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W R Markesbery

Publications and source records attributed to W R Markesbery.

At least 91 records · Page 5Linked to original sources
PubMed1998

Increased nuclear DNA oxidation in the brain in Alzheimer's disease.

Multiple lines of evidence indicate that oxidative stress is a contributor to neuronal death in Alzheimer's disease (AD). The oxidative damage that occurs to DNA may play a role in both normal aging and neurodegenerative diseases, including AD. This is a study of the oxidative damage that occurs in nuclear DNA in the brains of AD patients and cognitively intact, prospectively evaluated, age-matched control subjects. Nuclear DNA from frontal, temporal, and parietal lobes and cerebellum was isolated from 11 control subjects and 9 AD subjects, and oxidized purine and pyrimidine bases were quantitated using gas chromatography/mass spectrometry. Stable isotope-labeled oxidized base analogues were used as internal standards to measure 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyadenine, 4,6-diamino-5-formamidopyrimidine (Fapy-adenine), 8-hydroxyguanine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-guanine). Statistically significant elevations of 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine, and 8-hydroxyguanine were found in AD brain compared with control subjects (p < 0.05). There was an increased trend in the levels of Fapy-adenine in the AD brain, and Fapy-guanine showed a trend toward higher levels in control brains compared with AD. A generally higher level of oxidative DNA damage was present in neocortical regions than cerebellum. No significant correlation was observed between the oxidized bases and neurofibrillary tangle and senile plaque counts. Our results demonstrate that nuclear DNA damage by oxygen-derived radicals is increased in AD and support the concept that the brain is under increased oxidative stress in AD.

Adenine↗
PubMed1998

N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits.

The goals of this study were twofold: to determine whether species differences in Abeta N-terminal heterogeneity explain the absence of neuritic plaques in the aged dog and aged bear in contrast to the human; and to compare Abeta N-terminal isoforms in parenchymal vs cerebrovascular Abeta (CVA) deposits in each of the species, and in individuals with Alzheimer disease (AD) vs nondemented individuals. N-terminal heterogeneity can affect the aggregation, toxicity, and stability of Abeta. The human, polar bear, and dog brain share an identical Abeta amino acid sequence. Tissues were immunostained using affinity-purified polyclonal antibodies specific for the L-aspartate residue of Abeta at position one (AbetaN1[D]), D-aspartate at N1 (AbetaN1[rD]), and pyroglutamate at N3 (AbetaN3[pE]) and p3, a peptide beginning with leucine at N17 (AbetaN17[L]). The results demonstrate that each Abeta N-terminal isoform can be present in diffuse plaques and CVA deposits in AD brain, nondemented human, and the examined aged animal models. Though each Abeta N-terminal isoform was present in diffuse plaques, the average amyloid burden of each isoform was highest in AD vs polar bear and dog (beagle) brain. Moreover, the ratio of AbetaN3(pE) (an isoform that is resistant to degradation by most aminopeptidases) vs AbetaN17(L)-x (the potentially nonamyloidogenic p3 fragment) was greatest in the human brain when compared with aged dog or polar bear. Neuritic plaques in AD brain typically immunostained with antibodies against AbetaN1(D) and AbetaN3(pE), but not AbetaN17(L) or AbetaN1(rD). Neuritic deposits in nondemented individuals with atherosclerotic and vascular hypertensive changes could be identified with AbetaN1(D), AbetaN3(pE), and AbetaN1(rD). The presence of AbetaN1(rD) in neuritic plaques in nondemented individuals with atherosclerosis or hypertension, but not in AD, suggests a different evolution of the plaques in the two conditions. AbetaN1(rD) was usually absent in human CVA, except in AD cases with atherosclerotic and vascular hypertensive changes. Together, the results demonstrate that diffuse plaques, neuritic plaques, and CVA deposits are each associated with distinct profiles of Abeta N-terminal isoforms.

Aged↗
PubMed1998

Laser microprobe mass spectrometric study of aluminum and silicon in brain emboli related to cardiac surgery.

