Braak Neurofibrillary Tangle Stage Research Articles

Tau polygenic risk scoring: a cost-effective aid for prognostic counseling in Alzheimer's disease.

Tau deposition is one of two hallmark features of biologically defined Alzheimer's disease (AD) and is more closely related to cognitive decline than amyloidosis. Further, not all amyloid-positive individuals develop tauopathy, resulting in wide heterogeneity in clinical outcomes across the population with AD. We hypothesized that a polygenic risk score (PRS) based on tau PET (tau PRS) would capture the aggregate inherited susceptibility/resistance architecture influencing tau accumulation, beyond solely the measurement of amyloid-β burden. Leveraging rich multimodal data from a population-based sample of older adults, we found that this novel tau PRS was a strong surrogate of tau PET deposition and captured a significant proportion of the variance in tau PET levels as compared with amyloid PET burden, APOE (apolipoprotein E) ε4 (the most common risk allele for AD), and a non-APOE PRS of clinical case-control AD risk variants. In independent validation samples, the tau PRS was associated with cerebrospinal fluid phosphorylated tau levels in one cohort and with postmortem Braak neurofibrillary tangle stage in another. We also observed an association of the tau PRS with longitudinal cognitive trajectories, including a statistical interaction of the tau PRS with amyloid burden on cognitive decline. Although additional study is warranted, these findings demonstrate the potential utility of a tau PRS for capturing the collective genetic background influencing tau deposition in the general population. In the future, a tau PRS could be leveraged for cost-effective screening and risk stratification to guide trial enrollment and clinical interventions in AD.

Limbic-Predominant Age-Related TDP-43 Encephalopathy: Medical and Pathologic Factors Associated With Comorbid Hippocampal Sclerosis.

Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood. This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study. A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies. In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.

Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer's-type neuropathology.

Cancer and Alzheimer's disease are common diseases in ageing populations. Previous research has reported a lower incidence of Alzheimer's disease-type (amnestic) dementia among individuals with a diagnosis of cancer. Both cancer and amnestic dementia are prevalent and potentially lethal clinical syndromes. The current study was conducted to investigate the association of cancer diagnosis with neuropathological and cognitive features of dementia. Data were analysed from longitudinally evaluated participants in a community-based cohort study of brain ageing who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. These data were linked to the Kentucky Cancer Registry, a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini-Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline. Included participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants, and a diagnosis of mild cognitive impairment or dementia was determined in 539 (68.7%). APOE ɛ4 allele dosage was lower among participants with cancer diagnosis compared to cancer-free participants overall (P = 0.0072); however, this association was not observed among those who were cognitively normal at baseline. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini-Mental State Examination scores evaluated 6 and ≤2 years ante-mortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP-43, α-synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease.

Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer's Disease Continuum.

Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Using 18F-THK5351 as a tracer that binds to both tau and monoamine oxidase B (MAO-B), we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Cancer history associates with a lower burden of dementia and Alzheimer’s‐type neuropathology in autopsied research volunteers

Cancer and Alzheimer's disease (AD) are common diseases in aging populations. Intriguingly, prior research has reported a lower incidence of AD among individuals with a history of cancer. The current study was conducted to investigate the association of cancer history with neuropathological and cognitive features.Data were drawn from elderly, longitudinally evaluated participants in a community-based cohort study of aging and dementia who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center (UK-ADRC). The UK-ADRC data were linked to the Kentucky Cancer Registry (KCR), which is a population-based cancer state surveillance system, to obtain cancer-related data. We examined the causal relationship between cancer history and neuropathological features and clinical diagnoses using inverse probability weighting to address confounding and selection bias. Linear mixed-effects models with random intercepts and slopes were used to compare cognitive trajectories in participants with or without cancer history.Included participants (n=785) had a mean [SD] age of death of 83.8 [8.6] years; 60.1% were female (Table 1). History of cancer was reported in 190 (24.2%) participants. The prevalence of ≥1 APOE ε4 allele was lower among the participants with cancer history compared to cancer-free participants (32.6% vs 42%). Participants with cancer history had significantly lower odds of MCI/dementia at the last UK-ADRC visit (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.31-0.65). Participants with cancer history had lower odds of Braak neurofibrillary tangle stages III/IV (OR=0.52 [0.34-0.79]) and V/VI (OR=0.38 [0.26-0.55]) vs. 0/I/II. Cancer history was also associated with reduced odds of moderate/frequent neuritic plaques, OR=0.53 (0.37-0.76); moderate/frequent diffuse plaques, OR=0.53 (0.36-0.78); and moderate/frequent cerebral amyloid angiopathy, OR=0.58 (0.37-0.91). TDP-43, α-synuclein, and cerebrovascular pathologies were not associated with cancer history. The cancer-free participants had lower significantly more rapid decline in longitudinally assessed MMSE scores (β= -0.47 per year increase in age) than the participants with cancer history (Figure 1).In this study, we showed that cancer history was associated with lower burden of AD pathology and less risk of dementia. These findings provide an additional basis of support for prior epidemiological research reporting a protective association between cancer and AD-type dementia.

