Prior endogenous and exogenous estrogen and incident dementia in the 10th decade of life: The 90+ Study.

Objective: This study aimed to investigate the association of endogenous and exogenous estrogen exposure with risk of incident dementia in the oldest-old (age 90+ years).Methods: Participants were part of The 90+ Study, a longitudinal study begun in 2003 of aging and dementia among people aged 90+ years. Menstrual, reproductive, and menopausal data were collected in the 1980s as part of the population-based Leisure World Cohort Study. Cognitive status at baseline was determined from an in-person neurological evaluation with biannual follow-up through June 2019. Hazard ratios (HRs) of dementia associated with estrogen-related variables were estimated using Cox regression analysis. No adjustment was made for multiple comparisons.Results: A total of 424 women without dementia at baseline had at least one follow-up evaluation. The mean age was 68.5 years at enrollment in the Leisure World Cohort Study, 93.2 years at enrollment in The 90+ Study, and 96.5 years at last follow-up. During follow-up (mean 3.4 years) dementia was diagnosed in 209 (49%) participants. No individual menstrual, reproductive, menopausal, or estrogen replacement variable was associated with risk of incident dementia after age 90 years. However, women with a high endogenous estrogen exposure index (summarizing exposure from menarche to menopause) had a non-significant 25% lower risk (HR = 0.75, 95% confidence interval 0.53-1.06).Conclusions: Prior exposure to estrogen, endogenous or exogenous, had little effect on risk of dementia in the 10th decade of life.

Prevalence of dementia after age 90: results from the 90+ study.

BACKGROUND: Although the prevalence of dementia increases with age from ages 65 to 85, whether this increase continues after age 90 is unclear. Most studies reporting on dementia prevalence do not have sufficient participants to estimate prevalence for specific ages and sexes above age 90. Here, we estimate age- and sex-specific prevalence of all-cause dementia in the oldest-old, those aged 90 and older. METHODS: Participants are 911 elderly from The 90+ Study, a population-based study of aging and dementia in people aged 90 and above. Dementia was diagnosed using in-person examinations as well as telephone and informant questionnaires. RESULTS: The overall prevalence of all-cause dementia was higher in women (45%, 95% CI = 41.5-49.0) than men (28%, 95% CI = 21.7-34.2). Among women, prevalence increased with age after age 90, essentially doubling every 5 years. A lower prevalence of dementia was significantly associated with higher education in women but not in men. CONCLUSIONS: In a very large sample of participants aged 90 and older, prevalence of all-cause dementia doubled every 5 years for women but not men.

No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

Microtransplantation of functional receptors and channels from the Alzheimer's brain to frog oocytes.

About a decade ago, cell membranes from the electric organ of Torpedo and from the rat brain were transplanted to frog oocytes, which thus acquired functional Torpedo and rat neurotransmitter receptors. Nevertheless, the great potential that this method has for studying human diseases has remained virtually untapped. Here, we show that cell membranes from the postmortem brains of humans that suffered Alzheimer's disease can be microtransplanted to the plasma membrane of Xenopus oocytes. We show also that these postmortem membranes carry neurotransmitter receptors and voltage-operated channels that are still functional, even after they have been kept frozen for many years. This method provides a new and powerful approach to study directly the functional characteristics and structure of receptors, channels, and other membrane proteins of the Alzheimer's brain. This knowledge may help in understanding the basis of Alzheimer's disease and also help in developing new treatments.

Visual memory predicts Alzheimer's disease more than a decade before diagnosis.

BACKGROUND: Recent studies have suggested that AD may reflect a chronic process that begins many years before the clinical expression of dementia. The current study examines premorbid Benton Visual Retention Test (BVRT) and Wechsler Adult Intelligence Scale-vocabulary (WAIS-voc) test scores in order to determine whether long-term deficits in these tests can predict the development of AD decades later in the Baltimore Longitudinal Study of Aging (BLSA). METHOD: Participants are volunteers from the BLSA, a multidisciplinary study of normal aging conducted by the National Institute on Aging. A total of 1,425 BLSA participants who were older than 60 years were included in the analyses. Cox proportional hazards models were used to estimate the relative risk of developing AD associated with BVRT and WAIS-voc scores at different time periods up to 20 years before the diagnosis of AD. RESULTS: The relative risks for 6 or more BVRT errors vs less than 6 errors at 1 to 3, 3 to 5, 5 to 10, and 10 to 15 years before the diagnosis of AD were 5.69, 2.11, 1.76, and 1.83 (p < 0.05). The relative risk for 15 or more years before diagnosis was not significant (p > 0.10). WAIS-voc scores were not significantly associated with the risk of AD in any time period. CONCLUSIONS: A greater number of errors on the BVRT is associated with an increased risk of AD up to 15 years later. Poor visual memory performance may represent an early expression of AD years before diagnosis. This result suggests the need to continue to revise views on the natural history of AD and the possibility of an increased window of opportunity for preventive treatment before definitive diagnosis.

