Neurofibrillary Tangle Pathology Research Articles

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses

Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Corpora amylacea negatively correlate with hippocampal tau pathology in Alzheimer's disease.

Severity and distribution of aggregated tau and neurofibrillary tangles (NFT) are strongly correlated with the clinical presentation of Alzheimer's disease (AD). Clearance of aggregated tau could decrease the rate of NFT formation and delay AD onset. Recent studies implicate corpora amylacea (CA) as a regulator of onset or accumulation of tau pathology. Normally, CA clear brain waste products by amassing cellular debris, which are then extruded into the cerebrospinal fluid to be phagocytosed. The proper functioning of CA may slow progression of AD-associated NFT pathology, and this relationship may be influenced by amount and distribution of phospho-tau (pTau) produced, age, sex, and genetic risk. The goal of this study was to determine if CA size and number are associated with hippocampal location and local pTau severity while accounting for variations in age, sex, and genetic risk. Postmortem brain hippocampal tissue sections from 40 AD and 38 unaffected donors were immunohistochemically stained with AT8 (pTau) and counter stained with periodic acid Schiff (PAS). Stained sections of the CA1 and CA3 regions of the hippocampus were analyzed. The percent area occupied (%AO) of CA, pTau, and NFT was calculated. Pairwise comparisons and regression modeling were used to analyze the influence of age, pTau %AO, and genetic risk on %AO by CA in each region, separately in donors with AD and unaffected donors. CA %AO was significantly higher in the CA3 region compared to CA1 in both groups. A significant negative correlation of CA %AO with both pTau %AO and neurofibrillary tangle %AO in the CA3 region of AD brain donors was found. Regression analysis in the CA3 region revealed a significant negative association between CA with both pTau and age. We found an increase of CA in the CA3 region, compared to CA1 region, in AD and unaffected donors. This may suggest that the CA3 region is a hub for waste removal. Additionally, the negative correlation between %AO by CA and NFT in the CA3 region of the hippocampus in donors with AD suggests CA could play a role in AD pathologic progression by influencing tau clearance.

EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A.In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.

Amidst an amygdala renaissance in Alzheimer's disease.

The amygdala was highlighted as an early site for neurofibrillary tau tangle pathology in Alzheimer's disease in the seminal 1991 article by Braak and Braak. This knowledge has, however, only received traction recently with advances in imaging and image analysis techniques. Here, we provide a cross-disciplinary overview of pathology and neuroimaging studies on the amygdala. These studies provide strong support for an early role of the amygdala in Alzheimer's disease and the utility of imaging biomarkers of the amygdala in detecting early changes and predicting decline in cognitive functions and neuropsychiatric symptoms in early stages. We summarize the animal literature on connectivity of the amygdala, demonstrating that amygdala nuclei that show the earliest and strongest accumulation of neurofibrillary tangle pathology are those that are connected to brain regions that also show early neurofibrillary tangle accumulation. Additionally, we propose an alternative pathway of neurofibrillary tangle spreading within the medial temporal lobe between the amygdala and the anterior hippocampus. The proposed existence of this pathway is strengthened by novel experimental data on human functional connectivity. Finally, we summarize the functional roles of the amygdala, highlighting the correspondence between neurofibrillary tangle accumulation and symptomatic profiles in Alzheimer's disease. In summary, these findings provide a new impetus for studying the amygdala in Alzheimer's disease and a unique perspective to guide further study on neurofibrillary tangle spreading and the occurrence of neuropsychiatric symptoms in Alzheimer's disease.

