Necrosome-positive granulovacuolar degeneration is associated with TDP-43 pathological lesions in the hippocampus of ALS/FTLD cases.

AIM: Granulovacuolar degeneration (GVD) in Alzheimer's disease (AD) involves the necrosome, which is a protein complex consisting of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3 and phosphorylated mixed lineage kinase domain-like protein (pMLKL). Necrosome-positive GVD was associated with neuron loss in AD. GVD was recently linked to the C9ORF72 mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with transactive response DNA-binding protein (TDP-43) pathology (FTLD-TDP). Therefore, we investigated whether GVD in cases of the ALS-FTLD-TDP spectrum (ALS/FTLD) shows a similar involvement of the necrosome as in AD, and whether it correlates with diagnosis, presence of protein aggregates and cell death in ALS/FTLD. METHODS: We analysed the presence and distribution of the necrosome in post-mortem brain and spinal cord of ALS and FTLD-TDP patients (n = 30) with and without the C9ORF72 mutation, and controls (n = 22). We investigated the association of the necrosome with diagnosis, the presence of pathological protein aggregates and neuronal loss. RESULTS: Necrosome-positive GVD was primarily observed in hippocampal regions of ALS/FTLD cases and was associated with hippocampal TDP-43 inclusions as the main predictor of the pMLKL-GVD stage, as well as with the Braak stage of neurofibrillary tangle pathology. The central cortex and spinal cord, showing motor neuron loss in ALS, were devoid of any accumulation of pRIPK1, pRIPK3 or pMLKL. CONCLUSIONS: Our findings suggest a role for hippocampal TDP-43 pathology as a contributor to necrosome-positive GVD in ALS/FTLD. The absence of necroptosis-related proteins in motor neurons in ALS argues against a role for necroptosis in ALS-related motor neuron death.

Review: sporadic cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) may result from focal to widespread amyloid-ß protein (Aß) deposition within leptomeningeal and intracortical cerebral blood vessels. In addition, pericapillary Aß refers to Aß depositions in the glia limitans and adjacent neuropil, whereas in capillary CAA Aß depositions are present in the capillary wall. CAA may cause lobar intracerebral haemorrhages and microbleeds. Hypoperfusion and reduced vascular autoregulation due to CAA might cause infarcts and white matter lesions. CAA thus causes vascular lesions that potentially lead to (vascular) dementia and may further contribute to dementia by impeding the clearance of solutes out of the brain and transport of nutrients across the blood brain barrier. Severe CAA is an independent risk factor for cognitive decline. The clinical diagnosis of CAA is based on the assessment of associated cerebrovascular lesions. In addition, perivascular spaces in the white matter and reduced concentrations of both Aß(40) and Aß(42) in cerebrospinal fluid may prove to be suggestive for CAA. Transgenic mouse models that overexpress human Aß precursor protein show parenchymal Aß and CAA, thus corroborating the current concept of CAA pathogenesis: neuronal Aß enters the perivascular drainage pathway and may accumulate in vessel walls due to increased amounts and/or decreased clearance of Aß, respectively. We suggest that pericapillary Aß represents early impairment of the perivascular drainage pathway while capillary CAA is associated with decreased transendothelial clearance of Aß. CAA plays an important role in the multimorbid condition of the ageing brain but its contribution to neurodegeneration remains to be elucidated.

Filamentous tau pathology in nerve cells, astrocytes, and oligodendrocytes of aged baboons.

Intracellular filamentous inclusions containing abnormally phosphorylated tau protein are hallmarks of several human neurodegenerative disorders. This study reveals tau-positive cytoskeletal abnormalities in neurons and glial cells of aged baboons. The brains of four baboons (Papio hamadryas, 20-30 yr of age) were examined using the Gallyas silver technique for neurofibrillary changes and phosphorylation-dependent anti-tau antibodies (AT8, AT100, AT270, PHF-1, TG-3). Conspicuous changes were noted in two animals, 26 and 30 yr of age. In both animals, a combination of neuronal and glial cytoskeletal pathology was seen preferentially affecting limbic brain areas, including the hippocampal formation. In the 30-yr-old animal, numerous tau-positive inclusions were seen in the granule cells of the fascia dentata. These cells even exhibited an accumulation of argyrophilic neurofibrillary tangles. The glial changes affected both astrocytes and oligodendrocytes. Tau-positive astrocytes were seen in perivascular, subpial, and subependymal locations. Tau-positive oligodendrocytes preferentially occurred in limbic fiber tracts including the entorhinal perforant path. Ultrastructurally, tau-positive straight filaments (10-14 nm) in both neurons and glial cells were revealed by anti-tau immunoelectron microscopy. This study thus indicates the potential usefulness of aged baboons for experimental investigation of neuronal and glial filamentous tau pathology. This nonhuman primate species may provide valuable information pertinent to the broad spectrum of human tauopathies.

