Hyman, Bradley T.

Background While it is clear that abnormal tau structures contribute to the clinical symptoms of Alzheimer's disease (AD), which of the many structural entities found in the AD brain underlie templated misfolding and progression of disease remains uncertain. However, their identification is crucial to target for more effective diagnostics and therapeutics. Objective To identify the most pathogenic tau species driving Alzheimer's disease progression. Methods We compared the biochemical and templated seeding properties of tau isolated from post-mortem brain tissue of patients with varying rates of clinical progression, categorized as rapid, slow, or typical, based on longitudinal decline in cognitive performance assessed by Clinical Dementia Rating Sum of Boxes scores. Sarkosyl-insoluble filamentous preparations were compared to aqueous-soluble preparations. Focusing on the aqueous-soluble proteins, we further characterized the most efficient seeding species using size-exclusion chromatography and quantifying oligomers using dot blot under both native and denaturing conditions. Results A rapidly progressive course corresponded to enhanced tau seeding behavior, with the strongest correlations observed in the aqueous-soluble fraction. Using size-exclusion chromatography, we demonstrated that the seeding activity of fractions containing oligomers, correlated most strongly with disease aggressiveness. Moreover, quantifying oligomers using dot blot under both native and denaturing conditions, we found that rapid progressors had higher levels of oligomeric tau, which was also more stable. Conclusions Aqueous-soluble oligomeric tau species may be an important driver of AD progression. Substantial heterogeneity was observed even in purified samples, suggesting that variations in tau conformers among patients may contribute to differences in clinical disease progression.

Abstract As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau‐targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau‐centered diagnostics and therapeutics. Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau‐targeting therapeutics, and interplay between anti‐amyloid and anti‐tau therapies and strategic design of combination trials.

AbstractDespite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor.Highlights A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

AbstractBackgroundIn Alzheimer’s disease (AD), tau accumulates with a stereotyped progressive involvement of brain regions. The cellular mechanism for this is the neuron‐to‐neuron propagation of tau, but the factors that influence tau propagation are not fully understood. We hypothesize that AD‐associated post‐translational modifications (PTMs) of tau reduce its propagation since lysines are critical for LRP1‐mediated tau uptake.MethodA construct was designed to model tau propagation in Chinese hamster ovary (CHO) cells and allow identification of donor and recipient cells by immunocytochemistry and flow cytometry. In addition to the wildtype (WT) tau sequence, constructs were made with pseudophosphorylation and pseudoacetylation mutations corresponding to the phosphorylations and acetylations found on low molecular weight (LMW) and high molecular weight (HMW) tau species in AD brains. Additionally, individual PTM mimic mutations corresponding to PTMs of the LMW tau species were made. The constructs were transfected into CHO cells and tau propagation was assessed by flow cytometry after 48 hours. Statistical analysis was performed by ANOVA with adjustment for multiple comparisons.ResultTau propagation using this cell culture model was demonstrated by immunocytochemistry and flow cytometry. Comparison of the WT, LMW‐mimic (8D2Q mutant), and HMW‐mimic (20D3Q mutant) tau propagation constructs revealed that the 8D2Q and 20D3Q mutants displayed reduced tau propagation compared to WT by 23.7% (p = 0.0186) and 26.5% (p = 0.0087), respectively. Comparing the ten single mutant constructs to WT, T181D and T231D showed increased tau propagation by 20.3% (p = 0.0002) and 15.9% (p = 0.0094), respectively. Compared to WT, T217D, K281Q, K353Q, and S404D showed reduced tau propagation by 17.3% (p = 0.0030), 15.3% (p = 0.0123), 23.7% (p <0.0001), and 16.6% (p = 0.0046), respectively.ConclusionThe mimics of AD‐associated tau PTMs found on LMW and HMW tau reduce tau propagation, consistent with the initial hypothesis. The impact of individual PTM mimics on tau propagation is variable, but notably both pseudoacetylation mimics reduce propagation, possibly due to lower affinity with LRP1. Understanding how AD‐associated tau PTMs impact tau propagation may suggest novel targets to slow the progression of AD pathology.

Abstract Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p &lt; 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.

AbstractStudies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau‐related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first‐ever Tau2020 Global Conference in Washington, DC, co‐organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research‐advancing tools and insights that are now rapidly accelerating the pace of tau research.

Abstract Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.