Recent investigations have shown numerous fatty microemboli, which we previously termed small capillary and arteriolar dilatations (SCADs), in brain microvessels of patients who died after cardiac surgery assisted by cardiopulmonary bypass (CPB). The hypothesis of this study was that extraneous trace elements such as aluminum (Al) and silicon (Si) might be contaminating the blood and causing the formation of SCADs or coating the SCADs already formed in the extracorporeal circulation during CPB. Small capillary and arteriolar dilatations were identified in thick celloidin sections of the brains of 8 patients who died after cardiac surgery supported with a membrane oxygenator, and of 2 dogs that underwent CPB with a bubble oxygenator. The sections were infiltrated with Spurr's embedding medium for electron microscopy. Resin sections 0.5 microm thick were placed on 100-mesh copper grids and analyzed with laser microprobe mass spectrometry. Brain sections without SCADs from 3 patients (controls) whose deaths were not related to cardiac surgery were processed similarly. In SCADs and nearby neuropil sites of the 8 patients who had cardiac surgery, both Al and Si values were higher than in the neuropil, including vessels of the 3 controls. Si values were also high in the 2 dogs, in which a bubble oxygenator was used. Our results indicate that contamination with Al and Si continues to occur during cardiac surgery assisted by CPB. Our data also suggest that switching to membrane oxygenators from bubble oxygenators for CPB may have reduced Si contamination of blood. Further refinements of CPB aimed at eliminating microemboli formation and Al and Si entry into the circulation are warranted.

Adult↗
PubMed1998

4-Hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats.

The mechanisms that underlie cholinergic neuronal degeneration in Alzheimer disease (AD) are unclear, but recent data suggest that oxidative stress plays a role. We report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, damages and kills basal forebrain cholinergic neurons when administered intraparenchymally. Examination of Nissl-stained brain sections following unilateral HNE infusion revealed widespread neuronal loss in basal forebrain ipsilateral to the injection, but not on the contralateral side. Levels of choline acetyltransferase activity and immunoreactivity in the ipsilateral basal forebrain and hippocampus were significantly reduced by 60-80% seven days following HNE administration. Performance in Morris water maze tasks of visuospatial memory was severely impaired in a dose-dependent manner seven days following bilateral administration of HNE. Bilateral infusion of FeCl2 (an inducer of membrane lipid peroxidation) into the basal forebrain caused neuron loss and decreased choline acetyltransferease immunoreactivity and deficits in visuospatial memory. Additionally, FeCl2 infusion increased HNE immunoreactivity, implicating HNE in iron-induced oxidative damage. Because recent studies have demonstrated HNE adducts in degenerating neurons in AD brain, the present findings suggest a role for HNE in damage to cholinergic neurons in AD.

Aldehydes↗
PubMed1998

Distribution of reducible 4-hydroxynonenal adduct immunoreactivity in Alzheimer disease is associated with APOE genotype.

Two major risk factors for late-onset familial and sporadic Alzheimer disease (AD), a leading cause of dementia worldwide, are increasing age and inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE4). Several isoform-specific effects of apoE have been proposed; however, the mechanisms by which apoE isoforms influence the pathogenesis of AD are unknown. Also associated with AD is increased lipid peroxidation in the regions of the brain most damaged by disease. 4-hydroxynonenal (HNE), the most potent neurotoxic product of lipid peroxidation, is thought to be deleterious to cells through reactions with protein nucleophiles. We tested the hypothesis that accumulation of the most common forms of HNE-protein adducts, borohydride-reducible adducts, is associated with AD and examined whether there was a relationship to APOE. Our results demonstrated that reducible HNE adducts were increased in the hippocampus, entorhinal cortex, and temporal cortex of patients with AD. Furthermore, our data showed that the pattern of reducible HNE adduct accumulation was related to APOE genotype; AD patients homozygous for APOE4 had pyramidal neuron cytoplasmic accumulation of reducible HNE adducts, while AD APOE3 homozygotes had both pyramidal neuron and astrocyte accumulation of reducible HNE adducts. This is in contrast to our previous observations that a distinct HNE protein adduct, the pyrrole adduct, accumulates on neurofibrillary tangles in AD patients. We conclude that APOE genotype influences the cellular distribution of increased reducible HNE adduct accumulation in AD.

Aged↗
PubMed1998

Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer's disease.