APOE genotype and survival in men and women with Alzheimer's disease.

BACKGROUND: The epsilon 4 allele of the APOE gene (APOE) is more frequent in patients with AD than in the general population, but studies are inconclusive as to whether it affects rate of progression or survival. Because survival in AD is generally longer in women than in men, the authors investigated whether APOE affects 10-year survival equally in men and women. METHODS: APOE testing was performed on 125 patients with probable AD enrolled in the Johns Hopkins AD Research Center between November 1984 and March 1987. The 39 men and 86 women were followed at 6-month intervals until censoring (by death or withdrawal from the study) or March 1997. Patients were dichotomized into those with and those without at least one epsilon 4 allele. For each sex, a Cox proportional hazards regression, allowing for delayed entry and covarying for age at onset, was used to examine the effect of epsilon 4 on survival. RESULTS: All patients who died during the study period and had autopsy (n = 92) were found to have definite AD. Average survival from disease onset did not differ by sex (12.1 years in men; 12.3 years in women). In neither sex were differences found between epsilon 4-positive and epsilon 4-negative subgroups in education, duration of AD at entry, or severity of dementia. However, in both sexes the epsilon 4-positive subgroup was approximately 3 years older at onset of AD and at entry to the study than the epsilon 4-negative subgroup. Adjusting for age at onset, the presence of an epsilon 4 allele significantly increased the relative risk of death only for men (RR = 2.69; 95% CI = 1.23 to 5.87). CONCLUSIONS: In this sample of mostly white, well-educated research participants with AD, the APOE epsilon 4 allele was associated with shorter survival in men but not in women.

Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway.

Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta-protein (Abeta). We demonstrate in vitro that LRP mediates the clearance of both Abeta40 and Abeta42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble Abeta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for Abeta, this work provides the first in vivo evidence that the LRP pathway may modulate Abeta deposition and AD susceptibility by regulating the removal of soluble Abeta.

The CA1 region of the human hippocampus is a hot spot in Alzheimer's disease.

Data from an ongoing study of differences in the total number of neurons in the five major subdivisions of the hippocampal regions of the brains of patients with Alzheimer's disease (AD) and normal age-matched controls confirm an earlier finding from our laboratories of a pronounced loss of CA1 neurons associated with AD. In view of an earlier finding that the CA1 region does not suffer normal age-related neuronal loss, these data support the earlier conclusion that the neuropathologic mechanisms involved in the AD-related losses in CA1 are not related to normal aging and that the study of the cellular and molecular events involved in the AD-related loss of CA1 cells can aid in the identification of the unique pathologic processes associated with AD.

Clinical trials in Alzheimer disease: debate on the use of placebo controls.

During the past 10 years, there has been a rapidly growing number of pharmaceutical industry-sponsored drug trials for treatment of Alzheimer disease (AD) and other neurodegenerative diseases. As public awareness and concerns about AD have grown, so has interest in developing drug therapies for retarding symptom progression, delaying onset, and ultimately curing the disease. Ethical debate on the use of placebo control trials in AD research has come of age in the United States with the availability of treatments approved by the Food and Drug Administration. The experts and the public agree that more effective therapies are necessary, and new therapeutic options are being developed as rapidly as possible. The arguments on each side of the debate are provocative and important but do not provide unequivocal justification for either the abandonment or the maintenance of placebo-controlled trials in all AD research. Clinical trials differ with respect to scientific and practical goals, and these factors inherently affect the ethical priorities of each study. We present these contrasting points of view to delineate some of the issues rather than to make specific recommendations other than to urge that all clinical trials in AD should be designed with careful consideration of the ethical issues surrounding the use of placebo controls. As new and more effective treatments emerge, the ethical framework for placebo use in AD studies will require frequent re-examination. To make wise choices, patients, caregivers, physicians, and ethicists (among others) must have a voice in this continuing discussion.

