APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study.

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. ß-amyloid neuritic plaques (Aß-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.

Oxidative lipid modification of nicastrin enhances amyloidogenic γ-secretase activity in Alzheimer's disease.

The cause of elevated level of amyloid ß-peptide (Aß42) in common late-onset sporadic [Alzheimer's disease (AD)] has not been established. Here, we show that the membrane lipid peroxidation product 4-hydroxynonenal (HNE) is associated with amyloid and neurodegenerative pathologies in AD and that it enhances γ-secretase activity and Aß42 production in neurons. The γ-secretase substrate receptor, nicastrin, was found to be modified by HNE in cultured neurons and in brain specimens from patients with AD, in which HNE-nicastrin levels were found to be correlated with increased γ-secretase activity and Aß plaque burden. Furthermore, HNE modification of nicastrin enhanced its binding to the γ-secretase substrate, amyloid precursor protein (APP) C99. In addition, the stimulation of γ-secretase activity and Aß42 production by HNE were blocked by an HNE-scavenging histidine analog in a 3xTgAD mouse model of AD. These findings suggest a specific molecular mechanism by which oxidative stress increases Aß42 production in AD and identify HNE as a novel therapeutic target upstream of the γ-secretase cleavage of APP.

Increased 5S rRNA oxidation in Alzheimer's disease.

It is widely accepted that oxidative stress is involved in neurodegenerative disorders such as Alzheimer's disease (AD). Ribosomal RNA (rRNA) is one of the most abundant molecules in most cells and is affected by oxidative stress in the human brain. Previous data have indicated that total rRNA levels were decreased in the brains of subjects with AD and mild cognitive impairment concomitant with an increase in rRNA oxidation. In addition, level of 5S rRNA, one of the essential components of the ribosome complex, was significantly lower in the inferior parietal lobule (IP) brain area of subjects with AD compared with control subjects. To further evaluate the alteration of 5S rRNA in neurodegenerative human brains, multiple brain regions from both AD and age-matched control subjects were used in this study, including IP, superior and middle temporal gyro, temporal pole, and cerebellum. Different molecular pools including 5S rRNA integrated into ribosome complexes, free 5S rRNA, cytoplasmic 5S rRNA, and nuclear 5S rRNA were studied. Free 5S rRNA levels were significantly decreased in the temporal pole region of AD subjects and the oxidation of ribosome-integrated and free 5S rRNA was significantly increased in multiple brain regions in AD subjects compared with controls. Moreover, a greater amount of oxidized 5S rRNA was detected in the cytoplasm and nucleus of AD subjects compared with controls. These results suggest that the increased oxidation of 5S rRNA, especially the oxidation of free 5S rRNA, may be involved in the neurodegeneration observed in AD.

Molecular changes in brain aging and Alzheimer's disease are mirrored in experimentally silenced cortical neuron networks.

Activity-dependent modulation of neuronal gene expression promotes neuronal survival and plasticity, and neuronal network activity is perturbed in aging and Alzheimer's disease (AD). Here we show that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and Ca(2+) signaling; alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to Ca(2+)-mediated degeneration.

Elevated 4-hydroxyhexenal in Alzheimer's disease (AD) progression.

Multiple studies have demonstrated elevations of α, ß-unsaturated aldehydes including 4-hydroxynonenal (HNE) and acrolein, in vulnerable regions of mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), and late stage Alzheimer's disease (LAD) brain. However, there has been limited study of a third member, 4-hydroxyhexenal (HHE), a diffusible lipid peroxidation product of the ω-3 polyunstataturated fatty acids (PUFAs). In the present study levels of extractable and protein-bound HHE were quantified in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of MCI, PCAD, LAD, and normal control (NC) subjects. Levels of extractable and protein-bound HHE were increased in multiple regions in the progression of Alzheimer's disease (AD). Extractable HHE was significantly elevated in the hippocampus/parahippocampal gyrus (HPG) of PCAD and LAD subjects and protein-bound HHE was significantly higher in MCI, PCAD, and LAD HPG. A time- and concentration-dependent decrease in survival and a concentration-dependent decrease in glucose uptake were observed in primary cortical cultures treated with HHE. Together these data support a role for lipid peroxidation in the progression of Alzheimer's disease.

Proteomic analysis of brain proteins in APP/PS-1 human double mutant knock-in mice with increasing amyloid ß-peptide deposition: insights into the effects of in vivo treatment with N-acetylcysteine as a potential therapeutic intervention in mild cognitive impairment and Alzheimer's disease.