Development and implementation of plasma P‐tau immunoassays

AbstractBackgroundMultiple advances in plasma biomarkers have been reported in recent times, one of these being the development of plasma p‐tau assays.MethodsIn this invited presentation as part of the Perspectives Session on “Advances in plasma Alzheimer’s disease biomarkers,” I will provide an expert review of the current state of analytical development of plasma p‐tau biomarkers.ResultsSpecifically, I will discuss the biochemical and molecular bases of why specific p‐tau forms are accessible in blood whilst others are not, as well as why these blood p‐tau markers tend to associate predominantly with brain amyloid but not tau pathology. Furthermore, I will highlight new discoveries in the development of biofluid‐based tau markers (both phosphorylated and non‐phosphorylated) that associate with neurofibrillary tangle pathology. Other aspects of my talk will focus on associations of the novel biomarker plasma brain‐derived tau with AD‐signature neurodegeneration. Additionally, I will discuss how newly improved preanalytical handling protocols enable plasma biomarker measurements in remote and resource‐limited settings, towards democratizing access to diagnostics.ConclusionFinally, I will discuss and suggest solutions to challenges around cut‐off generation, inter‐laboratory and inter‐assay measurements.

Discovering correlates of off‐target 18F‐MK6240 signal in community‐dwelling adults

AbstractBackground18F‐MK6240 binds hyperphosphorylated tau protein in neurofibrillary tangles, a hallmark of Alzheimer’s disease(AD); however, the tracer may also bind to other similarly structured molecules, known as off‐target binding. Off‐target binding is inconsistent across individuals and can lead to biased quantitative assessment, making it difficult to accurately identify neurofibrillary tangle pathology. We examined variable off‐target binding by performing a correlation analysis with demographic factors, vascular risk, lifestyle factors, and co‐morbidities.MethodNinety‐five participants (65±3yrs; 67% women; 42/58% White/Black; 66% Hispanic; 12±4yrs education) in the Northern Manhattan Study of Metabolism and Mind(NOMEM) underwent 18F‐MK6240(90‐110min) and 18F‐Florbetaben(90‐110min) PET imaging and completed surveys, including age, sex, education, exercise levels, and medical history. Only visually‐determined amyloid‐negative participants were included to increase the likelihood that elevated tau PET signal was off‐target. Tau SUVR (cerebellar gray matter reference region) was calculated for composite Braak stages (I/II, III/IV, V/VI) and two known off‐target regions, the choroid plexus and the extra‐cerebral space around the brain. The extra‐cerebral mask was generated by dilating the gray/CSF boundary of the ANTs probability map and then subtracting the brain. Percent of variance explained (r2) from general linear models are reported between off‐target regions and factors of interest.ResultDescriptively, 18F‐MK6240 off‐target binding in choroid plexus was positively correlated with SUVR in Braak stage regions I/II (r2 = 0.37;p<0.001) and III/IV (r2 = 0.44;p<0.001) to a larger extent than V/VI (r2 = 0.21;p<0.001), while off‐target binding in the extra‐cerebral space was positively correlated with Braak stages I/II (r2 = 0.07;p<0.001) to a lesser extent than III/IV (r2 = 0.13;p<0.001) and V/VI (r2 = 0.18;p<0.001), suggesting that proximity of key AD regions to off‐target regions increases the likelihood of confounded signal. Off‐target binding in the choroid plexus was elevated amongst self‐identified Hispanic participants (r2 = 0.19;p<0.001). Extra‐cerebral off‐target binding was negatively associated with participant weight (r2 = 0.12;p<0.001).ConclusionExtra‐cerebral off‐target binding of 18F‐MK6240 may confound signal in key AD regions in amyloid‐negative participants. Off‐target binding should be accounted for regionally and methods for capturing extra‐cerebral signal are critical. Understanding the role of factors related to tracer distribution, including weight, and sociodemographic factors will enhance the quantification of 18F‐MK6240 for the early detection of neurofibrillary tangle pathology.

