Mechanisms linking cerebrovascular dysfunction and tauopathy: Adding a layer of epiregulatory complexity.

Intracellular accumulation of hyperphosphorylated misfolded tau proteins are found in many neurodegenerative tauopathies, including Alzheimer's disease (AD). Tau pathology can impact cerebrovascular physiology and function through multiple mechanisms. In vitro and in vivo studies have shown that alterations in the blood-brain barrier (BBB) integrity and function can result in synaptic abnormalities and neuronal damage. In the present review, we will summarize how tau proteostasis dysregulation contributes to vascular dysfunction and, conversely, we will examine the factors and pathways leading to tau pathological alterations triggered by cerebrovascular dysfunction. Finally, we will highlight the role epigenetic and epitranscriptomic factors play in regulating the integrity of the cerebrovascular system and the progression of tauopathy including a few observartions on potential therapeutic interventions. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Tridimensional Structural Analysis of Tau Isoforms Generated by Intronic Retention.

Background: Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Recently, we have discovered a new, human specific, tau isoform termed W-tau that originates by intron 12 retention. Our preliminary data suggests this newly discovered W-tau isoform might prevent aberrant aggregation of other tau isoforms but is significantly downregulated in tauopathies such as Alzheimer's disease. Objective: To accurately predict, examine, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Methods: A tridimensional deep learning-based approach and in vitro polymerization assay was included to accurately predict, analyze, and understand tau protein structure and the conformational basis for the neuroprotective role of W-tau. Results: Our findings demonstrate: a) the predicted protein tridimensionality structure of the tau isoforms raised by intron retention and their comparison with the other tau isoforms; b) the interaction of W-tau peptide (from W-tau isoform) with other tau isoforms; c) the effect of W-tau peptide in the polymerization of those tau isoforms. Conclusions: This study supports the importance of the structure-function relationship on the neuroprotective behavior of W-tau inhibiting tau fibrillization in vitro.

Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer's disease.

Neurogenesis, crucial for brain resilience, is reduced in Alzheimer's disease (AD) that induces astroglial reactivity at the expense of the pro-neurogenic potential, and restoring neurogenesis could counteract neurodegenerative pathology. However, the molecular mechanisms promoting pro-neurogenic astroglial fate despite AD pathology are unknown. In this study, we used APP/PS1dE9 mouse model and induced Nerve growth factor receptor (Ngfr) expression in the hippocampus. Ngfr, which promotes neurogenic fate of astroglia during the amyloid pathology-induced neuroregeneration in zebrafish brain, stimulated proliferative and neurogenic outcomes. Histological analyses of the changes in proliferation and neurogenesis, single-cell transcriptomics, spatial proteomics, and functional knockdown studies showed that the induced expression of Ngfr reduced the reactive astrocyte marker Lipocalin-2 (Lcn2), which we found was sufficient to reduce neurogenesis in astroglia. Anti-neurogenic effects of Lcn2 was mediated by Slc22a17, blockage of which recapitulated the pro-neurogenicity by Ngfr. Long-term Ngfr expression reduced amyloid plaques and Tau phosphorylation. Postmortem human AD hippocampi and 3D human astroglial cultures showed elevated LCN2 levels correlate with reactive gliosis and reduced neurogenesis. Comparing transcriptional changes in mouse, zebrafish, and human AD brains for cell intrinsic differential gene expression and weighted gene co-expression networks revealed common altered downstream effectors of NGFR signaling, such as PFKP, which can enhance proliferation and neurogenesis in vitro when blocked. Our study suggests that the reactive non-neurogenic astroglia in AD can be coaxed to a pro-neurogenic fate and AD pathology can be alleviated with Ngfr. We suggest that enhancing pro-neurogenic astroglial fate may have therapeutic ramifications in AD.

The Caribbean-Hispanic Alzheimer's disease brain transcriptome reveals ancestry-specific disease mechanisms.

