Walter A. Kukull

Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid β-protein precursor (APP) mutations linked to familial Alzheimers disease (FAD) increase the extracellular concentration of amyloid β–protein (Aβ) ending at Aβ42(43) in vivo, we performed a blinded comparison of plasma Aβ levels in carriers of these mutations and controls. Aβ1 –42(43) was elevated in plasma from subjects with FAD–linked PS1 (P < 0.0001), PS2N141I (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV717I (one subject) mutations. Aβ ending at Aβ42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or P52 (P = 0.03) mutations. These findings indicate that the FAD–linked mutations may all cause Alzheimers disease by increasing the extracellular concentration of Aβ42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older

Context Some studies suggest that people with high levels of physical activity are less likely to develop dementia. Content All 1740 participants in this cohort study were 65 years of age or older and were cognitively intact at baseline. Over 6.2 years, the rate of dementia was 13.0 per 1000 person-years in those who exercised 3 or more times per week and 19.7 per 1000 person-years in those who exercised less than 3 times per week. Limitations The only measure of exercise intensity was self-reported frequency. The cohort was largely white and well-educated. Implications This study adds to the evidence that regular exercise is associated with a lower risk for dementia. However, the existing evidence does not prove that regular exercise is associated with a lower dementia risk. The Editors Alzheimer disease and other dementing illnesses are major sources of morbidity and mortality (1-3) that affect millions of persons in the increasingly aging society of the United States. Research designed to discover strategies to delay onset and progression of these potentially devastating illnesses is ongoing worldwide. Effective prevention strategies would result in substantial benefits through improved quality of life, prolonged independent life expectancy, and reduced economic cost and social burdens. Regular physical exercise is an important element in overall health promotion (4) and might also be an effective strategy to delay onset of dementia (5). A biological basis for how physical exercise might preserve brain function includes improved cerebral blood flow and oxygen delivery (6) and inducing fibroblast growth factor in the hippocampus (7). More recent evidence suggests that reduced loss of hippocampal brain tissue in the aging brain is related to level of physical fitness (8). Evidence from some longitudinal studies and randomized trials suggests that physical exercise enhances cognitive function in older adults (9-15), whereas other studies have failed to observe the benefits of physical exercise in preserving cognitive function (16-19). Many people regard Alzheimer disease as one of the most dreaded consequences of aging. If regular physical exercise were shown to be effective in reducing the risk or delaying the onset of dementing illnesses, it would be another compelling reason to promote physical exercise. Few population-based longitudinal studies have examined the role of physical exercise on the risk for dementia in elderly persons. One recent longitudinal study showed that physical exercise was associated with decreased risk for decline in cognitive function (odds ratio [OR], 0.58), Alzheimer disease (OR, 0.50), and any dementia (OR, 0.63) (11), whereas another longitudinal study showed no association between physical exercise and dementia (16). More recent studies showed that walking was associated with a reduced risk for dementia and Alzheimer disease in a cohort of Japanese-American men (20) and that engaging in more diverse physical activities was associated with a reduced risk for dementia in the Cardiovascular Health Study (21). The purpose of this study was 2-fold: 1) to determine whether regular exercise is associated with a reduced risk for incidence of dementia (in particular, Alzheimer disease) in a cohort followed biennially over 6 years and 2) to examine whether the association of physical exercise with incident dementia is modulated by other potential risk factors, such as depression, cardiovascular and cerebrovascular disease, diabetes, apolipoprotein E 4 allele, cognitive function, physical function, self-rated health, and lifestyle characteristics. Methods Study Sample The Adult Changes in Thought (ACT) study is a population-based, longitudinal study of aging and dementia. The ACT study was designed to determine the incidence of Alzheimer disease, other types of dementia, and cognitive impairment as well as to determine risk factors for these conditions. The details of the ACT study have been described elsewhere (22, 23). Briefly, a random sample of 6782 individuals was drawn from Seattle-area members of Group Health Cooperative (GHC), a consumer-governed health maintenance organization. The participants were 65 years of age and older when the study began in 1994 to 1996. Those who had an existing diagnosis of dementia, were current residents of a nursing home, or were participating in other studies were ineligible (n= 1360). Of 5422 eligible persons, 2581 participated and 2841 declined participation. Age, sex, and ethnicity of the remaining 2581 participants did not differ significantly from those who were excluded. Nonresponse has been described elsewhere (22). Declining to participate was more common among the oldest age group (>85 years), women, and African-American and minority groups (22). Additional details regarding the incident rates of dementia and Alzheimer disease from the ACT study have been published elsewhere and are consistent with rates reported in U.S. and European cohort studies (22). The institutional review boards of the University of Washington and Group Health Cooperative approved the ACT study. Participants received the Cognitive Ability Screening Instrument (CASI) (24) as initial screening for cognitive function and were interviewed with structured questionnaires to obtain data, including demographic characteristics, medical history, memory and general functioning, and potential epidemiologic risk factors. Persons scoring 86 or higher on the CASI were entered directly into the ACT cohort as being cognitively intact. (The CASI scores range from 0 to 100; a score of 86 corresponds to a Mini-Mental State Examination score of 25 to 26.) Persons with a score lower than 86 had additional medical record review and standardized clinical and neuropsychological evaluation for dementia. Persons who did not meet established criteria for dementia (25) were included in the ACT cohort. The current study sample was selected from the 2581 ACT participants to examine the temporal relationship of physical exercise preceding development of dementia. By design, we selected the 1895 persons whose CASI scores were above the 25th percentileCASI scores 91 to 100. We excluded 686 persons whose CASI scores were in the lowest quartileCASI scores 62 to 90because the lowest quartile group might include persons who had mild cognitive impairment or impending dementia (26). We did not collect information about the history of exercise before the participants entered the study. Therefore, in the group with low CASI scores, we could not be certain whether a reported low level of physical exercise preceded the development of dementia or was a consequence of the development of cognitive impairment or dementia. Of 1895 participants selected, 155 withdrew after the baseline visit and did not have a follow-up examination and were thus excluded from the analyses, leaving the analytic sample of 1740 persons. Incident Dementia We conducted biennial examinations to identify cases of incident dementia, when participants were rescreened with the CASI. Those who scored 86 or higher on the CASI remained in the ACT cohort. Scores on the CASI that were less than 86 at follow-up prompted a full standardized clinical examination. The results of rescreening by the CASI and by the clinical and neuropsychological examinations were reviewed at a consensus diagnosis conference that included at least the examining physician, a neuropsychologist, another study physician, and the study nurse. Persons who did not meet the criteria for dementia were considered as not having dementia and were followed in the ACT cohort (22, 23). Persons who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria (25) for dementia were considered to have incident dementia. Dementia type was determined by the National Institute of Neurological and Communicative Diseases and Stroke-Alzheimers Disease and Related Disorders Association (NINCDS-ADRDA) criteria (27) for Alzheimer disease and by the DSM-IV criteria (25) for other types of dementia. Level of physical activity was not considered at the consensus conference. Physical Exercise Physical exercise was assessed at baseline by asking participants the number of days per week they did each of the following activities for at least 15 minutes at a time during the past year: walking, hiking, bicycling, aerobics or calisthenics, swimming, water aerobics, weight training or stretching, or other exercise. The frequency of exercise was calculated by the times per week that participants engaged in any of these forms of exercise. In this study, persons who exercised at least 3 times a week, above the lowest quartile, were classified as exercising regularly. Baseline Variables as Potential Confounders Numerous factors may influence the relationship between exercise and risk for dementia, including physical functioning, cognitive function, depression, health conditions, and lifestyle characteristics. Physical function was assessed by a performance-based physical function (PPF) test (23), which consisted of 4 performance tests: 10-foot timed walk, time to stand from a seated position in a chair to a standing position 5 times, balance test, and grip strength in the dominant hand. Each test was scored from 0 to 4 points. The final PPF score was the sum of the scores for the 4 performance tests and ranged from 0 to 16; higher scores indicated better physical function. Details of the PPF test have been reported elsewhere (23). Cognitive function was assessed by using the CASI, which provides quantitative assessment of attention, concentration, orientation, short-term memory, long-term memory, language ability, visual construction, list-generating fluency, abstraction, and judgment (24). At baseline, depression was measured by using the 11-item Center for Epidemiologic Studies Depression (CES-D) scale (28). The CES-D scores ranged from 0 to 33, with higher scores represe

Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Abstract Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. &bgr;-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective forunderstanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of A&bgr; plaques and neurofibrillary tangles. Although A&bgr; plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

GAB2 Alleles Modify Alzheimer's Risk in APOE ε4 Carriers

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimers disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimers neuropathology.

Neuropathology of nondemented aging: Presumptive evidence for preclinical Alzheimer disease

OBJECTIVE To determine the frequency and possible cognitive effect of histological Alzheimers disease (AD) in autopsied older nondemented individuals. DESIGN Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimers Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. SETTING Washington University Alzheimers Disease Research Center. PARTICIPANTS Ninety-seven nondemented participants who were age 60 years or older at death (mean=84 years). RESULTS About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. CONCLUSIONS Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

The Uniform Data Set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer disease centers

A Clinical Task Force, composed of clinical leaders from Alzheimers Disease Centers (ADC), was convened by the National Institute on Aging to develop a uniform set of assessment procedures to characterize individuals with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented aging. The resulting Uniform Data Set (UDS) defines a common set of clinical observations to be collected longitudinally on ADC participants in accordance with standard methods. The UDS was implemented at all ADCs on September 1, 2005. Data obtained with the UDS are submitted to the National Alzheimers Coordinating Center and represent a unique and valuable source of data to support and stimulate collaborative research.

Primary age-related tauopathy (PART): a common pathology associated with human aging

We recommend a new term, “primary age-related tauopathy” (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer’s disease (AD), in the absence of amyloid (Aβ) plaques. For these “NFT+/Aβ−” brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as “tangle-only dementia” and “tangle-predominant senile dementia”, are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

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 Alzheimers disease (AD) were evaluated because of previous reports that the APOE locus ϵ4 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 ϵ4-Alzheimers disease association. Affected men with higher TC and age under 80 years had the highest ϵ4 allele frequencies. The ϵ4 frequency declined significantly with age. Significance A pathologic role of higher TC or cholesterol-based differential survival of ϵ4-carrying individuals may be involved in the relationship of the ϵ4 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.

Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010

Abstract The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer’s Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer’s Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on “probable” and “possible” AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.

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-ε4 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 ε4 (OR = 3.3) than among ε4 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-ε4 compared with those having one or two ε4 alleles, suggesting that these risk factors may have a common biologic underpinning.