Discovering correlates of off‐target 18F‐MK6240 signal in community‐dwelling adults

AbstractBackground18F‐MK6240 binds hyperphosphorylated tau protein in neurofibrillary tangles, a hallmark of Alzheimer’s disease(AD); however, the tracer may also bind to other similarly structured molecules, known as off‐target binding. Off‐target binding is inconsistent across individuals and can lead to biased quantitative assessment, making it difficult to accurately identify neurofibrillary tangle pathology. We examined variable off‐target binding by performing a correlation analysis with demographic factors, vascular risk, lifestyle factors, and co‐morbidities.MethodsNinety‐five participants (65±3yrs; 67% women; 42/58% White/Black; 66% Hispanic; 12±4yrs education) in the Northern Manhattan Study of Metabolism and Mind(NOMEM) underwent 18F‐MK6240(90‐110min) and 18F‐Florbetaben(90‐110min) PET imaging and completed surveys, including age, sex, education, exercise levels, and medical history. Only visually‐determined amyloid‐negative participants were included to increase the likelihood that elevated tau PET signal was off‐target. Tau SUVR (cerebellar gray matter reference region) was calculated for composite Braak stages (I/II, III/IV, V/VI) and two known off‐target regions, the choroid plexus and the extra‐cerebral space around the brain. The extra‐cerebral mask was generated by dilating the gray/CSF boundary of the ANTs probability map and then subtracting the brain. Percent of variance explained (r2) from general linear models are reported between off‐target regions and factors of interest.ResultsDescriptively, 18F‐MK6240 off‐target binding in choroid plexus was positively correlated with SUVR in Braak stage regions I/II (r2 = 0.37;p<0.001) and III/IV (r2 = 0.44;p<0.001) to a larger extent than V/VI (r2 = 0.21;p<0.001), while off‐target binding in the extra‐cerebral space was positively correlated with Braak stages I/II (r2 = 0.07;p<0.001) to a lesser extent than III/IV (r2 = 0.13;p<0.001) and V/VI (r2 = 0.18;p<0.001), suggesting that proximity of key AD regions to off‐target regions increases the likelihood of confounded signal. Off‐target binding in the choroid plexus was elevated amongst self‐identified Hispanic participants (r2 = 0.19;p<0.001). Extra‐cerebral off‐target binding was negatively associated with participant weight (r2 = 0.12;p<0.001).ConclusionExtra‐cerebral off‐target binding of 18F‐MK6240 may confound signal in key AD regions in amyloid‐negative participants. Off‐target binding should be accounted for regionally and methods for capturing extra‐cerebral signal are critical. Understanding the role of factors related to tracer distribution, including weight, and sociodemographic factors will enhance the quantification of 18F‐MK6240 for the early detection of neurofibrillary tangle pathology.

Using an ex vivo MRI atlas of the human medial temporal lobe to characterize the 3D distribution of neurofibrillary tangle burden across histologically defined subregions

AbstractBackgroundAccumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.MethodWe combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion.ResultFig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3).ConclusionBuilding on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values>0.31) nor p‐tau (p‐values>0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values>0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values<0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Association between military service identified through public data tracing and Alzheimer’s disease neuropathology at autopsy

AbstractBackgroundMilitary veterans face increased risk of Alzheimer’s disease and related dementias (ADRD) compared to the general population, but the association between the military exposome and ADRD pathology is poorly understood. Existing biobanks rarely collect military service information, complicating efforts to characterize military risk factors. Public data tracing methods linking the military exposome to existing neuropathological data have the potential to catalyze research on the mechanisms driving brain health disparities.MethodSubjects were decedents from two Alzheimer’s Disease Research Center brain banks who died between 1986‐2018 and were characterized on neurofibrillary tangle burden (NFT‐B score, n = 1154). Military service was characterized through public data tracing (Figure 1): systematic extractions from public records including obituaries, newspapers, and enlistment records (Figure 2). NFT‐B score, per National Institute of Aging and Alzheimer’s Association guidelines for neuropathologic change, was extracted from the standardized Neuropathology Dataset form or from original autopsy reports. Generalized ordered logistic regression with site‐level clustered standards errors was used to model NFT‐B score, adjusting for age, sex, and year of death.ResultPublic data tracing identified 373 decedents (32% of the sample) with a history of military service. After adjusting for age, sex, and year of death, decedents with a history of military service had a 12% greater odds (OR = 1.12, 95% CI: 1.11–1.13) of a more severe NFT burden compared to those without a history of military service, which was proportional when comparing the odds at each increasing B score level (B score = (1,2, or 3), vs (0), B score = (2,3) vs (0,1) and B score = (3) vs (0,1,2)) (Table 1).ConclusionPublic data tracing offers a promising way to retrospectively add the military exposome into brain tissue biomarkers research. Military service was associated with more severe neurofibrillary tangle pathology, one of the primary neuropathological features of Alzheimer’s disease. Future research should explore the feasibility and validity of public data tracing for more detailed characterization of military service, such as length and branch of service, involvement in specific conflicts, or exposure to environmental toxins, which may elucidate mechanisms underlying its association with ADRD pathology.

