Pathological Diagnosis Of Alzheimer's Disease Research Articles

Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease.

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.

Trends in Postmortem Neurodegenerative and Cerebrovascular Neuropathologies Over 25 Years

With rapid aging of the US population, understanding trends over time in dementia occurrence is essential to public health planning and intervention; this understanding includes trends in neuropathologies underlying clinical dementia. To characterize trends in pathways underlying dementia by examining prevalence of postmortem neuropathologies in birth cohorts across 25 years. Two longitudinal cohorts, the Religious Orders Study and the Rush Memory and Aging Project, with autopsy data from 1997 to 2022 with up to 27 years follow-up were analyzed. Deceased individuals with complete postmortem neuropathology evaluations were included, and 177 individuals with most distant (<1905) or recent (>1930) years of birth were excluded. Four categories of year of birth: 1905-1914, 1915-1919, 1920-1924, and 1925-1930. Outcomes included pathologic diagnosis of Alzheimer disease (AD), global AD pathology, amyloid load, tau tangles, neocortical Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy neuropathological change, atherosclerosis, arteriolosclerosis, gross chronic infarcts, and chronic microinfarcts. For comparison, pathologies in each birth epoch were age-standardized to age distribution of the cohorts. χ2 Tests were used for categorical outcomes, and analysis of variance was used to compare means across birth epochs. Overall, 1554 participants were examined (510 [33%] male; median [range] age at death, 90 [66-108] years). Participants were distributed fairly evenly across birth epochs (1905-1914: n = 374; 1915-1919: n = 360; 1920-1924: n = 466; 1925-1930: n = 354). Across year of birth groups, no differences were found in prevalence of pathologic AD diagnosis; age-standardized prevalence fluctuated between 62% and 68% in the birth cohorts (χ2 test: P = .76 across birth epochs). Similarly, no differences were found in mean levels of global AD pathology, although there was greater density specifically of tau tangles in later birth cohorts (eg, age-standardized mean [SD], 1.53 [1.20] years for the 1905-1914 cohort and 1.87 [1.47] years for the 1925-1930 cohort; analysis of variance test: P = .01 across birth cohorts). There were no differences over time in other neurodegenerative pathologies. In contrast, atherosclerosis and arteriosclerosis were dramatically lower over time; for example, age-standardized prevalence of moderate to severe atherosclerosis ranged from 54% among those born from 1905-1914 to 22% for 1925-1930 (χ2 test: P < .001 across birth epochs). In this study, few differences in neurodegenerative pathologies were found, but there may be worse levels of tau tangles across birth cohorts over 25 years. This indicates that any improvements over time in clinical dementia observed by cohorts are likely in part associated with improved resilience to pathology rather than reduced AD pathology. Finally, vessel pathologies were markedly lower over birth cohorts, indicating the assocation with brain health of populationwide improvements in several vascular risk factors.

Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias.

Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies. Participants were community-dwelling older adults from 2 cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We use Alzheimer disease (AD) to refer to pathologically defined disease and Alzheimer dementia to refer to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TAR DNA binding protein 43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified with mass spectrometry-based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer dementia, including angiotensin-converting enzyme, calcium-regulated heat-stable protein 1 (CHSP1), procathepsin H (CATH), double C2-like domain-containing protein α, islet cell autoantigen 1-like protein, serine β-lactamase-like protein LACTB, mitochondrial, pleckstrin homology domain-containing family A member 1, replication termination factor 2, sorting nexin-32, syntaxin-4, and syntaxin-6 (STX6), were previously identified with an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices. A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. In contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Furthermore, while higher STX6 expression increased the risk of Alzheimer dementia, the protein was not associated with any of the neuropathologic indices investigated. Cortical proteins implicated in Alzheimer dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases and other pathways are at play. Furthermore, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.

Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.

To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention. Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR. Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region. We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.

Characteristics of Epigenetic Clocks Across Blood and Brain Tissue in Older Women and Men.