Lack of relation between race and cognitive test performance in Alzheimer's disease.

This study evaluated cognitive test performance in African-American and European-American Alzheimer's disease patients with equivalent years of education. Group differences were negligible on a variety of memory, language, and attentional measures, including several widely used neuropsychological tests. Differences between racial groups observed in earlier studies may have stemmed, in part, from differences in education, which may itself serve as a proxy for other potentially important sociologic and health variables.

Neuropathology of preclinical and clinical late-onset Alzheimer's disease.

We report on the neuropathological examinations of a 74-year-old woman with Alzheimer's disease (AD) and of her 47-year-old nondemented daughter. The brain of the mother showed fully developed pathological changes of AD. By contrast, the brain of the daughter revealed only perineuronal deposition of diffuse amyloid in cerebral cortex and striking abnormalities of the endosomal-lysosomal system, without neurofibrillary, glial, or microglial changes. These observations suggest that amyloid deposition and endosomal-lysosomal changes are early events in late-onset AD and that they may precede the onset of dementia by several decades.

Neuronal cell death in Alzheimer's disease correlates with apoE uptake and intracellular Abeta stabilization.

The brains of individuals with Alzheimer's disease (AD) are characterized by extracellular deposition of beta-amyloid protein (Abeta), intracellular neurofibrillary tangles, and loss of neurons. To study molecular markers associated with dying cells in the AD brain, in situ DNA labeling techniques were used to visualize cells with DNA fragmentation. We observed that intracellular accumulation of apolipoprotein E (apoE) is correlated with the detection of intracellular Abeta-like immunoreactivity within the same cytoplasmic granules, suggesting that uptake of lipids may have stabilized the hydrophobic Abeta protein within the cell. These apoE-containing neurons also exhibit high expression of a cell surface receptor, gp330, which is known to bind apoE. Cells containing significant nuclear DNA fragmentation express the highest level of cell surface gp330. Extracellular deposition of Abeta is detected only upon neuronal cell death, initially as halos of Abeta immunoreactivity around individual dying neurons, and subsequently as Abeta plaques containing numerous neuronal cell ghosts. Based on our in situ analysis of nuclear DNA fragmentation, we conclude that neuronal cell death likely occurs before the extracellular deposition of Abeta in AD brains.

In situ labeling of dying cortical neurons in normal aging and in Alzheimer's disease: correlations with senile plaques and disease progression.

We examined the degeneration of neocortical neurons in normal aging and Alzheimer's disease (AD) using terminal transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP)-biotin nick-end labeling (TUNEL), a method that identifies DNA strand breaks and constitutes a positive marker for dying neurons. TUNEL was positive in neurons, glia, and microglial cells in AD but not in younger or age-matched cognitively characterized controls. Neuronal labeling in AD was most conspicuous in cortical layer III in the early stages of the disease and became more widespread as the disease progressed. In addition, we observed TUNEL of lamina III neurons in a subset of older subjects who had normal cognition but abundant neocortical senile plaques. In concert, the availability of a direct marker of dying neurons allows for specific correlations of cell death with other neuropathological markers as well as clinical variables. Observations from the present study suggest that the death of cortical neurons precedes the symptomatic stage of AD and evolves in parallel with the clinical progression of the disease and that there appears to be an association between the degree of cell death and the severity of senile plaques.

Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging.

To establish correlations among cognitive states and neuropathology, we have examined 22 subjects (69-97 years of age) from the Baltimore Longitudinal Study of Aging (BLSA), of whom 15 had normal and stable cognitive performances and seven had dementia of variable severity. In the majority of normal subjects, few or no beta-amyloid (A beta) deposits or senile plaques (SP) were present in the neocortex, but neurofibrillary tangles (NFT) were consistently found in CA1 of hippocampus and layer II of entorhinal cortex. In two (15%) normal individuals, the densities of SP were consistent with the diagnosis of possible Alzheimer's disease (AD). We speculate that these cases with normal cognitive states and abundant neocortical SP may represent preclinical AD. We conclude that the neocortex of a majority of cognitively intact individuals can remain free of A beta deposits or SP, even into the tenth decade of life.