FMRI Complexity Correlates with Tau-PET and Cognitive Decline in Late-Onset and Autosomal Dominant Alzheimer's Disease.

Neurofibrillary tangle pathology detected with tau-PET correlates closely with neuronal injury and cognitive symptoms in Alzheimer's disease (AD). Complexity of rs-fMRI has been demonstrated to decrease with cognitive decline in AD. We hypothesize that the rs-fMRI complexity provides an index for tau-related neuronal injury and cognitive decline in the AD process. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI3) and the Estudio de la Enfermedad de Alzheimer en Jalisciences (EEAJ) study. Associations between tau-PET and rs-fMRI complexity were calculated. Potential pathways relating complexity to cognitive function mediated through tau-PET were assessed by path analysis. We found significant negative correlations between rs-fMRI complexity and tau-PET in medial temporal lobe of both cohorts, and associations of rs-fMRI complexity with cognitive scores were mediated through tau-PET. The association of rs-fMRI complexity with tau-PET and cognition, suggests that a reduction in complexity is indicative of tau-related neuropathology and cognitive decline in AD processes.

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

Unbiased proteomics and multivariable regularized regression techniques identify SMOC1, NOG, APCS, and NTN1 in an Alzheimer’s disease brain proteomic signature

Advancements in omics methodologies have generated a wealth of high-dimensional Alzheimer’s disease (AD) datasets, creating significant opportunities and challenges for data interpretation. In this study, we utilized multivariable regularized regression techniques to identify a reduced set of proteins that could discriminate between AD and cognitively normal (CN) brain samples. Utilizing eNetXplorer, an R package that tests the accuracy and significance of a family of elastic net generalized linear models, we identified 4 proteins (SMOC1, NOG, APCS, NTN1) that accurately discriminated between AD (n = 31) and CN (n = 22) middle frontal gyrus (MFG) tissue samples from Religious Orders Study participants with 83 percent accuracy. We then validated this signature in MFG samples from Baltimore Longitudinal Study of Aging participants using leave-one-out logistic regression cross-validation, finding that the signature again accurately discriminated AD (n = 31) and CN (n = 19) participants with a receiver operating characteristic curve area under the curve of 0.863. These proteins were strongly correlated with the burden of neurofibrillary tangle and amyloid pathology in both study cohorts. We additionally tested whether these proteins differed between AD and CN inferior temporal gyrus (ITG) samples and blood serum samples at the time of AD diagnosis in ROS and BLSA, finding that the proteins differed between AD and CN ITG samples but not in blood serum samples. The identified proteins may provide mechanistic insights into the pathophysiology of AD, and the methods utilized in this study may serve as the basis for further work with additional high-dimensional datasets in AD.