OBJECTIVE: To investigate the levels of glutathione transferase (GST), a protective enzyme against aldehydes, and especially 4-hydroxynonenal (HNE) in the brain and ventricular CSF of autopsied AD and normal control subjects. BACKGROUND: Studies have implicated increased levels of oxidative stress in the brain in the pathogenesis of AD. Decreased levels of polyunsaturated fatty acids and increased levels of markers of lipid peroxidation have been reported in the brain in AD, particularly in areas severely affected in the disease. HNE, one marker of lipid peroxidation, is neurotoxic in neuronal culture and in vivo and is elevated in AD brain and CSF. METHODS: We measured levels of GST activity and protein in multiple brain regions and ventricular CSF in short-postmortem-interval AD patients and age-matched prospectively evaluated control subjects. RESULTS: A decrease in GST activity in all brain areas was observed in AD compared with controls with significant decreases in the amygdala, hippocampus and parahippocampal gyrus, inferior parietal lobule, and nucleus basalis of Meynert. Levels of GST protein also were depleted in most brain regions in AD. A significant decrease in GST activity and protein levels was also found in ventricular CSF in AD. CONCLUSION: Reduced levels of GST, a protective mechanism against HNE, may have a role in the pathogenesis of neuron degeneration in AD.

Aged↗
PubMed1998

The expression of key oxidative stress-handling genes in different brain regions in Alzheimer's disease.

Alzheimer's disease (AD) has been hypothesized to be associated with oxidative stress. In this study, the expression of key oxidative stress-handling genes was studied in hippocampus, inferior parietal lobule, and cerebellum of 10 AD subjects and 10 control subjects using reverse transcriptase-polymerase chain reaction (RT-PCR). The content of Mn-, Cu,Zn-superoxide dismutases (Mn- and Cu,Zn-SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) mRNAs, and the "marker genes" (beta-actin and cyclophilin) mRNAs was determined. This study suggests that gene responses to oxidative stress can be significantly modulated by the general decrease of transcription in the AD brain. To determine if the particular oxidative stress handling gene transcription was induced or suppressed in AD, the "oxidative stress-handling gene/beta-actin" ratios were quantified and compared with control values in all brain regions studied. The Mn-SOD mRNA/beta-actin mRNA ratio was unchanged in all regions of the AD brain studied, but an increase of the Cu,Zn-SOD mRNA/beta-actin mRNA ratio was observed in the AD inferior parietal lobule. The levels of peroxidation handling (CAT, GSHPx, and GSSG-R) mRNAs normalized to beta-actin mRNA level were elevated in hippocampus and inferior parietal lobule, but not in cerebellum of AD patients, which may reflect the protective gene response to the increased peroxidation in the brain regions showing severe AD pathology. The results of this study suggest that region-specific differences of the magnitude of ROS-mediated injury rather than primary deficits of oxidative stress handling gene transcription are likely to contribute to the variable intensity of neurodegeneration in different areas of AD brain.

Actins↗
PubMed1998

Temporal relations among amyloid beta-peptide-induced free-radical oxidative stress, neuronal toxicity, and neuronal defensive responses.

Amyloid beta-peptide (Abeta), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is hypothesized to be a key factor in the neurodegeneration seen in AD. Recently it has been shown that the neurotoxicity of Abeta occurs in conjunction with free-radical oxidative stress associated with the peptide. In the present study, we investigated the temporal relations among the formation of Abeta-associated free radicals, the oxidative damage to, and the activation of antioxidant defense mechanisms in rat embryonic hippocampal neuronal culture subjected to toxic Abeta(25-35). Temporal electron paramagnetic resonance (EPR) spectroscopy results show that synthetic Abeta(25-35) forms free radicals rapidly after solubilization with a high signal intensity at initial time points. At those time points, neuronal toxicity and oxidative stress gradually increase as assessed by reduction of 3-[4,5-dimethylthiazol-2-yl)-2,5-diphenyl] tetrazolium bromide, trypan blue exclusion, formation of reactive oxygen species, and detection of protein carbonyl levels. The latter occurs before neurotoxicity. When the EPR signal intensity of Abeta solution decreases at later time points, neuronal toxicity levels off and remains the same until the end of the experiment. The oxidative-sensitive enzyme creatine kinase (CK) (brain isoform) (CK-BB) content increases at initial points of the Abeta treatment in correlation with the EPR signal to keep the CK activity constant, presumably to overcome the Abeta-induced oxidative insult. CK-BB content returns to normal levels by the end of the experiment. CK activity normalized to CK content implies the presence of inactivated CK molecules during the treatment. Both Mn SOD and Cu/Zn superoxide dismutase (SOD) mRNA levels show robust increases initially, which later return to control level with decreasing oxidative insult. These results are consistent with the notion that Abeta(25-35) promotes a rapid free-radical oxidative stress to neurons, which respond by modulating various oxidative stress-handling genes.