Apolipoprotein E genotype and rate of decline in probable Alzheimer's disease.

BACKGROUND: The risk of Alzheimer's disease (AD) appears to increase, and the age at onset to decrease, with the number of epsilon 4 alleles. If this relationship is due to increased rate of pathophysiological change, the presence of epsilon 4 would be expected to influence progression of disease, predicting a more rapid decline with increasing number of epsilon 4 alleles. OBJECTIVE: To determine if the frequency of the epsilon 4 allele of the apolipoprotein E (ApoE) gene affects the rate of clinical progression in AD. SETTING: Alzheimer's Disease Research Center. SUBJECTS: One hundred one subjects meeting criteria of the National Institute of Neurological Disorders and Stroke for probable AD or of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) for definite AD; 78 of these subjects met the additional criterion of having a Mini-Mental State Examination score of at least 10 for analysis of rate of decline. MEASUREMENTS: The subjects' characteristics and neuropsychological battery, including the Mini-Mental state Examination, Spatial Delayed Recognition Span, Boston Naming Test, Category Fluency Test, and the Physical Capacity Subscale of the Psychogeriatric Dependency Rating Scale. DESIGN: The subjects were followed up longitudinally for approximately one decade. Medical histories were taken and physical and neurologic examinations and neuropsychological testing were performed every 6 months. Three and a half years of data were available for most tests and 5.5 for the Psychogeriatric Dependency Rating Scale; thereafter, patients were no longer testable. A general linear model analysis of variance was used to assess the influence of ApoE on demographic characteristics and baseline performances on neuropsychological measures. A random-effects regression model was used to predict change over time associated with presence of epsilon 4 on clinical and cognitive measures. RESULTS: The age at onset was greatest for the epsilon 4-heterozygous subjects and least for the epsilon 4-negative subjects. The heterozygous subjects declined more rapidly on the Mini-Mental State Examination and the Category Fluency Test than the subjects without the epsilon 4 allele or with epsilon homozygosity. The homozygous subjects declined faster on only one subscale: the Physical Capacity subscale of the Psychogeriatric Dependency Rating Scale. Covarying for age at onset did not affect the results. CONCLUSIONS: The ApoE genotype does not strongly influence the rate of decline in AD, implying that epsilon 4 might predispose to the development of the disease without accelerating its pathogenesis or progression. The effects of epsilon 4 on both age at onset and rate of decline need to be further investigated.

Lack of association of the apoE4 allele with hippocampal sclerosis dementia.

We determined the apolipoprotein E4 (apoE) genotype in 12 cases of autopsy-confirmed hippocampal sclerosis dementia (HSD), a disorder characterized pathologically by neuronal degeneration, predominantly of temporal lobe structures, without senile plaques or neurofibrillary tangles. The frequency of the apoE4 allele in HSD was 12.5%, similar to that of a control population and significantly different from the approximately 40% found in Alzheimer's disease (AD) (P < 0.001). These observations suggest that apoE4 is not a risk factor for HSD.

Displacement of corticotropin releasing factor from its binding protein as a possible treatment for Alzheimer's disease.

In Alzheimer's disease (AD) there are dramatic reductions in the content of corticotropin releasing factor (CRF), reciprocal increases in CRF receptors, and morphological abnormalities in CRF neurons in affected brain areas. Cognitive impairment in AD patients is associated with a lower cerebrospinal fluid concentration of CRF, which is known to induce increases in learning and memory in rodents. This suggests that CRF deficits contribute to cognitive impairment. The identification in post-mortem brain of CRF-binding protein (CRF-BP), a high-affinity binding protein that inactivates CRF, and the differential distribution of CRF-BP and CRF receptors, provides the potential for improving learning and memory without stress effects of CRF receptor agonists. Here we show that ligands that dissociate CRF from CRF-BP increase brain levels of 'free CRF' in AD to control levels and show cognition-enhancing properties in models of learning and memory in animals without the characteristic stress effects of CRF receptor agonists.

Cognitive problems in the elderly.

We have summarized the literature on cognitive changes in normal aging. The concepts of normal aging, age-associated memory impairment, and their possible continuum with dementia are discussed. Epidemiologic, genetic, radiological, as well as neuropsychological and endocrine contributions to the understanding of cognition in the elderly, are reviewed.