Proteomics analyses were performed on the brains of wild-type (WT) controls and an Alzheimer's disease (AD) mouse model, APP/PS-1 human double mutant knock-in mice. Mice were given either drinking water or water supplemented with N-acetylcysteine (NAC) (2 mg/kg body weight) for a period of five months. The time periods of treatment correspond to ages prior to Aß deposition (i.e. 4-9 months), resembling human mild cognitive impairment (MCI), and after Aß deposition (i.e. 7-12 months), more closely resembling advancing stages of AD. Substantial differences exist between the proteomes of WT and APP/PS-1 mice at 9 or 12 months, indicating that Aß deposition and oxidative stress lead to downstream changes in protein expression. Altered proteins are involved in energy-related pathways, excitotoxicity, cell cycle signaling, synaptic abnormalities, and cellular defense and structure. Overall, the proteomic results support the notion that NAC may be beneficial for increasing cellular stress responses in WT mice and for influencing the levels of energy- and mitochondria-related proteins in APP/PS-1 mice.

Proteomic identification of specifically carbonylated brain proteins in APP(NLh)/APP(NLh) × PS-1(P264L)/PS-1(P264L) human double mutant knock-in mice model of Alzheimer disease as a function of age.

Alzheimer disease (AD) is the most common type of dementia and is characterized pathologically by the presence of neurofibrillary tangles (NFTs), senile plaques (SPs), and loss of synapses. The main component of SP is amyloid-beta peptide (Aß), a 39 to 43 amino acid peptide, generated by the proteolytic cleavage of amyloid precursor protein (APP) by the action of beta- and gamma-secretases. The presenilins (PS) are components of the γ-secretase, which contains the protease active center. Mutations in PS enhance the production of the Aß42 peptide. To date, more than 160 mutations in PS1 have been identified. Many PS mutations increase the production of the ß-secretase-mediated C-terminal (CT) 99 amino acid-long fragment (CT99), which is subsequently cleaved by γ-secretase to yield Aß peptides. Aß has been proposed to induce oxidative stress and neurotoxicity. Previous studies from our laboratory and others showed an age-dependent increase in oxidative stress markers, loss of lipid asymmetry, and Aß production and amyloid deposition in the brain of APP/PS1 mice. In the present study, we used APP (NLh)/APP(NLh) × PS-1(P246L)/PS-1(P246L) human double mutant knock-in APP/PS-1 mice to identify specific targets of brain protein carbonylation in an age-dependent manner. We found a number of proteins that are oxidatively modified in APP/PS1 mice compared to age-matched controls. The relevance of the identified proteins to the progression and pathogenesis of AD is discussed.

Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer's disease: insights into memory loss in MCI.

Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed 'preclinical' or 'asymptomatic' AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment. Results of global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology. Proteomics analysis of the IPL revealed differences in protein levels and specific carbonylation that are consistent with preservation of memory in PCAD and apparent memory decline in MCI. Our data suggest that marked changes occur at the protein level in MCI that may cause or reflect memory loss and other AD symptoms.

Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study.

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through ß-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.

Neuron specific toxicity of oligomeric amyloid-ß: role for JUN-kinase and oxidative stress.

Recent studies have demonstrated a potential role for oligomeric forms of amyloid-ß (Aß) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aß. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aß oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aß. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aß toxicity in neurons. These data indicate that oligomeric Aß is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aß as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD.

Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: toward therapeutic modulation of mild cognitive impairment.

Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly. Although the underlying cause has yet to be established, numerous data have shown that oxidative stress is implicated in AD as well as in preclinical stages of AD, such as mild cognitive impairment (MCI). The oxidative stress observed in brains of subjects with AD and MCI may be due, either fully or in part, to increased free radicals mediated by amyloid-beta peptide (Abeta). By using double human mutant APP/PS-1 knock-in mice as the AD model, the present work demonstrates that the APP/PS-1 double mutation results in elevated protein oxidation (as indexed by protein carbonyls), protein nitration (as indexed by 3-nitrotyrosine), as well as lipid peroxidation (as indexed by protein-bound 4-hydroxy-2-nonenal) in brains of mice aged 9 months and 12 months. APP/PS-1 mice also exhibited lower levels of brain glutathione peroxidase (GPx) in both age groups studied, whereas glutathione reductase (GR) levels in brain were unaffected by the mutation. The activities of both of these antioxidant enzymes were significantly decreased in APP/PS-1 mouse brains, whereas the activity of glucose-6-phosphate dehydrogenase (G6PDH) was increased relative to controls in both age groups. Levels of peptidyl prolyl isomerase 1 (Pin1) were significantly decreased in APP/PS-1 mouse brain aged 9 and 12 months. Administration of N-acetyl-L-cysteine (NAC), a glutathione precursor, to APP/PS-1 mice via drinking water suppressed increased protein oxidation and nitration and also significantly augmented levels and activity of GPx in brain from both age groups. Oral administration of NAC also increased the diminished activity of GR and protected against lipid peroxidation in brains of 9-month-old APP/PS-1 mice only. Pin1 levels, GR levels, and G6PDH activity in brain were unaffected by oral administration of NAC in both age groups. These results are discussed with reference to the therapeutic potential of this brain-accessible glutathione precursor in the treatment of MCI and AD.