Epigenetic clocks are among the most promising biomarkers of aging. It is particularly important to establish biomarkers of brain aging to better understand neurodegenerative diseases. To advance application of epigenetic clocks—which were largely created with DNA methylation levels in blood samples—for use in brain, we need clearer evaluation of epigenetic clock behavior in brain, including direct comparisons of brain specimens with blood, a more accessible tissue for research. We leveraged data from the Religious Orders Study and Rush Memory and Aging Project to examine three established epigenetic clocks (Horvath, Hannum, PhenoAge clocks) and a newer clock, trained in cortical tissue. We calculated each clock in three different specimens: (1) antemortem CD4+ cells derived from blood (n = 41); (2) postmortem dorsolateral prefrontal cortex (DLPFC, n = 730); and (3) postmortem posterior cingulate cortex (PCC, n = 186), among older women and men, age 66–108 years at death. Across all clocks, epigenetic age calculated from blood and brain specimens was generally lower than chronologic age, although differences were smallest for the Cortical clock when calculated in the brain specimens. Nonetheless, we found that Pearson correlations of epigenetic to chronologic ages in brain specimens were generally reasonable for all clocks; correlations for the Horvath, Hannum, and PhenoAge clocks largely ranged from 0.5 to 0.7 (all p < 0.0001). The Cortical clock outperformed the other clocks, reaching a correlation of 0.83 in the DLFPC (p < 0.0001) for epigenetic vs. chronologic age. Nonetheless, epigenetic age was quite modestly correlated across blood and DLPFC in 41 participants with paired samples [Pearson r from 0.21 (p = 0.2) to 0.32 (p = 0.05)], indicating that broader research in neurodegeneration may benefit from clocks using CpG sites better conserved across blood and brain. Finally, in analyses stratified by sex, by pathologic diagnosis of Alzheimer disease, and by clinical diagnosis of Alzheimer dementia, correlations of epigenetic to chronologic age remained consistently high across all groups. Future research in brain aging will benefit from epigenetic clocks constructed in brain specimens, including exploration of any advantages of focusing on CpG sites conserved across brain and other tissue types.

A Machine Learning Method for Identifying Critical Interactions Between Gene Pairs in Alzheimer's Disease Prediction.

Background: Alzheimer's disease (AD) is the most common type of dementia. Scientists have discovered that the causes of AD may include a combination of genetic, lifestyle, and environmental factors, but the exact cause has not yet been elucidated. Effective strategies to prevent and treat AD therefore remain elusive. The identified genetic causes of AD mainly focus on individual genes, but growing evidence has shown that complex diseases are usually affected by the interaction of genes in a network. Few studies have focused on the interactions and correlations between genes and how they are gradually destroyed or disappear during AD progression. A differential network analysis has been recognized as an essential tool for identifying the underlying pathogenic mechanisms and significant genes for prediction analysis. We therefore aim to conduct a differential network analysis to reveal potential networks involved in the neuropathogenesis of AD and identify genes for AD prediction.Methods: In this paper, we selected 365 samples from the Religious Orders Study and the Rush Memory and Aging Project, including 193 clinically and neuropathologically confirmed AD subjects and 172 no cognitive impairment (NCI) controls. Then, we selected 158 genes belonging to the AD pathway (hsa05010) of the Kyoto Encyclopedia of Genes and Genomes. We employed a machine learning method, namely, joint density-based non-parametric differential interaction network analysis and classification (JDINAC), in the analysis of gene expression data (RNA-seq data). We searched for the differential networks in the RNA-seq data with a pathological diagnosis of AD. Finally, an optimal prediction model was built through cross-validation, which showed good discrimination and calibration for AD prediction.Results: We used JDINAC to derive a gene co-expression network and to explore the relationship between the interaction of gene pairs and AD, and the top 10 differential gene pairs were identified. We then compared the prediction performance between JDINAC and individual genes based on prediction methods. JDINAC provides better accuracy of classification than the latest methods, such as random forest and penalized logistic regression.Conclusions: The interaction between gene pairs is related to AD and can provide more insight than the individual genes in AD prediction.

Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick’s disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing β-amyloid, α-synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline, suggesting that MAO enzymes do not appear to be a significant binding target of any of these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.

ANK1 is up-regulated in laser captured microglia in Alzheimer's brain; the importance of addressing cellular heterogeneity.

Recent epigenetic association studies have identified a new gene, ANK1, in the pathogenesis of Alzheimer’s disease (AD). Although strong associations were observed, brain homogenates were used to generate the data, introducing complications because of the range of cell types analyzed. In order to address the issue of cellular heterogeneity in homogenate samples we isolated microglial, astrocytes and neurons by laser capture microdissection from CA1 of hippocampus in the same individuals with a clinical and pathological diagnosis of AD and matched control cases. Using this unique RNAseq data set, we show that in the hippocampus, ANK1 is significantly (p<0.0001) up-regulated 4-fold in AD microglia, but not in neurons or astrocytes from the same individuals. These data provide evidence that microglia are the source of ANK1 differential expression previously identified in homogenate samples in AD.

Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p < 5 × 10(-8)) for pathologic AD for all variants. APOE ε4 allele was associated with greater odds of pathologic AD (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.67-5.46, p = 1.9 × 10(-13)), while ε2 allele was associated with lower odds of pathologic AD (OR 0.42, 95% CI 0.30-0.61, p = 3.1 × 10(-6)). Four additional genomic variants including rs6656401 (CR1), rs1476679 (ZCWPW1), rs35349669 (INPP5D), and rs17125944 (FERMT2) had p values less than 0.05. Remarkably, half of the previously reported AD dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies.

Brain arterial aging and its relationship to Alzheimer dementia.