Identifying ancestry-specific molecular profiles of late-onset Alzheimer's Disease (LOAD) in brain tissue is crucial to understand novel mechanisms and develop effective interventions in non-European, high-risk populations. We performed gene differential expression (DE) and consensus network-based analyses in RNA-sequencing data of postmortem brain tissue from 39 Caribbean Hispanics (CH). To identify ancestry-concordant and -discordant expression profiles, we compared our results to those from two independent non-Hispanic White (NHW) samples (n = 731). In CH, we identified 2802 significant DE genes, including several LOAD known-loci. DE effects were highly concordant across ethnicities, with 373 genes transcriptome-wide significant in all three cohorts. Cross-ancestry meta-analysis found NPNT to be the top DE gene. We replicated over 82% of meta-analyses genome-wide signals in single-nucleus RNA-seq data (including NPNT and LOAD known-genes SORL1, FBXL7, CLU, ABCA7). Increasing representation in genetic studies will allow for deeper understanding of ancestry-specific mechanisms and improving precision treatment options in understudied groups.

RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.

Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched methyltransferases able to methylate mammalian non-coding RNAs. NSun2 loss of function due to autosomal-recessive mutations has been associated with neurological abnormalities in humans. Here, we show NSun2 is expressed in adult human neurons in the hippocampal formation and prefrontal cortex. Strikingly, we unravel decreased NSun2 protein expression and an increased ratio of pTau/NSun2 in the brains of patients with Alzheimer's disease (AD) as demonstrated by Western blotting and immunostaining, respectively. In a well-established Drosophila melanogaster model of tau-induced toxicity, reduction of NSun2 exacerbated tau toxicity, while overexpression of NSun2 partially abrogated the toxic effects. Conditional ablation of NSun2 in the mouse brain promoted a decrease in the miR-125b m6A levels and tau hyperphosphorylation. Utilizing human induced pluripotent stem cell (iPSC)-derived neuronal cultures, we confirmed NSun2 deficiency results in tau hyperphosphorylation. We also found that neuronal NSun2 levels decrease in response to amyloid-beta oligomers (AßO). Notably, AßO-induced tau phosphorylation and cell toxicity in human neurons could be rescued by overexpression of NSun2. Altogether, these results indicate that neuronal NSun2 deficiency promotes dysregulation of miR-125b and tau phosphorylation in AD and highlights a novel avenue for therapeutic targeting.

Retromer deficiency in Tauopathy models enhances the truncation and toxicity of Tau.

Alteration of the levels, localization or post-translational processing of the microtubule associated protein Tau is associated with many neurodegenerative disorders. Here we develop adult-onset models for human Tau (hTau) toxicity in Drosophila that enable age-dependent quantitative measurement of central nervous system synapse loss and axonal degeneration, in addition to effects upon lifespan, to facilitate evaluation of factors that may contribute to Tau-dependent neurodegeneration. Using these models, we interrogate the interaction of hTau with the retromer complex, an evolutionarily conserved cargo-sorting protein assembly, whose reduced activity has been associated with both Parkinson's and late onset Alzheimer's disease. We reveal that reduction of retromer activity induces a potent enhancement of hTau toxicity upon synapse loss, axon retraction and lifespan through a specific increase in the production of a C-terminal truncated isoform of hTau. Our data establish a molecular and subcellular mechanism necessary and sufficient for the depletion of retromer activity to exacerbate Tau-dependent neurodegeneration.