Fleecy amyloid deposits in the internal layers of the human entorhinal cortex are comprised of N-terminal truncated fragments of Abeta.

The deposition of amyloid in the brain is a hallmark of Alzheimer disease (AD). Amyloid deposits consist of accumulations of beta-amyloid (Abeta), which is a 39-43 amino-acid peptide cleaved from the Abeta-protein precursor (APP). Another cleavage product of APP is the P3-peptide, which consists of the amino acids 17-42 of the Abeta-peptide. In order to study the deposition of N-terminal truncated forms of Abeta in the human entorhinal cortex, serial sections from 16 autopsy cases with AD-related pathology were immunostained with antibodies against Abeta1-40, Abeta1-42, Abeta17-23, and Abeta8-17, as well as with the Campbell-Switzer silver impregnation for amyloid. In the external entorhinal layers (pre-beta and pre-gamma), sharply delineated diffuse plaques were seen. They were labeled by silver impregnation and by all Abeta-antibodies used. By comparison, in the internal layers (pri-alpha, pri-beta, and pri-gamma) blurred, ill-defined clouds of amyloid existed, in addition to sharply delineated diffuse plaques. These clouds of amyloid were termed "fleecy amyloid." Immunohistochemically, fleecy amyloid was stained by Abeta17-23 and Abeta1-42 antibodies, but not with antibodies against Abeta8-17 and Abeta1-40. Using the Campbell-Switzer technique, the fleecy amyloid deposits were found to be fine argyrophilic amyloid fibrils. Thus, the internal entorhinal layers are susceptible to a distinct type of amyloid, namely fleecy amyloid. This fleecy amyloid obviously corresponds to N-terminal truncated fragments of Abeta1-42, probably representing the P3-peptide. These N-terminal truncated fragments of Abeta are capable of creating fine fibrillar "amyloid."

Sequence of Abeta-protein deposition in the human medial temporal lobe.

The deposition of Abeta protein (Abeta) and the development of neurofibrillary changes are important histopathological hallmarks of Alzheimer disease (AD). In this study, the medial temporal lobe serves as a model for the changes in the anatomical distribution pattern of different types of Abeta-deposits occurring in the course of AD, as well as for the relationship between the development of Abeta-deposition and that of neurofibrillary pathology. In the first of 4 phases of beta-amyloidosis, diffuse non-neuritic plaques are deposited in the basal temporal neocortex. The same plaque type appears in the second phase within the external entorhinal layers pre-beta and pre-gamma, and fleecy amyloid deposits occur in the internal entorhinal layers pri-alpha, pri-beta, pri-gamma, and in CA1. In the third phase, Abeta-deposits emerge in the molecular layer of the fascia dentata, and band-like Abeta-deposits occur in the subpial portion of the molecular layer of both the entorhinal region and the temporal neocortex. In addition, confluent lake-like Abeta-deposits appear in the parvopyramidal layer of the presubicular region. The fourth phase is characterized by diffuse and core-only plaques in CA4. Diffuse plaques evolve sporadically in the external entorhinal layer pre-alpha. Parallel to the evolution of beta-amyloidosis as represented by the 4 phases, neuritic plaques gradually make their appearance in the temporal neocortex, entorhinal region, CA1, the molecular layer of the fascia dentata, and CA4. A prerequisite for their development is the presence of Abeta and the presence of neurofibrillary tangles in neurons targeting the regions where neuritic plaques evolve. Each of the different types of Abeta-deposits, including neuritic plaques, plays a specific role in the distinct developmental sequence as represented by the 4 phases so that the medial temporal lobe inexorably becomes involved to an ever greater extent. The step-for-step involvement of connected anatomical subfields highlights the importance of the entorhino-hippocampal pathways for the expansion of beta-amyloidosis. The 4 phases in the evolution of beta-amyloidosis correlate significantly with the stages of the neurofibrillary pathology proposed by Braak and Braak.

Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer's disease is different from plaque and cortical microglial pathology.