The apolipoprotein receptor LRP3 compromises APP levels

BackgroundMembers of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer’s disease (AD)-related pathology, and the relation of LRP3 with APP.MethodsThe effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aβ42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I–II, 68.4±8.8 years; III–IV, 80.4 ± 8.8 years; V–VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function.ResultsWe have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPβ) pathways, as well as Aβ peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels.ConclusionsApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidencesuggests anassociation with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease.

Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by each ELISAs differ depending on the epitopes of antibodies: non-AD control samples yield relatively high signals when an antibody against the N-terminal region of tau is used. On the other hand, ELISAs combining antibodies against the later-middle to C-terminal regions of tau produced substantially increased signals from AD samples, compared to those from non-AD controls. Such ELISAs better distinguish AD and non-AD controls, and the results are more closely associated with Braak neurofibrillary tangles stage, Aβ accumulation, and glial markers. Moreover, these ELISAs can reflect the pattern of tau spread across brain regions. In conclusion, Tau ELISAs that combine antibodies against the later-middle to C-terminal regions of tau can better reflect neuropathological tau accumulation, which would enable to evaluate tau accumulation in the brain at a biochemical level.

Four Common Late-Life Cognitive Trajectories Patterns Associate with Replicable Underlying Neuropathologies.

Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously. The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership. Data were drawn from autopsied longitudinally followed participants of two cohorts (total N = 1,346), community-based cohort at the University of Kentucky Alzheimer's Disease Research Center (n = 365) and National Alzheimer's Coordinating Center (n = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups. GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline. Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously.

Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition.

To assess the burden of transactive response DNA-binding protein of 43kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP). The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n=15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n=10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n=10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology. Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups. In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.

Significance of cerebral amyloid angiopathy and other co-morbidities in Lewy body diseases.

Lewy body dementia (LBD) and Parkinson's disease-dementia (PDD) are two major neurocognitive disorders with Lewy bodies (LB) of unknown etiology. There is considerable clinical and pathological overlap between these two conditions that are clinically distinguished based on the duration of Parkinsonism prior to development of dementia. Their morphology is characterized by a variable combination of LB and Alzheimer's disease (AD) pathologies. Cerebral amyloid angiopathy (CAA), very common in aged persons and particularly in AD, is increasingly recognized for its association with both pathologies and dementia. To investigate neuropathological differences between LB diseases with and without dementia, 110 PDD and 60 LBD cases were compared with 60 Parkinson's disease (PD) cases without dementia (PDND). The major demographic and neuropathological data were assessed retrospectively. PDD patients were significantly older than PDND ones (83.9 vs 77.8years; p < 0.05); the age of LB patients was in between both groups (mean 80.2years), while the duration of disease was LBD < PDD < PDND (mean 6.7 vs 12.5 and 14.3years). LBD patients had higher neuritic Braak stages (mean 5.1 vs 4.5 and 4.0, respectively), LB scores (mean 5.3 vs 4.2 and 4.0, respectively), and Thal amyloid phases (mean 4.1 vs 3.0 and 2.3, respectively) than the two other groups. CAA was more common in LBD than in the PDD and PDND groups (93 vs 50 and 21.7%, respectively). Its severity was significantly greater in LBD than in PDD and PDND (p < 0.01), involving mainly the occipital lobes. Moreover, striatal Aβ deposition highly differentiated LBD brains from PDD. Braak neurofibrillary tangle (NFT) stages, CAA, and less Thal Aβ phases were positively correlated with LB pathology (p < 0.05), which was significantly higher in LBD than in PDD < PDND. Survival analysis showed worse prognosis in LBD than in PDD (and PDND), which was linked to both increased Braak tau stages and more severe CAA. These and other recent studies imply the association of CAA-and both tau and LB pathologies-with cognitive decline and more rapid disease progression that distinguishes LBD from PDD (and PDND).

Simple Quantitative Indices for the Differentiation of Advanced-Stage Alzheimer's Disease and Other Limbic Tauopathies.

The differentiation of Alzheimer's disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.

Maturation of neuronal AD-tau pathology involves site-specific phosphorylation of cytoplasmic and synaptic tau preceding conformational change and fibril formation