Effects of Eph/ephrin signalling and human Alzheimer's disease-associated EphA1 on Drosophila behaviour and neurophysiology.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease placing a great burden on people living with it, carers and society. Yet, the underlying patho-mechanisms remain unknown and treatments limited. To better understand the molecular changes associated with AD, genome-wide association studies (GWAS) have identified hundreds of candidate genes linked to the disease, like the receptor tyrosine kinase EphA1. However, demonstration of whether and how these genes cause pathology is largely lacking. Here, utilising fly genetics, we generated the first Drosophila model of human wild-type and P460L mutant EphA1 and tested the effects of Eph/ephrin signalling on AD-relevant behaviour and neurophysiology. We show that EphA1 mis-expression did not cause neurodegeneration, shorten lifespan or affect memory but flies mis-expressing the wild-type or mutant receptor were hyper-aroused, had reduced sleep, a stronger circadian rhythm and increased clock neuron activity and excitability. Over-expression of endogenous fly Eph and RNAi-mediated knock-down of Eph and its ligand ephrin affected sleep architecture and neurophysiology. Eph over-expression led to stronger circadian morning anticipation while ephrin knock-down impaired memory. A dominant negative form of the GTPase Rho1, a potential intracellular effector of Eph, led to hyper-aroused flies, memory impairment, less anticipatory behaviour and neurophysiological changes. Our results demonstrate a role of Eph/ephrin signalling in a range of behaviours affected in AD. This presents a starting point for studies into the underlying mechanisms of AD including interactions with other AD-associated genes, like Rho1, Ankyrin, Tau and APP with the potential to identify new targets for treatment.

Admixture Mapping of Alzheimer's disease in Caribbean Hispanics identifies a new locus on 22q13.1.

Late-onset Alzheimer's disease (LOAD) is significantly more frequent in Hispanics than in non-Hispanic Whites. Ancestry may explain these differences across ethnic groups. To this end, we studied a large cohort of Caribbean Hispanics (CH, N = 8813) and tested the association between Local Ancestry (LA) and LOAD ("admixture mapping") to identify LOAD-associated ancestral blocks, separately for ancestral components (European [EUR], African [AFR], Native American[NA]) and jointly (AFR + NA). Ancestral blocks significant after permutation were fine-mapped employing multi-ethnic whole-exome sequencing (WES) to identify rare variants associated with LOAD (SKAT-O) and replicated in the UK Biobank WES dataset. Candidate genes were validated studying (A) protein expression in human LOAD and control brains; (B) two animal AD models, Drosophila and Zebrafish. In the joint AFR + NA model, we identified four significant ancestral blocks located on chromosomes 1 (p value = 8.94E-05), 6 (p value = 8.63E-05), 21 (p value = 4.64E-05) and 22 (p value = 1.77E-05). Fine-mapping prioritized the GCAT gene on chromosome 22 (SKAT-O p value = 3.45E-05) and replicated in the UK Biobank (SKAT-O p value = 0.05). In LOAD brains, a decrease of 28% in GCAT protein expression was observed (p value = 0.038), and GCAT knockdown in Amyloid-ß42 Drosophila exacerbated rough eye phenotype (68% increase, p value = 4.84E-09). In zebrafish, gcat expression increased after acute amyloidosis (34%, p value = 0.0049), and decreased upon anti-inflammatory Interleukin-4 (39%, p value = 2.3E-05). Admixture mapping uncovered genomic regions harboring new LOAD-associated loci that might explain the observed different frequency of LOAD across ethnic groups. Our results suggest that the inflammation-related activity of GCAT is a response to amyloid toxicity, and reduced GCAT expression exacerbates AD pathology.

Marked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer's-Type Tau Pathology.

Hyperphosphorylation and the subsequent aggregation of tau protein into neurofibrillary tangles (NFTs) are well-established neuropathological hallmarks of Alzheimer's disease (AD) and associated tauopathies. To further examine the impact and progression of human tau pathology in neurodegenerative contexts, the humanized tau (htau) mouse model was originally created. Despite AD-like tau pathological features recapitulated in the htau mouse model, robustness of behavioral phenotypes has not been fully established. With the ultimate goal of evaluating the htau mouse model as a candidate for testing AD therapeutics, we set out to verify, in-house, the presence of robust, replicable cognitive deficits in the htau mice. The present study shows behavioral data collected from a carefully curated battery of learning and memory tests. Here we report a significant short-term spatial memory deficit in aged htau mice, representing a novel finding in this model. However, we did not find salient impairments in long-term learning and memory previously reported in this mouse model. Here, we attempted to understand the discrepancies in the literature by highlighting the necessity of scrutinizing key procedural differences across studies. Reported cognitive deficits in the htau model may depend on task difficulty and other procedural details. While the htau mouse remains a unique and valuable animal model for replicating late onset AD-like human tau pathology, its cognitive deficits are modest under standard testing conditions. The overarching message is that before using any AD mouse model to evaluate treatment efficacies, it is imperative to first characterize and verify the presence of behavioral deficits in-house.

PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

Synonymous variants associated with Alzheimer disease in multiplex families.

OBJECTIVE: Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation. METHODS: To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an independent cohort of CHs, expression quantitative trait locus (eQTL) data, brain autopsy data, and functional experiments. RESULTS: Rare synonymous variants in 4 genes (CDH23, SLC9A3R1, RHBDD2, and ITIH2) segregated with AD status in multiplex families and had a significantly higher frequency in these families compared with reference populations of similar ancestry. In comparison to subjects without dementia, expression of CDH23 (ß = 0.53, p = 0.006) and SLC9A3R1 (ß = 0.50, p = 0.02) was increased, and expression of RHBDD2 (ß = -0.70, p = 0.02) decreased in individuals with AD at death. In line with this finding, increased expression of CDH23 (ß = 0.26 ± 0.08, p = 4.9E-4) and decreased expression of RHBDD2 (ß = -0.60 ± 0.12, p = 5.5E-7) were related to brain amyloid load (p = 0.0025). SLC9A3R1 expression was associated with burden of TDP43 pathology (ß = 0.58 ± 0.17, p = 5.9E-4). Using eQTL data, the CDH23 variant was in linkage disequilibrium with variants modulating CDH23 expression levels (top single nucleotide polymorphism: rs11000035, p = 4.85E-6, D' = 1.0). Using minigene splicing assays, the CDH23 and SLC9A3R1 variants affected splicing efficiency. CONCLUSIONS: These findings suggest that CDH23, SLC9A3R1, RHBDD2, and possibly ITIH2, which are involved in synaptic function, the glutamatergic system, and innate immunity, contribute to AD etiology. In addition, this study supports the notion that synonymous variants contribute to AD risk and that comprehensive scrutinization of this type of genetic variation is warranted and critical.

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep.

Multiple neurological, physiological, and behavioral functions are synchronized by circadian clocks into daily rhythms. Neurodegenerative diseases such as Alzheimer's disease and related tauopathies are associated with a decay of circadian rhythms, disruption of sleep patterns, and impaired cognitive function but the mechanisms underlying these alterations are still unclear. Traditional approaches in neurodegeneration research have focused on understanding how pathology impinges on circadian function. Since in Alzheimer's disease and related tauopathies tau proteostasis is compromised, here we sought to understand the role of tau protein in neuronal circadian biology and related behavior. Considering molecular mechanisms underlying circadian rhythms are conserved from Drosophila to humans, here we took advantage of a recently developed tau-deficient Drosophila line to show that loss of tau promotes dysregulation of daily circadian rhythms and sleep patterns. Strikingly, tau deficiency dysregulates the structural plasticity of the small ventral lateral circadian pacemaker neurons by disrupting the temporal cytoskeletal remodeling of its dorsal axonal projections and by inducing a slight increase in the cytoplasmic accumulation of core clock proteins. Taken together, these results suggest that loss of tau function participates in the regulation of circadian rhythms by modulating the correct operation and connectivity of core circadian networks and related behavior.

A Drosophila Model of Essential Tremor.

Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.1137 T > A, p.(D379E) in an electrically silent voltage-gated K+ channel α-subunit, Kv9.2, in a family with ET, that modulates the activity of Kv2 channels. We have produced transgenic Drosophila lines that express either the human wild type Kv9.2 (hKv9.2) or the ET causing mutant Kv9.2 (hKv9.2-D379E) subunit in all neurons. We show that the hKv9.2 subunit modulates activity of endogenous Drosophila K+ channel Shab. The mutant hKv9.2-D379E subunit showed significantly higher levels of Shab inactivation and a higher frequency of spontaneous firing rate consistent with neuronal hyperexcitibility. We also observed behavioral manifestations of nervous system dysfunction including effects on night time activity and sleep. This functional data further supports the pathogenicity of the KCNS2 (p.D379E) mutation, consistent with our prior observations including co-segregation with ET in a family, a likely pathogenic change in the channel pore domain and absence from population databases. The Drosophila hKv9.2 transgenic model recapitulates several features of ET and may be employed to advance our understanding of ET disease pathogenesis.

Extracellular Tau Paired Helical Filaments Differentially Affect Tau Pathogenic Mechanisms in Mitotic and Post-Mitotic Cells: Implications for Mechanisms of Tau Propagation in the Brain.

The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer's disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular "aggresomal" type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote "aggresomal" tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy.

Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau.

Tau is a highly abundant and multifunctional brain protein that accumulates in neurofibrillary tangles (NFTs), most commonly in Alzheimer's disease (AD) and primary age-related tauopathy. Recently, microRNAs (miRNAs) have been linked to neurodegeneration; however, it is not clear whether miRNA dysregulation contributes to tau neurotoxicity. Here, we determined that the highly conserved brain miRNA miR-219 is downregulated in brain tissue taken at autopsy from patients with AD and from those with severe primary age-related tauopathy. In a Drosophila model that produces human tau, reduction of miR-219 exacerbated tau toxicity, while overexpression of miR-219 partially abrogated toxic effects. Moreover, we observed a bidirectional modulation of tau levels in the Drosophila model that was dependent on miR-219 expression or neutralization, demonstrating that miR-219 regulates tau in vivo. In mammalian cellular models, we found that miR-219 binds directly to the 3'-UTR of the tau mRNA and represses tau synthesis at the post-transcriptional level. Together, our data indicate that silencing of tau by miR-219 is an ancient regulatory mechanism that may become perturbed during neurofibrillary degeneration and suggest that this regulatory pathway may be useful for developing therapeutics for tauopathies.

Primary age-related tauopathy (PART): a common pathology associated with human aging.

We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aß) plaques. For these "NFT+/Aß-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aß accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors.

Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aß42 to Aß40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aß42/40, and have characterized novel expression changes.

The MAPT H1 haplotype is associated with tangle-predominant dementia.

Tangle-predominant dementia (TPD) patients exhibit cognitive decline that is clinically similar to early to moderate-stage Alzheimer disease (AD), yet autopsy reveals neurofibrillary tangles in the medial temporal lobe composed of the microtubule-associated protein tau without significant amyloid-beta (Aß)-positive plaques. We performed a series of neuropathological, biochemical and genetic studies using autopsy brain tissue drawn from a cohort of 34 TPD, 50 AD and 56 control subjects to identify molecular and genetic signatures of this entity. Biochemical analysis demonstrates a similar tau protein isoform composition in TPD and AD, which is compatible with previous histological and ultrastructural studies. Further, biochemical analysis fails to uncover elevation of soluble Aß in TPD frontal cortex and hippocampus compared to control subjects, demonstrating that non-plaque-associated Aß is not a contributing factor. Unexpectedly, we also observed high levels of secretory amyloid precursor protein α (sAPPα) in the frontal cortex of some TPD patients compared to AD and control subjects, suggesting differences in APP processing. Finally, we tested whether TPD is associated with changes in the tau gene (MAPT). Haplotype analysis demonstrates a strong association between TPD and the MAPT H1 haplotype, a genomic inversion associated with some tauopathies and Parkinson disease (PD), when compared to age-matched control subjects with mild degenerative changes, i.e., successful cerebral aging. Next-generation resequencing of MAPT followed by association analysis shows an association between TPD and two polymorphisms in the MAPT 3' untranslated region (UTR). These results support the hypothesis that haplotype-specific variation in the MAPT 3' UTR underlies an Aß-independent mechanism for neurodegeneration in TPD.