Amyloid beta-Peptides↗
PubMed1998

Imbalances of trace elements related to oxidative damage in Alzheimer's disease brain.

Four elements that have been implicated in free-radical-induced oxidative stress in Alzheimer's disease (AD) were measured by instrumental neutron activation analysis (INAA) in seven brain regions from 58 AD patients and 21 control subjects. A statistically significant elevation of iron and zinc was observed in multiple regions of AD brain, compared with controls. Mercury was elevated in AD in most regions studied, but the high variability of mercury levels in both AD and control subjects prevented the AD-control difference from reaching significance. Selenium, a protective agent against mercury toxicity, was significantly elevated only in AD amygdala. The elevation of iron and zinc in AD brain has the potential of augmenting neuron degeneration through free radical processes.

Aged↗
PubMed1998

Apolipoprotein E allelic influence on human cerebrospinal fluid apolipoproteins.

The major apolipoproteins (apo) on human cerebrospinal fluid lipoproteins are apoA-I and apoE. Given the association between inheritance of the varepsilon4 allele of the apoE gene (APOE4) and increased susceptibility to Alzheimer's disease, we tested the hypothesis that cerebrospinal fluid apolipoproteins may be influenced by APOE genotype and Alzheimer's disease. Lipoprotein fractions (d < 1.210 g/ml) were isolated from cerebrospinal fluid obtained from individuals with different APOE genotypes and with or without pathologically verified Alzheimer's disease. Apolipoproteins were separated by SDS-polyacrylamide gel electrophoresis and identified by silver nitrate staining, Western blotting, and N-terminal amino acid sequencing. Four protein species were detected by silver nitrate staining in subjects with an APOE3 allele: apoA-I, apoE monomer, apoE-apoA-II heterodimer, and apoE homodimer. In APOE4 homozygotes, only apoA-I and apoE monomer were detected. ApoA-II homodimer was demonstrated in all subjects by Western blotting. The relative levels of apoE- and apoA-II-containing apolipoproteins correlated with APOE genotype but were not altered by Alzheimer's disease. In contrast to apoE, no apoA-II immunoreactivity was observed with pathological structures in Alzheimer's disease brain. These differences in cerebrospinal fluid apolipoproteins may influence lipoprotein trafficking and may be an element in the stratification of risk for Alzheimer's disease with APOE genotype.

Aged↗
PubMed1997

Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.

OBJECTIVE: To determine the relationship of brain infarction to the clinical expression of Alzheimer disease (AD). DESIGN: Cognitive function and the prevalence of dementia were determined for participants in the Nun Study who later died. At autopsy, lacunar and larger brain infarcts were identified, and senile plaques and neurofibrillary tangles in the neocortex were quantitated. Participants with abundant senile plaques and some neurofibrillary tangles in the neocortex were classified as having met the neuropathologic criteria for AD. SETTING: Convents in the Midwestern, Eastern, and Southern United States. PARTICIPANTS: A total of 102 college-educated women aged 76 to 100 years. MAIN OUTCOME MEASURES: Cognitive function assessed by standard tests and dementia and AD assessed by clinical and neuropathologic criteria. RESULTS: Among 61 participants who met the neuropathologic criteria for AD, those with brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts. Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter had an especially high prevalence of dementia, compared with those without infarcts (the odds ratio [OR] for dementia was 20.7, 95% confidence interval [95% CI], 1.5-288.0). Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter than in those without infarcts. In contrast, among 41 participants who did not meet the neuropathologic criteria for AD, brain infarcts were only weakly associated with poor cognitive function and dementia. Among all 102 participants, atherosclerosis of the circle of Willis was strongly associated with lacunar and large brain infarcts. CONCLUSION: These findings suggest that cerebrovascular disease may play an important role in determining the presence and severity of the clinical symptoms of AD.