Association between male gender and cortical Lewy body pathology in large autopsy series.

Sex-linked factors may alter risk for neurodegenerative diseases. Definitive diagnoses are not established until autopsy, so neuropathological studies are critical. There have not been reported gender-related differences in neocortical Lewy bodies (LBs) using large multi-center autopsy series. We evaluated the associations between gender and pathologically characterized neurodegenerative diseases. Cases with Alzheimer's disease (AD), neocortical LBs, AD + neocortical LBs, or neither pathology were evaluated as separate groups. Results were corrected for possible confounders including age at death, smoking history, and education. The settings were the University of Kentucky Alzheimer's Disease Center and the National Alzheimer's Coordinating Center (NACC) Registry autopsy series; 3,830 subjects met inclusion criteria. Patients with neocortical ("diffuse") or intermediate ("limbic") LB pathologies tended to be male (male:female odds ratios ~2.9 with 95% CI 2.02-4.18). The preponderance of males dying with neocortical LB pathology was seen consistently across age groups and was not due to the potential confounders evaluated. By contrast, individuals dying with AD pathology were more likely to be female if dying over 80 (male:female odds ratio 0.66, 95% CI 0.50-0.88), but that tendency was not seen in individuals dying with AD pathology prior to age 80. Increased understanding of the male predominance in neocortical LB pathology may help guide clinicians, because males are more likely to be "undercalled" for neocortical LBs clinically, and females are more likely to be "overcalled" (P < 0.05 for both). Males are far more likely than females to die with neocortical LB pathology. This phenomenon may help guide medical practice including clinical trial study design.

Omega-3 fatty acids: potential role in the management of early Alzheimer's disease.

Omega-3 fatty acids are essential for brain growth and development. They play an important role throughout life, as critical modulators of neuronal function and regulation of oxidative stress mechanisms, in brain health and disease. Docosahexanoic acid (DHA), the major omega-3 fatty acid found in neurons, has taken on a central role as a target for therapeutic intervention in Alzheimer's disease (AD). A plethora of in vitro, animal model, and human data, gathered over the past decade, highlight the important role DHA may play in the development of a variety of neurological and psychiatric disorders, including AD. Cross sectional and prospective cohort data have demonstrated that reduced dietary intake or low brain levels of DHA are associated with accelerated cognitive decline or the development of incipient dementia, including AD. Several clinical trials investigating the effects of omega-3 fatty acid supplementation in AD have been completed and all failed to demonstrate its efficacy in the treatment of AD. However, these trials produced intriguing data suggesting that the beneficial effects of omega-3 fatty acid supplementation may depend on the stage of disease, other dietary mediators, and apolipoprotein E status.

Preclinical Alzheimer disease: brain oxidative stress, Abeta peptide and proteomics.

Alzheimer disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory loss and subsequent dementia and neuropathologically by senile plaques, neurofibrillary tangles, and synapse loss. Interestingly, a small percentage of individuals with normal antemortem psychometric scores meet the neuropathological criteria for AD (termed 'preclinical' AD (PCAD)). In this study, inferior parietal lobule (IPL) from PCAD and control subjects was compared for oxidative stress markers by immunochemistry, amyloid beta peptide by ELISA, and identification of protein expression differences by proteomics. We observed a significant increase in highly insoluble monomeric Abeta42, but no significant differences in oligomeric Abeta nor in oxidative stress measurements between controls and PCAD subjects. Expression proteomics identified proteins whose trends in PCAD are indicative of cellular protection, possibly correlating with previous studies showing no cell loss in PCAD. Our analyses may reveal processes involved in a period of protection from neurodegeneration that mimic the clinical phenotype of PCAD.