In terminal Alzheimer's disease (AD) the frequency of plaques was found to be reduced in single cases. To test this finding in a larger sample, and in order to determine whether the number of plaques labeled with different markers and the distribution of neurofibrillary tangles are correlated positively to each other and to the degree of dementia, a sample of 134 autopsy brains with and 15 without AD-related pathology has been examined. All of the cases were staged according to Braak and Braak. Both the frequency of plaques immunopositive for beta-amyloid, amyloid precursor protein, and apolipoprotein E and that of microglial cells in the cortex and in the white matter were determined semiquantitatively. The content and distribution of PHF-tau was ascertained by ELISA and immunohistochemistry. Both the clinical dementia rating and the global deterioration scale were used as clinical parameters retrospectively. Correlation coefficients were calculated for all parameters and differences were evaluated statistically. With progressive distribution of neurofibrillary tangles and increasing content of PHF-tau the plaque stages and the degree of cortical microglia reaction increased up to the Braak-stages IV and V, thereafter showing a slightly decreasing tendency in the investigated regions. In end-stage AD resorption of beta-amyloid seems to surpass its deposition. The microglial reaction in the white matter correlated neither with the Braak-stage nor with the accumulation of amyloid. With regard to the degree of dementia, both scales correlated well with the pathological changes. Our data show that neuronal cytoskeletal alterations progressively increase with progressive dementia until the end stage of AD in contrast to the frequencies of plaques and cortical microglial cells, and are therefore preferable for staging purposes.

Ultrastructural differences of hippocampal lipofuscin in human development.

The lipofuscin of pyramidal cells in each hippocampal subfield of each of seven human autopsy cases without brain disease at the age of 3-12 months (infants) and of 17-23 years (young adults) was comparatively investigated at the electron microscopic level. In infant pyramidal neurons of the hippocampal subfields CA 1, CA 2, CA 3 and CA 4 O-2, very small lipofuscin particles were observed. The lipofuscin composition showed a slightly larger granular component compared to the vacuolar component with one or two small lipid droplets. No obvious ultrastructural variability of lipofuscin granules was observed. The CA 1 lipofuscin in young adults consists of larger particles than in infants, but no obvious difference in the composition of granular and vacuolar components from the infant lipofuscin was seen. The amount of lipofuscin in CA 1 strongly increased in young adults compared to infants and appeared in a perinuclear distribution. In young adults, in contrast to the infant group, the amount of lipofuscin in the subfields CA 2, CA 3 and CA 4 was significantly higher than in CA 1. In CA 2, CA 3 and CA 4 pyramidal neurons, the vacuolar component was significantly larger than the granular component. The similarity of infant hippocampal lipofuscin patterns in all subfields is discussed as a state of immaturity. To explain the observed differences between the CA 1 and the other subfields during neuronal development, as shown in the young adult group, several factors are discussed: the effects of cell specific metabolism, cellular functional activity, cytoprotective mechanisms and effects of efferent and afferent pathways connected with the subfields.

Gender and age modify the association between APOE and AD-related neuropathology.

OBJECTIVE: To assess the impact of apolipoprotein E (APOE) polymorphism on AD-related neurofibrillary tangle (NFT) formation and senile plaques (SP). METHODS: A sample of 729 routine autopsy brains (359 men, 370 women; age range, 60 to 99 years) was investigated. All brains were classified neuropathologically according to a procedure permitting differentiation of six NFT stages and three SP stages. APOE genotyping was performed on all cases. RESULTS: The epsilon4 allele of APOE was associated not only with SP (p < 0.0001) but also with NFT formation (p < 0.0001). The effect of the epsilon4 allele on NFT formation was noted at ages > or =80 years (p < 0.0001) but not between ages 60 and 79 years (p = 0.12). An association between the epsilon4 allele and SP for women was found at ages 60 to 79 years (p < 0.0001) but not at > or =80 years of age (p = 0.063). By comparison, men showed an association in both age categories (p = 0.001 and p = 0.001). CONCLUSION: The results confirm the association between the epsilon4 allele and both types of AD-related lesions and show that this association is differentially modified by age and gender.

The subunits of alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein, native and transformed alpha2-macroglobulin and interleukin 6 in Alzheimer's disease.