The relationship between traumatic brain injury and the neuropathology of dementia

AbstractBackgroundClinical studies indicate that traumatic brain injury (TBI) is linked to an increased risk of dementia during life. However, studies involving neuropathologically‐confirmed cases have shown conflicting results. This study was aimed at assessing a large brain bank cohort to identify any association between TBI and the presence of pathologies underlying the most commonly found dementias, Alzheimer’s disease (AD) and Lewy body disease (LBD).Method636 cases were assessed for this study (average age 76.2). Cases with a history of TBI were identified using donor records held at the Sydney Brain Bank. We use the term "TBI” to include a single or multiple TBIs, as well as repetitive mild neurotrauma that may be subconcussive (N = 109). Amyloid plaque and alpha synuclein pathologies were identified by immunohistochemistry. Neurofibrillary tangles were identified using modified Bielschowsky silver staining. Pathology was assessed according to current neuropathological diagnostic criteria. Multivariate regression statistics were used to assess the effect of TBI, age and gender on amyloid plaque (A score), neurofibrillary tangles (B score) and Lewy pathology stages. Multinomial logistic regression was used to examine the effect of TBI on pathological diagnosis.ResultsTBI was not significantly associated with increased amyloid (p = 0.05) or Lewy pathology stages (p = 0.65), however the odds of having a higher neurofibrillary tangle stage increased by 75% in the TBI group (p = 0.009)(Figure 1). Gender was not a significant predictor of amyloid (p = 0.29), neurofibrillary tangle (p = 0.89) or Lewy pathology (p = 0.15). Not unexpectedly, age was a significant predictor of AD pathologies, including amyloid (p = <0.0000001) and neurofibrillary tangle (p = 0.00002) stages, although age was not a significant driver of Lewy body pathology (p = 0.1). There was no association between TBI and overall diagnosis of AD neuropathologic change or LBD (p = 0.12).ConclusionsIn this elderly neurodegenerative cohort, age remains a risk factor for AD, but not LBD pathology. Gender did not have a significant association with these pathologies in this cohort. TBI did not increase the risk of AD but did increase the frequency of neurofibrillary tangles, suggesting that abnormal tau protein accumulation following TBI is an important long‐term consequence that may contribute to poor brain aging and future neurodegeneration.

Tau deposition in the locus coeruleus and depression in cognitively unimpaired older adults

AbstractBackgroundDepression is a common manifestation of Alzheimer’s disease (AD) and frequently observed at the early phase of the disease. Several postmortem studies demonstrated that tau deposition was found at the brainstem nuclei including the locus coeruleus (LC) and dossal raphe nucleus (DRN) (3, 4), even before early Braak stages of neurofibrillary tangle pathology. Given the disturbance of monoaminergic system is related to depression in general, tau deposition in the LC or DRN may underlie depression in late‐life, as suggested in a couple of postmortem studies. In this context, we tried to examine the hypothetical association between in vivo tau depostion at the brain stem monoaminergic nuclei and depression in cognitively unimpaired older adults.MethodA total of 69 cognitively unimpaired older adults from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included. All participants underwent comprehensive clinical assessment including the Hamilton Rating Scale for Depression (HRSD) and [18F] AV‐1451 positron emission tomography. Tau deposition in the LC and DRN was measured using the Harvard Ascending Arousal Network Atlas (AAN). Tau deposition in the pons was also assessed as a non‐monoaminergic control for comparison. Age, education, sex, and apolipoprotein E ε4 positivity were controlled as covariates in the analyses for the association between brain stem tau and HRSD score.ResultTau deposition in the LC was significantly associated with HRSD total score (β = 3.861, P = .009). In contrast, there was no significant association between tau deposition in the DRN and HRSD score (β = 2.229, P = .090). Tau deposition in the pons was also not related to HRSD score (β = 1.632, P = .207).ConclusionThe findings support the possibility that alteration of the noradrenergic neurons in the LC by tau pathology may underlie depressive manifestation in cognitively unimpaired older individuals.