To test the hypothesis that brain arterial aging is associated with the pathologic diagnosis of Alzheimer disease (AD). Brain large arteries were assessed for diameter, gaps in the internal elastic lamina (IEL), luminal stenosis, atherosclerosis, and lumen-to-wall ratio. Elastin, collagen, and amyloid were assessed with Van Gieson, trichrome, and Congo red staining intensities, and quantified automatically. Brain infarcts and AD (defined pathologically) were assessed at autopsy. We created a brain arterial aging (BAA) score with arterial characteristics associated with aging after adjusting for demographic and clinical variables using cross-sectional generalized linear models. We studied 194 autopsied brains, 25 (13%) of which had autopsy evidence of AD. Brain arterial aging consisted of higher interadventitial and lumen diameters, thickening of the wall, increased prevalence of IEL gaps, concentric intima thickening, elastin loss, increased amyloid deposition, and a higher IEL proportion without changes in lumen-to-wall ratio. In multivariable analysis, a high IEL proportion (B = 1.96, p = 0.030), thick media (B = 3.50, p = 0.001), elastin loss (B = 6.16, p < 0.001), IEL gaps (B = 3.14, p = 0.023), and concentric intima thickening (B = 7.19, p < 0.001) were used to create the BAA score. Adjusting for demographics, vascular risk factors, atherosclerosis, and brain infarcts, the BAA score was associated with AD (B = 0.022, p = 0.002). Aging of brain large arteries is characterized by arterial dilation with a commensurate wall thickening, elastin loss, and IEL gaps. Greater intensity of arterial aging was associated with AD independently of atherosclerosis and brain infarcts. Understanding the drivers of arterial aging may advance the knowledge of the pathophysiology of AD.

Validating novel tau positron emission tomography tracer [F-18]-AV-1451 (T807) on postmortem brain tissue.

To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid proteins. We applied [F-18]-AV-1451 phosphor screen autoradiography, [F-18]-AV-1451 nuclear emulsion autoradiography, and [H-3]-AV-1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau, frontotemporal lobar degeneration-transactive response DNA binding protein 43 (TDP-43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology. Our data suggest that [F-18]-AV-1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non-Alzheimer tauopathy brains or to lesions containing β-amyloid, α-synuclein, or TDP-43. [F-18]-AV-1451 off-target binding to neuromelanin- and melanin-containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified. Our data suggest that [F-18]-AV-1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament-tau-containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non-Alzheimer tauopathy cases and to the existence of some [F-18]-AV-1451 off-target binding. These findings provide important insights for interpreting in vivo patterns of [F-18]-AV-1451 retention.

Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.

Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination. Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.

Visuoperception test predicts pathologic diagnosis of Alzheimer disease in corticobasal syndrome.

To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale-2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%).

Virological and Immunological Characteristics of Human Cytomegalovirus Infection Associated With Alzheimer Disease

Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon γ was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-β (CD8+). Immunocytochemical analysis showed induction of amyloid-β in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-β. These data support an association between CMV and the development of Alzheimer disease.

Challenges in the Neuropathological Diagnosis of Dementias

Dementia, defined as deterioration in several cognitive domains, is a major public health problem that threatens to become the scourge of the 21th century. It is caused by dysfunction/loss of synapses and neurons inducing default neuronal networks. Consensus criteria for the diagnosis of different dementia disorders have recently been updated. Clinical diagnostic accuracy using revised research criteria and new chemical, imaging and genetic biomarkers ranges from 65 to 96% (for Alzheimer disease), with a sensitivity versus other dementias of 71 to 87% and specificity of 44 to 71%. Morphological assessment, using immunohistochemistry, molecular biological and genetic methods and based on homogenous definitions, harmonized inter-laboratory methods and assessment standards, can achieve a diagnosis/classificaion in almost 99%, without, however, clarifying the etiology of most of these disorders. The new National Institute on Aging-Alzheimer Association (ABC) guidelines for pathological diagnosis of Alzheimer disease combine βamyloid plaque phases, Braak neurofibrillary and neuritic plaque scores, also considering other pathologies. Major difficulties arise from recent separation of distinct clinico-pathological subtypes (tangleand plaque intensive, tangle predominant, limbic-predominant and -sparing) from classical Alzheimer disease. Revised research criteria are available for dementia with Lewy bodies, Parkinson disease-dementia, frontotemporal lobe degeneration, vascular cognitive impairment/dementia, prion diseases, and other neurodegenerative dementias. However, due to considerable overlap between various neurodegenerative proteinopathies and cases with mixed pathologies, human postmortem studies entail numerous biases that affect both their general applicability and the validity of correlations. Although most neurodegenerative dementias are incurable at present, concerted prospective clinico-pathological studies using validated protocols and data fusion are required to overcome the limitations of the current diagnostic framework as a basis for efficient new therapy options.