To explore the role of alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2M-R/LRP) and its ligands in the pathogenesis of Alzheimer's disease (AD), antibodies were raised against its alpha- and beta-subunits and their expression pattern in the CNS in AD and control cases was correlated with that of native and transformed alpha2-macroglobulin (alpha2M) and interleukin 6 (IL-6). The transmembranous beta-subunit of alpha2M-R/LRP and transformed alpha2M were found in plaque cores in AD. Extramembranous alpha-subunit and native alpha2M immunoreactivities were localized in activated plaque-associated astrocytes and extracellularly in plaques. IL-6 immunostaining was associated with neurofibrillary changes, and was also found extracellularly in the center of plaques and in microglial cells. Our finding that plaque cores contain a second transmembranous protein fragment, the beta-subunit of alpha2 M-R/LRP, suggests ongoing membrane-protein degradation. By altering clearance and scavenger-like functions, fragmentation and breakdown of alpha2M-R/LRP may have an important role in extracellular amyloid deposition and the formation of neurofibrillary tangles in AD.

Carotid artery dissection in a young adult: cystic medial necrosis associated with an increased elastase content.

A dissecting aneurysm of the right internal carotid artery was found in a 22-year-old man, who rapidly became unconscious and hemiparetic after an accident occurring during sport. The dissection was limited to the intima and internal elastic lamina. Patterns of cystic medial necrosis with mucoid degeneration were present in the right internal carotid artery proximal to the site of dissection, in the thoracic aorta, and in several visceral arteries. In the region of the right internal carotid artery affected with cystic medial necrosis, calcification and also splitting of the internal elastic lamina was found. Such calcification was also present at the site of the dissection, at the tip of the ruptured and recoiled elastic lamina. These changes, dissection as well as cystic medial necrosis, were associated with an elevated elastase content, a decrease of desmin and an increase of vimentin expression. Ultrastructurally, in areas affected by cystic medial necrosis a corresponding transformation of medial smooth muscle cell phenotype from the contractile to the metabolic state was found. The topographical relation of dissecting aneurysm, cystic medial necrosis, and an increased elastase content is suggestive of a causal relation, and the possibility of common etiological factors is discussed.

Diffuse plaques in the molecular layer show intracellular A beta(8-17)-immunoreactive deposits in subpial astrocytes.

The presence of A beta protein- (A beta) containing astrocytes in diffuse plaques of the cortical layers II-VI has recently been demonstrated with antibodies directed against A beta(17-23) and C-terminal epitopes, of A beta. We here confirm and extend this finding by use of immunocytochemical double-labeling and preembedding immune-electron microscopy. Diffuse subpial plaques are associated with both anti-A beta(8-17) and anti-A beta(17-23)-positive granules in astrocytes. The ultrastructural nature of these intracellular deposits has been demonstrated to be lysosomal and the deposits have a lipofuscin-like appearance. These data point to a role of subpial astrocytes in the degradation of A beta by lysosomal processing.

UV light-induced autofluorescence of full-length Abeta-protein deposits in the human brain.

The formation of amyloid plaques is a hallmark of Alzheimer's disease (AD). Amyloid plaques and vascular amyloid deposits in cerebral amyloid angiopathy (CAA) consist of the beta-amyloid protein (Abeta) in association with other proteins. These Abeta-deposits can be visualized by thioflavin S, Congo red staining, silver staining methods and immunohistochemistry. Senile plaques also have been shown to exhibit blue autofluorescence. Here we report that UV light-induced autofluorescence is restricted to full-length Abeta-containing amyloid plaques and is also seen in blood vessels affected by CAA. Different types of samples from AD and control cortices were examined: native samples, formalin-fixed paraffin and polyethylene glycol-embedded tissue sections. These samples were viewed with a fluorescence microscope under UV light excitation (360 - 370 nm). By emitting blue fluorescence (>420 nm), amyloid plaques and blood vessels affected by CAA were detected in AD and CAA samples. Combination with immunofluorescence against anti-Abeta1-42, anti-Abeta17-24, and anti-Abeta8-17 demonstrated co-localization of the autofluorescent deposits with full-length Abeta containing Abeta-deposits. N-terminal truncated Abeta-deposits, such as the fleecy amyloid, do not exhibit autofluorescence. In doing so, Abeta-autofluorescence is a suitable method for screening native tissue samples for full-length Abeta-deposits. In contradistinction to conventional and immunohistochemical procedures, detection of plaques and CAA by autofluorescence enables the recognition of full-length Abeta-deposits in the human brain without any chemical interaction whatsoever on the part of Abeta.