The analysis of fMRI complexity as a biomarker of cognitive decline compared to tau‐PET

AbstractBackgroundTau‐PET detects the neurofibrillary tangle pathology and is considered a biomarker of neuronal injury and cognitive decline. However, PET imaging has radiation exposure risks and is costly. Recently, brain entropy mapping based on rs‐fMRI has emerged as a brain functionality biomarker that indicates the complexity of BOLD signals. Various studies have implied that reduced brain entropy values correlate significantly with cognitive decline in Alzheimer’s disease. This study analyzes the effect of fMRI complexity as a biomarker of cognitive decline in AD compared to tau‐PET.MethodWe obtained the dataset for this study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The dataset consisted of 147 subjects (age = 72.5±7.5, M/F = 60/87, CN/MCI/AD = 95/45/7) with a tau‐PET (tracer: 18F‐AV1451) and two fMRI scans. FMRI images underwent standard processing to generate Multi‐Scale Entropy (MSE) maps. We calculated parametric SUVR values based on cerebellar reference regions from tau‐PET images. To determine the ability of MSE and PET images as a risk factor of cognitive decline in AD, convolutional neural networks were used to classify individuals into CN or MCI/AD groups. Each classifier was trained separately with fMRI complexity images or SUVR images. These two models had the same network structures and hyperparameters. We performed a 5‐fold cross‐validation to evaluate each model.ResultThe classifier using fMRI‐MSE achieved an accuracy equivalent to that using tau‐PET (0.7823 vs. 0.7687). We also calculated the Area Under the ROC curve (AUC) to evaluate sensitivity and specificity and observed that the model using fMRI‐MSE achieved AUC of 0.7022, and that using tau‐PET resulted in AUC of 0.6889.ConclusionThe classification performance showed that use of fMRI‐MSE could potentially be an AD biomarker alternative to tau‐PET. Further studies with multisite, larger datasets are required to validate our preliminary results and provide more conclusive evidence.

Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.

Medial Temporal Tau Predicts Memory Decline in Cognitively Unimpaired Elderly (P5-6.011)

<h3>Objective:</h3> Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau PET for predicting longitudinal memory decline in asymptomatic elderly individuals. <h3>Background:</h3> Alzheimer’s disease (AD) can be detected in living people using in vivo biomarkers of amyloid-β (Aβ) and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high affinity positron emission tomography (PET) tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early AD symptoms, such as memory decline, is unclear. <h3>Design/Methods:</h3> In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants from the Translational Biomarkers in Aging and Dementia (TRIAD) study (October 2017-July 2020, follow-up period of 12 months). All participants underwent tau PET with [18F]-MK-6420 and Aβ PET with [18F]-AZD-4694. <h3>Results:</h3> There were 111 eligible participants who were chosen based on the availability of Aβ PET, tau PET, magnetic resonance imaging (MRI), and APOEɛ4 genotyping. Among these participants, the mean (SD) age was 70.1 (8.6) years; 20 (18%) were tau PET positive and 71 of 111 (63.9%) were women. A significant association between baseline Braak I-II [18F]-MK-6240 SUVR positivity and change in composite memory score was observed at the 12 month follow-up, after correcting for age, sex, and years of education (Logical Memory and RAVLT, standardized beta = −0.52 (−0.82−0.21), p &lt; 0.001, for dichotomized tau PET and −1.22 (−1.84−(−0.61)), p &lt; 0.0001, for continuous tau PET). Moderate cognitive decline was observed for A+T+ over the follow-up period, whereas no significant change was observed for A-T+, A+T- and A-T−, though it should be noted that the A-T+ group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function. <h3>Conclusions:</h3> [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. <b>Disclosure:</b> Miss Kwan has nothing to disclose. Mr. Arfaie has nothing to disclose. Mr. Therriault has nothing to disclose. Dr. Azizi has nothing to disclose. Miss Lussier has nothing to disclose. Mrs. Tissot has nothing to disclose. Dr. Chamoun has nothing to disclose. Dr. Bezgin has nothing to disclose. Dr. Servaes has nothing to disclose. Miss Stevenson has nothing to disclose. Ms. Rahmouni has nothing to disclose. Miss Pallen has nothing to disclose. The institution of Dr. Rosa Neto has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk.

Assessment of tau phosphorylation and β-amyloid pathology in human drug-resistant epilepsy.

Epilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy. Cortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ). We found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong. These findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.