In Alzheimer's disease (AD), tau-protein undergoes a multi-step process involving the transition from a natively unfolded monomer to large, aggregated structures such as neurofibrillary tangles (NFTs). However, it is not yet clear which events initiate the early preclinical phase of AD tauopathy and whether they have impact on the propagation of tau pathology in later disease stages. To address this question, we analyzed the distribution of tau species phosphorylated at T231, S396/S404 and S202/T205, conformationally modified at the MC1 epitope and fibrillary tau detected by the Gallyas method (Gallyas-tau), in the brains of 15 symptomatic and 20 asymptomatic cases with AD pathology as well as of 19 nonAD cases. As initial tau lesions, we identified phosphorylated-T231-tau diffusely distributed within the somatodendritic compartment (IC-tau) and phosphorylated-S396/pS404-tau in axonal lesions of the white matter and in the neuropil (IN-tau). The subcellular localization of pT231-tau in the cell body and pS396/pS404-tau in the presynapse was confirmed in hP301L mutant Drosophila larvae. Phosphorylated-S202/T205-tau, MC1-tau and Gallyas-tau were negative for these lesions. IC- and IN-tau were observed in all analyzed regions of the human brain, including early affected regions in nonAD cases (entorhinal cortex) and late affected regions in symptomatic AD cases (cerebellum), indicating that tau pathology initiation follows similar processes when propagating into previously unaffected regions. Furthermore, a sequence of AD-related maturation of tau-aggregates was observed, initiated by the appearance of IC- and IN-tau, followed by the formation of pretangles exhibiting pT231-tau, pS396/pS404-tau and pS202/pT205-tau, then by MC1-conformational tau, and, finally, by the formation of Gallyas-positive NFTs. Since cases classified as nonAD [Braak NFT stages < I (including a-1b)] already showed IC- and IN-tau, our findings suggest that these lesions are a prerequisite for the development of AD.

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

Background:Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.Objective:To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.Methods:Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.Results:Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.Conclusion:The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.

Cognitive impairment and risk factors of LATE in the oldest old: The 90+ Study

AbstractBackgroundLimbic predominant age related TDP‐43 encephalopathy (LATE) is a newly proposed term to denote the contribution of TDP‐43 pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old.Method240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multi‐disciplinary post‐mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neurofibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP‐43 pathology (stage&gt;2). We explored the association of LATE and ADNP with cognition measures as outcome by logistic regression analyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.Result52% of the participants (N=125) died with dementia and of those, 33% were LATE positive (Table 1). There was no association between LATE and sex, age at death, or education. Compared with ADNP, LATE was as important a predictor of dementia and clinical diagnosis of Alzheimer’s at death (Table 2). Both pathologies were associated with impaired memory, language, visuospatial ability, and orientation. Only ADNP, but not TDP‐43, was associated with impaired executive function. Lower likelihood of LATE was associated with histories of hypertension (but not hypertension medications), cataract, alcohol use (median 1 drink/day), and macular degeneration (trended toward significant association). History of COPD was significantly associated and history of autoimmune conditions (thyroid or rheumatological diseases) trended towards an association with a higher likelihood of LATE (Figure). None of the above relationships were seen for ADNP.ConclusionLATE is an important degenerative pathology in the oldest old comparable to ADNP in its relation to dementia and clinical diagnosis of Alzheimer’s. The intriguing associations of LATE with other health conditions warrant further investigation of the potential effect of autoimmunity, reduced brain perfusion, and chronic hypoxia in its development.

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.

315 - Prevalence and clinical associations of tau in Lewy body dementias: a systematic review and meta-analysis

Background:Neurofibrillary tangles (NFT) formed by tau proteins, a pathological hallmark of Alzheimer’s disease, are a common co-pathology in people with Lewy body dementias, which include dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).Aims:To investigate the prevalence of tau in Lewy body dementia, and its association with clinical outcomes.Methods:A systematic search was conducted on Medline, Embase and PubMed using the search term: (“dementia with Lewy bodies” OR “diffuse Lewy body disease”) AND (“tau protein” OR “tauopathy” OR “neurofibrillary tangle”). A total of 42 articles met the inclusion criteria for data extraction. Random-effect meta-analyses were performed to obtain pooled estimates for prevalence, and risk ratios (RR) or standardised mean difference (SMD) for clinical outcomes measures.Results:Braak NFT stage ≥III was observed in 67% (n=1399, 95%CI 59%-76%) of DLB and 52% (n=429, 95%CI 26%-78%) of PDD at autopsy. Abnormal CSF phosphorylated-tau levels were present in 27% (n=705, 95%CI 23%-30%) of DLB and 15% (n=172, 95%CI 5%-24%) of PDD cases. Higher tau burden in DLB was associated with reduced likelihood of manifesting visual hallucinations (RR 0.56; 95%CI 0.40-0.77) and motor parkinsonism (RR 0.62; 95%CI 0.40-0.98), lower diagnostic accuracy of DLB during life (RR 0.49; 95%CI 0.38-0.64) and worse cognition prior to death (SMD 0.60; 95%CI 0.44-0.76).Conclusions:Tau is more common in DLB than PDD and may negatively impact clinical diagnostic accuracy in people with DLB. Prospective longitudinal studies are needed to understand the roles of co-morbid neuropathologies in Lewy body dementias.

Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood. To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort. This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019. Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (≤13 points) ranges during the 12 years before death. The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range. Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid α-synuclein and TDP-43 with Alzheimer disease pathology (tau and Aβ) may complicate efforts to identify therapies to treat and prevent Alzheimer disease.

The histopathological staging of tau, but not amyloid, corresponds to antemortem cognitive status, dementia stage, functional abilities and neuropsychiatric symptoms

Purpose Alzheimer’s disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies. Methods We investigated this possibility using data from the National Alzheimer’s Coordinating Center (NACC) database, which contains data from patients in the United States of America. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment. Results Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains. Conclusions These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.