Cognitive reserve, presynaptic proteins and dementia in the elderly

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N=253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein–protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N=97 (38.3%), a pathologic diagnosis of AD in N=142 (56.1%) and cerebral infarcts in N=77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio=0.36–0.68, P<0.001 to P=0.03) and better cognitive function (P<0.001 to P=0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P=0.01) and lower SNAP-25/syntaxin interaction (P<0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein–protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype

TAR DNA-binding protein 43 (TDP-43) is one of the major disease proteins in frontotemporal lobar degeneration with ubiquitin immunoreactivity. Approximately one-fourth of subjects with pathologically confirmed Alzheimer disease (AD) have abnormal TDP-43 (abTDP-43) immunoreactivity. The aim of this study was to determine whether subjects with pathologically confirmed AD and abTDP-43 immunoreactivity have distinct clinical, neuropsychological, imaging, or pathologic features compared with subjects with AD without abTDP-43 immunoreactivity. Eighty-four subjects were identified who had a pathologic diagnosis of AD, neuropsychometric testing, and volumetric MRI. Immunohistochemistry for TDP-43 was performed on sections of hippocampus and medial temporal lobe, and positive cases were classified into one of three types. Neuropsychometric data were collated and compared in subjects with and without abTDP-43 immunoreactivity. Voxel-based morphometry was used to assess patterns of gray matter atrophy in subjects with and without abTDP-43 immunoreactivity compared with age- and sex-matched controls. Twenty-nine (34%) of the 84 AD subjects had abTDP-43 immunoreactivity. Those with abTDP-43 immunoreactivity were older at onset and death and performed worse on the Clinical Dementia Rating scale, Mini-Mental State Examination, and Boston Naming Test than subjects without abTDP-43 immunoreactivity. Subjects with and without abTDP-43 immunoreactivity had medial temporal and temporoparietal gray matter loss compared with controls; however, those with abTDP-43 immunoreactivity showed greater hippocampal atrophy. Multivariate logistic regression adjusting for age at death demonstrated that hippocampal sclerosis was the only pathologic predictor of abTDP-43 immunoreactivity. The presence of abnormal TDP-43 immunoreactivity is associated with a modified Alzheimer disease clinicopathologic and radiologic phenotype.

Relation between vascular risk factors and neuropsychological test performance among elderly persons with Alzheimer's disease

Background Vascular risk factors increase the risk of Alzheimer's disease (AD). The mechanisms for these associations are unclear, and may be due to misdiagnosis of a vascular dementia syndrome as AD. Objective To examine differences in neuropsychological profile among persons diagnosed clinically with AD with and without vascular risk factors or stroke. Methods Community based cohort study. Individual and composite scores of neuropsychological tests at the time of clinical diagnosis of incident AD were compared among 243 persons with and without vascular risk factors or stroke. Results Among subjects with incident AD, diabetes was associated with lower performance in Delayed Recall of the Selective Reminding Test (SRT), while persons diagnosed with hypertension scored lower in consistent long term recall (CLTR) of the SRT and current smokers scored lower in Category Fluency. None of the risk factors was associated with differences in composite scores in memory, abstract/visuospatial or language domain, nor was the number of risk factors per person. Persons with stroke had a higher delayed recall score at the time of AD diagnosis. Conclusion The presence of vascular risk factors among persons with clinically diagnosed AD was associated with subtle differences in neuropsychological profile at the time of diagnosis. This study needs to be replicated in samples with brain imaging, a comprehensive executive abilities battery, and pathological diagnosis of AD.

Amyloid‐β in Alzheimer's disease: the horse or the cart? Pathogenic or protective?

While the pathogenesis of Alzheimer's disease (AD) is unclear, amyloid-beta plaques remain major lesions in the brain of individuals with AD. Likewise, amyloid-beta is one of the best-studied proteins relating to the pathogenesis of AD. Indeed, the pathological diagnosis of AD tends to be congruous with the quantity of amyloid-beta. However, it is important to recognize that pathological diagnosis merely represents the association of a pattern of pathological changes with a clinical phenotype. Therefore, it should be acknowledged that, although amyloid-beta detection and semiquantification have some diagnostic utility, the simple presence of amyloid plaques, as with proteinaceous accumulations in essentially all neurodegenerative diseases, does not presume aetiology. Thus, in this review, we discuss the role of amyloid-beta in the pathogenesis of AD and provide an alternative view to the widely accepted dogma.

Memory complaints in nondemented men predict future pathologic diagnosis of Alzheimer disease

The validity of memory complaints as a predictor of Alzheimer disease (AD) was assessed in 237 Japanese-American men autopsied at ages 74 to 97 years. These men were free of dementia at the time memory complaints were assessed 1 to 11 years earlier. Memory complaints were found to predict the neuropathologic diagnosis of AD after adjusting for age, time to death, education, depression, and cognitive functioning.