Increased protein hydrophobicity in response to aging and Alzheimer disease.

Increased levels of misfolded and damaged proteins occur in response to brain aging and Alzheimer disease (AD), which presumably increase the amount of aggregation-prone proteins via elevations in hydrophobicity. The proteasome is an intracellular protease that degrades oxidized and ubiquitinated proteins, and its function is known to be impaired in response to both aging and AD. In this study we sought to determine the potential for increased levels of protein hydrophobicity occurring in response to aging and AD, to identify the contribution of proteasome inhibition to increased protein hydrophobicity, and last to identify the contribution of ubiquitinated and oxidized proteins to the pool of hydrophobic proteins. In our studies we identified that aging and AD brain exhibited increases in protein hydrophobicity as detected using Bis ANS, with dietary restriction (DR) significantly decreasing age-related increases in protein hydrophobicity. Affinity chromatography purification of hydrophobic proteins from aging and AD brains identified increased levels of oxidized and ubiquitinated proteins in the pool of hydrophobic proteins. Pharmacological inhibition of the proteasome in neurons, but not astrocytes, resulted in an increase in protein hydrophobicity. Taken together, these data indicate that there is a relationship between increased protein oxidation and protein ubiquitination and elevations in protein hydrophobicity within the aging and the AD brain, which may be mediated in part by impaired proteasome activity in neurons. Our studies also suggest a potential role for decreased oxidized and hydrophobic proteins in mediating the beneficial effects of DR.

Neuropathologic alterations in mild cognitive impairment: a review.

Mild cognitive impairment (MCI), the earliest clinically detectable phase of the trajectory toward dementia and Alzheimer's disease (AD), led to the need for even earlier detection and prevention of AD. Although it is a clinical diagnosis, its underlying neuropathological findings are just being defined. MCI is best studied in longitudinally followed patients in centers that are experienced in dementing disorders. In this review of the few major clinical-pathological reports of longitudinally followed patients, it appears that most autopsied amnestic MCI (aMCI) patients are on a pathway toward AD. Neurofibrillary pathology in entorhinal cortex, hippocampus, and amygdala--not amyloid plaques--is the major substrate for aMCI and for memory decline. In addition, many MCI patients have other concomitant pathological alterations, the most common of which are strokes, but also include argyrophilic grains and Lewy bodies. These findings are not surprising because most MCI autopsied cases have been in the older (80 to 90 year) range where these findings are common. In early AD, the phase following MCI, the significant change is an increase in neurofibrillary tangles in the neocortex that correlates with an increase in Braak score and the observed clinical progression.

Quantitative changes in the mitochondrial proteome from subjects with mild cognitive impairment, early stage, and late stage Alzheimer's disease.

The major barrier to treating or preventing Alzheimer's disease (AD) is its unknown etiology and pathogenesis. Although increasing evidence supports a role for mitochondrial dysfunction in the pathogenesis of AD, there have been few studies that simultaneously evaluate changes in multiple mitochondrial proteins. To evaluate changes in sites of potentially interacting mitochondrial proteins, we applied 2-dimensional liquid chromatography coupled with tandem mass spectrometry and the isotope coded affinity tag method to identify and quantify proteins in mitochondrial enriched fractions isolated from short postmortem interval temporal pole specimens from subjects with mild cognitive impairment (4 subjects pooled), early AD (4 subjects pooled), late-stage AD (8 subjects pooled) and age-matched normal control (7 subjects pooled) subjects. A total of 112 unique, non-redundant proteins were identified and quantified in common to all three stages of disease progression. Overall, patterns of protein change suggest activation of mitochondrial pathways that include proteins responsible for transport and utilization of ATP. These proteins include adenine nucleotide translocase, voltage dependent anion channels, hexokinase, and creatine kinase. Comparison of protein changes throughout the progression of AD suggests the most pronounced changes occur in early AD mitochondria.

Age-related loss of phospholipid asymmetry in APP(NLh)/APP(NLh) x PS-1(P264L)/PS-1(P264L) human double mutant knock-in mice: relevance to Alzheimer disease.

