MRI than for change measures based on cognitive tests/rating scales.

Comparison of memory fMRI response among normal, MCI, and Alzheimer's patients.

OBJECTIVE: To determine whether an fMRI memory encoding task distinguishes among cognitively normal elderly individuals, patients with mild cognitive impairment (MCI), and patients with early Alzheimer's disease (AD). METHODS: Twenty-nine subjects (11 normal, 9 MCI, 9 AD) were studied with an fMRI memory encoding task. A passive sensory task was also performed to assess potential intergroup differences in fMRI responsiveness. Activation in the medial temporal lobe for the memory task and in the anatomic rolandic area for the sensory task was studied. Intergroup comparisons were performed using receiver operating characteristic (ROC) analyses. The ROC method provides rigorous control of artifactual false-positive "activation." Subjects were tested for recall and recognition of the encoding task stimuli following the fMRI study. RESULTS: Medial temporal lobe activation was greater in normal subjects than MCI and AD patients (p = 0.03 and p = 0.04). There was no difference between AD and MCI patients in fMRI memory performance [corrected]. There was an association between fMRI memory activation (area under the ROC curve) and post-fMRI performance on recognition and free recall. There was no difference among the three groups on the sensory task. CONCLUSIONS: MCI and AD patients had less medial temporal lobe activation on the memory task than the normal subjects but similar activation as normal subjects on the sensory task. These findings suggest decreased medial temporal activation may be a specific marker of limbic dysfunction due to the neurodegenerative changes of AD. In addition, fMRI is sufficiently sensitive to detect changes in the prodromal, MCI, phase of the disease.

Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE).

Insulin degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid peptide implicated in Alzheimer's disease (AD). We reexamined data on five previously reported IDE polymorphisms stratifying the analysis by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele. Three IDE variants were associated with AD within epsilon4-negative subjects (genotype exact test P-values < or =0.02). A haplotype containing the minor variant at each of these sites represented an estimated 4.2% of case haplotypes versus 12.3% of control haplotypes among epsilon4-negative subjects. Lack of this minor haplotype may be predictive of AD, potentially explaining some fraction of disease within subjects without the APOE epsilon4 risk allele. Confirmation of this finding with a larger sample of cases and controls is warranted.

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.

Total intracranial volume: normative values and lack of association with Alzheimer's disease.

A larger premorbid brain is hypothesized to provide neuronal reserve against AD. Using MRI data from ongoing studies of normal aging and AD, the authors tested this hypothesis. Mean total intracranial volume was 15.8 cm(3) smaller for cases among women (n = 121 normal and 104 AD; p = 0.24) and 10.1 cm(3) larger for cases among men (n = 63 normal and 62 AD; p = 0.59). These differences are small and nonsignificant, suggesting that head size per se is not a critical determinant of AD.

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.

Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: The goal of this project was to determine whether screening different groups of elderly individuals in a general or specialty practice would be beneficial in detecting dementia. BACKGROUND: Epidemiologic studies of aging and dementia have demonstrated that the use of research criteria for the classification of dementia has yielded three groups of subjects: those who are demented, those who are not demented, and a third group of individuals who cannot be classified as normal or demented but who are cognitively (usually memory) impaired. METHODS: The authors conducted computerized literature searches and generated a set of abstracts based on text and index words selected to reflect the key issues to be addressed. Articles were abstracted to determine whether there were sufficient data to recommend the screening of asymptomatic individuals. Other research studies were evaluated to determine whether there was value in identifying individuals who were memory-impaired beyond what one would expect for age but who were not demented. Finally, screening instruments and evaluation techniques for the identification of cognitive impairment were reviewed. RESULTS: There were insufficient data to make any recommendations regarding cognitive screening of asymptomatic individuals. Persons with memory impairment who were not demented were characterized in the literature as having mild cognitive impairment. These subjects were at increased risk for developing dementia or AD when compared with similarly aged individuals in the general population. RECOMMENDATIONS: There were sufficient data to recommend the evaluation and clinical monitoring of persons with mild cognitive impairment due to their increased risk for developing dementia (Guideline). Screening instruments, e.g., Mini-Mental State Examination, were found to be useful to the clinician for assessing the degree of cognitive impairment (Guideline), as were neuropsychologic batteries (Guideline), brief focused cognitive instruments (Option), and certain structured informant interviews (Option). Increasing attention is being paid to persons with mild cognitive impairment for whom treatment options are being evaluated that may alter the rate of progression to dementia.

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.

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including beta-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5'-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5' flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK ( P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.