Giant cell arteritis in a 19-year-old woman associated with vertebral artery aneurysm and subarachnoid hemorrhage.

Giant cell arteritis (GCA) is a disease chiefly found in elderly patients. Intracranial vessels are rarely involved in GCA. Here we report the case of a 19-year-old woman with GCA in the basilar and vertebral arteries. Two weeks after the first symptoms, she developed an aneurysmatical dilatation of the right vertebral artery which ruptured leading to subarachnoid hemorrhage. Although the ruptured right vertebral artery was clipped neurosurgically, she died two days later. Autopsy revealed GCA with focal medial necrosis and intimal thickening of the vertebral arteries and the basilar artery. No other arteries were affected. In the involved vessels, the media exhibited C1q immunoreactivity. At the intimal site of the internal elastic lamina there were increased levels of elastase. Other arterial diseases showing the pattern of GCA were excluded. This case demonstrates that GCA is not necessarily restricted to elderly people. Moreover, this case shows that a GCA-induced aneurysm is a very rare reason for subarachnoid hemorrhage even in young adults.

Selective quantitative analysis of the intensity of immunohistochemical reactions.

The present study reports a new method for the densitometric measurement of the intensity of immunohistochemical reactions. This method is based on a programm for the Kontron VIDAS image analysis system and has been designed for the measurement of small differences in the relative intensity of immunohistochemical reactions. Immunohistochemistry was performed with the avidin-biotin-peroxidase complex and diaminobenzidine-HCl and H2O2 for enzyme visualization. Several methods for shade correction and image processing were elaborated. The study was carried out on gerbil Purkinje cells using monoclonal antibodies raised against calbindin D28k. Prerequesites of correct measurement were standardized preparation, i.e., identical thickness of the paraffin sections, identical performance of immunohistochemistry, and avoidance of any counterstaining. The evaluation of small intensity differences of immunohistochemical reactions was found to be feasible either by substractive shade correction and standardized normalization or by shade correction by division by a reference image and standardized thresholding. Small differences in antigen concentration were not detectable without additional image processing.

Ultrastructural morphometric analysis of lipofuscin in pyramidal cells of the human Ammon's horn.

Lipofuscin is a waste product of autolysosomal metabolism. The amount of lipofuscin in the cytoplasm depends on cell type, cell function and age. In most studies, either the fluorescent or the stained component of lipofuscin was investigated. Quantitative morphological investigations of the lipofuscin composition separated into the vacuolar and granular component were missing. For the hippocampal pyramidal cells we have determined the lipofuscin quantity and, separately, the vacuolar and granular component at the ultrastructural level. The hippocampal subfields CA 1, CA 2, CA 3 and CA 4 were observed at the ages 20, 40, 60 and 80 years (+/-3 years). Quantitative determinations of the vacuolar and granular component of neuronal lipofuscin in pyramidal cells were performed with a semi-automatic image analysis system. In CA 1 pyramidal cells the lipofuscin content was significantly lower than in the other sectors, which did not differ significantly in their lipofuscin content. The amount of the granular component in relation to the vacuolar component in CA 1 was larger than in the other sectors. With advancing age the lipofuscin content per cell increased. The vacuolar component of all hippocampal subfields experienced a larger increase than the granular component. Consequently the relation of the vacuolar and granular component changed; the relative amount of the vacuolar component increased, while that of the granular component decreased with age. The differences between sector CA 1 and the other hippocampal subfields were discussed with reference to differences of metabolic and functional activity of the neurons. Cytoprotective factors like Calbindin D28k were discussed for CA 1.

Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease.

OBJECTIVE: DNA damage accumulation in brain is associated with the development of Alzheimer disease (AD), but newly identified protein markers of DNA damage have not been evaluated in the diagnosis of AD and other forms of dementia. METHODS: Here, we analyzed the level of novel biomarkers of DNA damage and telomere dysfunction (chitinase activity, N-acetyl-glucosaminidase activity, stathmin, and EF-1α) in CSF of 94 patients with AD, 41 patients with non-AD dementia, and 40 control patients without dementia. RESULTS: Enzymatic activity of chitinase (chitotriosidase activity) and stathmin protein level were significantly increased in CSF of patients with AD and non-AD dementia compared with that of no dementia control patients. As a single marker, chitinase activity was most powerful for distinguishing patients with AD from no dementia patients with an accuracy of 85.8% using a single threshold. Discrimination was even superior to clinically standard CSF markers that showed an accuracy of 78.4% (ß-amyloid) and 77.6% (tau). Combined analysis of chitinase with other markers increased the accuracy to a maximum of 91%. The biomarkers of DNA damage were also increased in CSF of patients with non-AD dementia compared with no dementia patients, and the new biomarkers improved the diagnosis of non-AD dementia as well as the discrimination of AD from non-AD dementia. CONCLUSIONS: Taken together, the findings in this study provide experimental evidence that DNA damage markers are significantly increased in AD and non-AD dementia. The biomarkers identified outperformed the standard CSF markers for diagnosing AD and non-AD dementia in the cohort investigated.