Using APP(NLh)/APP(NLh) x PS-1(P246L)/PS-1(P246L) human double knock-in (APP/PS-1) mice, we examined whether phosphatidylserine (PtdSer) asymmetry is significantly altered in brain of this familial Alzheimer disease mouse model in an age-dependent manner as a result of oxidative stress, toxic Abeta(1-42) oligomer production, and/or apoptosis. Annexin V (AV) and NBD-PS fluorescence in synaptosomes of wild-type (WT) and APP/PS-1 mice were used to determine PtdSer exposure with age, while Mg(2+) ATPase activity was determined to correlate PtdSer asymmetry changes with PtdSer translocase, flippase, activity. AV and NBD-PS results demonstrated significant PtdSer exposure beginning at 9 months compared to 1-month-old WT controls for both assays, a trend that was exacerbated in synaptosomes of APP/PS-1 mice. Decreasing Mg(2+) ATPase activity confirms that the age-related loss of PtdSer asymmetry is likely due to loss of flippase activity, more prominent in APP/PS-1 brain. Two-site sandwich ELISA on SDS- and FA-soluble APP/PS-1 brain fractions were conducted to correlate Abeta(1-40) and Abeta(1-42) levels with age-related trends determined from the AV, NBD-PS, and Mg(2+) ATPase assays. ELISA revealed a significant increase in both SDS- and FA-soluble Abeta(1-40) and Abeta(1-42) with age, consistent with PtdSer and flippase assay trends. Lastly, because PtdSer exposure is affected by pro-apoptotic caspase-3, levels of both latent and active forms were measured. Western blotting results demonstrated an increase in both active fragments of caspase-3 with age, while levels of pro-caspase-3 decrease. These results are discussed with relevance to loss of lipid asymmetry and consequent neurotoxicity in brain of subjects with Alzheimer disease.

NOX activity is increased in mild cognitive impairment.

This study was undertaken to investigate the profile of NADPH oxidase (NOX) in the clinical progression of Alzheimer's disease (AD). Specifically, NOX activity and expression of the regulatory subunit p47phox and the catalytic subunit gp91phox was evaluated in affected (superior and middle temporal gyri) and unaffected (cerebellum) brain regions from a longitudinally followed group of patients. This group included both control and late-stage AD subjects, and also subjects with preclinical AD and with amnestic mild cognitive impairment (MCI) to evaluate the profile of NOX in the earliest stages of dementia. Data show significant elevations in NOX activity and expression in the temporal gyri of MCI patients as compared with controls, but not in preclinical or late-stage AD samples, and not in the cerebellum. Immunohistochemical evaluations of NOX expression indicate that whereas microglia express high levels of gp91phox, moderate levels of gp91phox also are expressed in neurons. Finally, in vitro experiments showed that NOX inhibition blunted the ability of oligomeric amyloid beta peptides to injure cultured neurons. Collectively, these data show that NOX expression and activity are upregulated specifically in a vulnerable brain region of MCI patients, and suggest that increases in NOX-associated redox pathways in neurons might participate in the early pathogenesis of AD.

Low sensitivity in clinical diagnoses of dementia with Lewy bodies.

The success of future neurodegenerative disease (ND) therapies depends partly on accurate antemortem diagnoses. Relatively few prior studies have been performed on large, multicenter-derived datasets to test the accuracy of final clinical ND diagnoses in relation to definitive neuropathological findings. Data were analyzed from the University of Kentucky Alzheimer's Disease Center autopsy series and from the National Alzheimer's Coordinating Center (NACC) registry. NACC data are derived from 31 different academic medical centers, each with strong clinical expertise and infrastructure pertaining to NDs. The final clinical diagnoses were compared systematically with subsequent neuropathology diagnoses. Among subjects meeting final inclusion criteria (N = 2,861 for NACC Registry data), the strength of the associations between clinical diagnoses and subsequent ND diagnoses was only moderate. This was particularly true in the case of dementia with Lewy bodies (DLB): the sensitivity of clinical diagnoses was quite low (32.1% for pure DLB and 12.1% for Alzheimer's disease (AD + DLB) although specificity was over 95%. AD clinical diagnoses were more accurate (85.0% sensitivity and 51.1% specificity). The accuracy of clinical DLB diagnoses became somewhat lower over the past decade, due apparently to increased "over-calling" the diagnosis in patients with severe cognitive impairment. Furthermore, using visual hallucinations, extrapyramidal signs, and/or fluctuating cognition as part of the clinical criteria for DLB diagnosis was of minimal utility in a group (N = 237) with high prevalence of severe dementia. Our data suggest that further work is needed to refine our ability to identify specific aging-related brain disease mechanisms, especially in DLB.