Aged↗
PubMed1997

The expression of creatine kinase isoenzymes in neocortex of patients with neurodegenerative disorders: Alzheimer's and Pick's disease.

Creatine kinase (CK) activity was found decreased in the brains of patients with Alzheimer's disease (AD) and Pick's disease (PD). However, the decrease of total CK activity in AD was more pronounced than in PD. Analysis of the activity of two CK isoforms, BCK and ubiquitous mitochondrial CK, demonstrated that the decrease of total CK activity in AD and PD was related to the decrease of BCK activity. The decline of CK activity both in AD and PD correlated well with the decline of the content of immunoreactive BCK in brain extracts. The BCK mRNA level in AD and PD was not significantly different from control patients and could not be the primary reason for decreases in CK content and activity. The decreased level of BCK in AD and PD brains might be caused by posttranscriptional events, which could affect the translation of BCK mRNA and/or lead to the inactivation and degradation of the enzyme. Because CK is sensitive to oxidative modification, it is possible that the changes observed in this study result from free radical damage.

Aged↗
PubMed1997

Oxidative stress hypothesis in Alzheimer's disease.

The major hurdle in understanding Alzheimer's disease (AD) is a lack of knowledge about the etiology and pathogenesis of selective neuron death. In recent years, considerable data have accrued indicating that the brain in AD is under increased oxidative stress and this may have a role in the pathogenesis of neuron degeneration and death in this disorder. The direct evidence supporting increased oxidative stress in AD is: (1) increased brain Fe, Al, and Hg in AD, capable of stimulating free radical generation; (2) increased lipid peroxidation and decreased polyunsaturated fatty acids in the AD brain, and increased 4-hydroxynonenal, an aldehyde product of lipid peroxidation in AD ventricular fluid; (3) increased protein and DNA oxidation in the AD brain; (4) diminished energy metabolism and decreased cytochrome c oxidase in the brain in AD; (5) advanced glycation end products (AGE), malondialdehyde, carbonyls, peroxynitrite, heme oxygenase-1 and SOD-1 in neurofibrillary tangles and AGE, heme oxygenase-1, SOD-1 in senile plaques; and (6) studies showing that amyloid beta peptide is capable of generating free radicals. Supporting indirect evidence comes from a variety of in vitro studies showing that free radicals are capable of mediating neuron degeneration and death. Overall, these studies indicate that free radicals are possibly involved in the pathogenesis of neuron death in AD. Because tissue injury itself can induce reactive oxygen species (ROS) generation, it is not known whether this is a primary or secondary event. Even if free radical generation is secondary to other initiating causes, they are deleterious and part of a cascade of events that can lead to neuron death, suggesting that therapeutic efforts aimed at removal of ROS or prevention of their formation may be beneficial in AD.

Alzheimer Disease↗
PubMed1997

A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide.

Peroxidation of membrane lipids results in release of the aldehyde 4-hydroxynonenal (HNE), which is known to conjugate to specific amino acids of proteins and may alter their function. Because accumulating data indicate that free radicals mediate injury and death of neurons in Alzheimer's disease (AD) and because amyloid beta-peptide (A beta) can promote free radical production, we tested the hypothesis that HNE mediates A beta 25-35-induced disruption of neuronal ion homeostasis and cell death. A beta induced large increases in levels of free and protein-bound HNE in cultured hippocampal cells. HNE was neurotoxic in a time- and concentration-dependent manner, and this toxicity was specific in that other aldehydic lipid peroxidation products were not neurotoxic. HNE impaired Na+, K(+)-ATPase activity and induced an increase of neuronal intracellular free Ca2+ concentration. HNE increased neuronal vulnerability to glutamate toxicity, and HNE toxicity was partially attenuated by NMDA receptor antagonists, suggesting an excitotoxic component to HNE neurotoxicity. Glutathione, which was previously shown to play a key role in HNE metabolism in nonneuronal cells, attenuated the neurotoxicities of both A beta and HNE. The antioxidant propyl gallate protected neurons against A beta toxicity but was less effective in protecting against HNE toxicity. Collectively, the data suggest that HNE mediates A beta-induced oxidative damage to neuronal membrane proteins, which, in turn, leads to disruption of ion homeostasis and cell degeneration.