Atypical teratoid-rhabdoid tumor spreading along the trigeminal nerve.

We here describe the case of a boy with an atypical teratoid-rhabdoid tumor (ATRT) of the 4th ventricle at 1 year of age and a local tumor recurrence at 19 months of age. Due to brainstem infiltration, only incomplete tumor resection was possible each time. High-dose chemotherapy, stem cell transplantation and irradiation resulted in complete tumor remission on a control MRI. At 8 years of age, another tumor appeared extending from the cerebellopontine angle along the right trigeminal nerve through Meckel's cave into the cavernous sinus. The trigeminal tumor was not in continuity with the primary ATRT but was located within the field of prior irradiation, neuroradiologically mimicking a schwannoma or a meningioma. The origin of the trigeminal tumor as a late metastasis of the former ATRT or as a less likely irradiation-induced secondary ATRT and the operative approach are discussed.

[Post-mortem diagnosis of Alzheimer's disease]. / Postmortale Diagnosestellung bei Morbus Alzheimer. Stadiengliederungen der kennzeichnenden Hirnveränderungen.

Alzheimer's disease is a slowly but continuously progressive degenerative disorder of the human central nervous system seen in approximately 15% of elderly people over the age of 65 years. Morphological hallmarks of this process are intra- and extracellular protein aggregates. The intraneuronal protein aggregates are primarily made up of abnormal phosphorylated tau-protein, which builds neurofibrillary tangles, neuropil threads and dystrophic neurites in neuritic plaques. The extracellular deposits consist of amyloid beta-protein (Abeta) aggregates showing the characteristics of amyloid fibrils. The evolution of neurofibrillary changes as well as Abeta-deposition in brain regions follows a distinct hierarchical sequence spanning many decades. Abeta deposition begins in the neocortex whereas neurofibrillary pathology starts in the allocortical nerve cells of the transentorhinal region. Both transformations continue to increase in severity and expand into further areas and regions. The hierarchical pattern allows an easily understandable staging of neurofibrillary and Abeta pathology which in turn reflects the clinical gravity of the disease. According to these stages a dementing disorder can be diagnostically attributed to Alzheimer's disease.

The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology.

Argyrophilic grain disease (AGD) constitutes a neurodegenerative disorder that occurs in the brains of the elderly and affects 5% of all patients with dementia. Tau protein-containing lesions known as argyrophilic grains and located predominantly in limbic regions of the brain characterize this disease. Dementia is encountered in only a subset of cases that display the morphological pattern of AGD. The aim of this study is to determine the role of concurrent Alzheimer's disease (AD)-related pathology for the development of dementia in AGD patients. A total of 204 post-mortem brains from 30 demented and 49 nondemented AGD patients, 39 AD patients, and from 86 nondemented controls without AGD were staged for AD-related neurofibrillary tangles (NFTs) as well as amyloid beta-protein (Abeta) deposition. To identify differences in AD-related pathology between demented and nondemented AGD cases, and to differentiate the pattern of AD-related changes in demented and nondemented AGD cases from that seen in AD and nondemented controls, we statistically compared the stages of Abeta and NFT distribution among these groups. Using a logistic regression model, we showed that AGD has a significant effect on the development of dementia beyond that attributable to AD-related pathology (P < 0.005). Demented AGD cases showed lower stages of AD-related pathology than did pure AD cases but higher stages than nondemented AGD patients. AGD associated dementia was seen in the presence of NFT (Braak)-stages II-IV and Abeta-phases 2-3, whereas those stages were not associated with dementia in the absence of AGD. In conclusion, AGD is a clinically relevant neurodegenerative entity that significantly contributes to the development of dementia by lowering the threshold for cognitive deficits in the presence of moderate amounts of AD-related pathology.