Aldehydes↗
PubMed1997

4-hydroxy-2-nonenal pyrrole adducts in human neurodegenerative disease.

Increasing age and inheritance of the epsilon 4 allele of apolipoprotein E (APOE4) are significant risk factors for sporadic and late onset familial Alzheimer disease (AD); however, the mechanisms by which either leads to AD are unknown. Numerous studies have associated advancing age with increased indices of oxidative challenge to brain, and with still further increased oxidative damage to relevant brain regions in AD patients. A major consequence of oxidative damage to brain is lipid peroxidation with production of the neurotoxic metabolite 4-hydroxy-2-nonenal (HNE). HNE reacts with protein to yield several adducts, including a pyrrole adduct that forms irreversibly in biological systems. Previously, we have shown in a small number of AD and control patients that HNE pyrrole adduct antiserum is immunoreactive with neurofibrillary tangles (NFT), and that this reactivity was significantly associated with inheritance of APOE4. Others have confirmed this pattern of immunoreactivity in AD brain but did not observe an association with APOE4. Herein, we have expanded the study group to 19 AD patients homozygous for APOE4 or APOE3, as well as 30 patients with other neurodegenerative diseases, including diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, Parkinson's disease, and human immunodeficiency virus-1 encephalitis. HNE pyrrole adduct immunoreactivity on NFT in AD patients was strongly associated with APOE4 homozygosity. With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients. We propose that there is a significant difference between the interaction of apoE3 and apoE4 with lipid peroxidation in the brains of AD patients.

Adult↗
PubMed1996

Standardization in biological analyses of aluminum: what are the needs?

A review of the literature of aluminum (Al) levels in biological samples, particularly Alzheimer's disease (AD) brain, reveals a lack of interlaboratory agreement at both the bulk and microprobe levels. One possible reason for this controversy may be the methods chosen for quantitation and standardization. Currently, the major problem affecting quantitation of Al at the bulk level is the lack of low-Al-concentration, matrix-matched certified standards. Although a number of certified aluminum bulk standards are available, most do not match well in matrix with the samples of interest. A similar situation exists for micro-probe standards in which commercially available pure metal foils and thin films of materials, such as metal oxides, are available but again do not match well in matrix. A review of the current status of quantitation of Al levels in biological analyses at the bulk and microprobe level is presented. Future directions to develop standards include the submission of currently used microprobe standards to a central laboratory for critical analysis and selection of the optimum standard, followed by establishment of interlaboratory and intertechnique comparisons. Other future directions include the adaptation of a standard protocol for the selection of tissue for analysis and criteria for data rejection, as well as the development of a standard system for data normalization and reporting.

Aluminum↗
PubMed1996

Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study.

OBJECTIVE: To determine if linguistic ability in early life is associated with cognitive function and Alzheimer's disease in late life. DESIGN: Two measures of linguistic ability in early life, idea density and grammatical complexity, were derived from autobiographies written at a mean age of 22 years. Approximately 58 years later, the women who wrote these autobiographies participated in an assessment of cognitive function, and those who subsequently died were evaluated neuropathologically. SETTING: Convents in the United States participating in the Nun Study; primarily convents in the Milwaukee, Wis, area. PARTICIPANTS: Cognitive function was investigated in 93 participants who were aged 75 to 95 years at the time of their assessments, and Alzheimer's disease was investigated in the 14 participants who died at 79 to 96 years of age. MAIN OUTCOME MEASURES: Seven neuropsychological tests and neuropathologically confirmed Alzheimer's disease. RESULTS: Low idea density and low grammatical complexity in autobiographies written in early life were associated with low cognitive test scores in late life. Low idea density in early life had stronger and more consistent associations with poor cognitive function than did low grammatical complexity. Among the 14 sisters who died, neuropathologically confirmed Alzheimer's disease was present in all of those with low idea density in early life and in none of those with high idea density. CONCLUSIONS: Low linguistic ability in early life was a strong predictor of poor cognitive function and Alzheimer's disease in late life.

Adult↗