Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease.

L-type voltage-gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA-binding protein (RBP) Parkinsonism-associated deglycase (DJ-1). DJ-1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and α2δ2, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ-1-mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ-1-regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.

Conserved cell types with divergent features in human versus mouse cortex.

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers.

The formation of toxic Amyloid ß-peptide (Aß) oligomers is one of the earliest events in the molecular pathology of Alzheimer's Disease (AD). These oligomers lead to a variety of downstream effects, including impaired neuronal signaling, neuroinflammation, tau phosphorylation, and neurodegeneration, and it is estimated that these events begin 10 to 20 y before the presentation of symptoms. Toxic Aß oligomers contain a nonstandard protein structure, termed α-sheet, and designed α-sheet peptides target this main-chain structure in toxic oligomers independent of sequence. Here we show that a designed α-sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic α-sheet-containing Aß oligomers produce strong SOBA signals, while monomeric and ß-sheet protofibrillar Aß do not. α-sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, we developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected Aß oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, we adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson's disease and Lewy body dementia.

Aß and tau prions feature in the neuropathogenesis of Down syndrome.

Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer's disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aß and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aß and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aß and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aß and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aß and tau prions increased with age. In contrast to DS brains, the levels of Aß and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.

Evidence of mutant huntingtin and tau-related pathology within neuronal grafts in Huntington's disease cases.

A number of post-mortem studies conducted in transplanted Huntington's disease (HD) patients from various trials have reported the presence of pathological and misfolded proteins, in particular mutant huntingtin (mHtt) and phosphorylated tau neuropil threads, in the healthy grafted tissue. Here, we extended these observations with histological analysis of post-mortem tissue from three additional HD patients who had received similar striatal allografts from the fetal tissue transplantation trial conducted in Los Angeles in 1998. Immunohistochemical staining was performed using anti-mHtt antibodies, EM48 and MW7, as well as anti-hyperphosphorylated tau antibodies, AT8 and CP13. Immunofluorescence was used to assess the colocalization of EM48+ mHtt aggregates with the neuronal marker MAP2 and/or the extracellular matrix protein phosphacan in both the host and grafts. We confirmed the presence of mHtt aggregates within grafts of all three cases as well as tau neuropil threads in the grafts of two of the three transplanted HD patients. Phosphorylated tau was also variably expressed in the host cerebral cortex of all three subjects. While mHtt inclusions were present within neurons (immunofluorescence co-localization of MAP2 and EM48) as well as within the extracellular matrix of the host (immunofluorescence co-localization of phosphacan and EM48), their localization was limited to the extracellular matrix in the grafted tissue. This study corroborates previous findings that both mHtt and tau pathology can be found in the host and grafts of HD patients years post-grafting.

Ferroptosis of Microglia in Aging Human White Matter Injury.

OBJECTIVE: Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia. METHODS: We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM. RESULTS: We found that DM, which accumulated myelin debris were selectively enriched in the iron-binding protein light chain ferritin, and accumulated PLIN2-labeled lipid droplets. DM displayed lipid peroxidation injury and enhanced expression for TOM20, a mitochondrial translocase, and a sensor of oxidative stress. DM also displayed enhanced expression of the DNA fragmentation marker phospho-histone H2A.X. We identified a unique set of ferroptosis-related genes involving iron-mediated lipid dysmetabolism and oxidative stress that were preferentially expressed in WM injury relative to gray matter neurodegeneration. INTERPRETATION: Ferroptosis appears to be a major mechanism of WM injury in Alzheimer's disease and vascular dementia. WM DM are a novel therapeutic target to potentially reduce the impact of WM injury and myelin loss on the progression of cognitive impairment. ANN NEUROL 2023;94:1048-1066.

Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioral alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. In addition, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the in situ relationship of a-series gangliosides with either 18 or 20 carbon sphingosine chains (d18:1 or d20:1, respectively) in the post-mortem human AD brain. Here, we expanded upon previous literature and demonstrated a significant decrease in the GM1 d20:1 to GM1 d18:1 ratio in regions of the dentate gyrus and entorhinal cortex in AD relative to control brain tissue. Then, we demonstrated that the MALDI-MSI profile of GM3 co-localizes with histologically confirmed amyloid beta (Aß) plaques and found a significant increase in both GM1 and GM3 in proximity to Aß plaques. Collectively, this study demonstrates a perturbation of the ganglioside profile in AD, and validates a pipeline for MALDI-MSI and classic histological staining in the same tissue sections. This demonstrates feasibility for integrating untargeted mass spectrometry imaging approaches into a digital pathology framework.

Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.

Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.

Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.

Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.

Neurotrophic signaling deficiency exacerbates environmental risks for Alzheimer's disease pathogenesis.

The molecular mechanism of Alzheimer's disease (AD) pathogenesis remains obscure. Life and/or environmental events, such as traumatic brain injury (TBI), high-fat diet (HFD), and chronic cerebral hypoperfusion (CCH), are proposed exogenous risk factors for AD. BDNF/TrkB, an essential neurotrophic signaling for synaptic plasticity and neuronal survival, are reduced in the aged brain and in AD patients. Here, we show that environmental factors activate C/EBPß, an inflammatory transcription factor, which subsequently up-regulates δ-secretase that simultaneously cleaves both APP and Tau, triggering AD neuropathological changes. These adverse effects are additively exacerbated in BDNF+/- or TrkB+/- mice. Strikingly, TBI provokes both senile plaque deposit and neurofibrillary tangles (NFT) formation in TrkB+/- mice, associated with augmented neuroinflammation and extensive neuronal loss, leading to cognitive deficits. Depletion of C/EBPß inhibits TBI-induced AD-like pathologies in these mice. Remarkably, amyloid aggregates and NFT are tempospatially distributed in TrkB+/- mice brains after TBI, providing insight into their spreading in the progression of AD-like pathologies. Hence, our study revealed the roles of exogenous (TBI, HFD, and CCH) and endogenous (TrkB/BDNF) risk factors in the onset of AD-associated pathologies.

Suppression of eEF2 phosphorylation alleviates synaptic failure and cognitive deficits in mouse models of Down syndrome.

INTRODUCTION: Cognitive impairment is a core feature of Down syndrome (DS), and the underlying neurobiological mechanisms remain unclear. Translation dysregulation is linked to multiple neurological disorders characterized by cognitive impairments. Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. METHODS: We used genetic and pharmacological methods to suppress eEF2K in two lines of DS mouse models. We further applied multiple approaches to evaluate the effects of eEF2K inhibition on DS pathophysiology. RESULTS: We found that eEF2K signaling was overactive in the brain of patients with DS and DS mouse models. Inhibition of eEF2 phosphorylation through suppression of eEF2K in DS model mice improved multiple aspects of DS-associated pathophysiology including de novo protein synthesis deficiency, synaptic morphological defects, long-term synaptic plasticity failure, and cognitive impairments. DISCUSSION: Our data suggested that eEF2K signaling dysregulation mediates DS-associated synaptic and cognitive impairments. HIGHLIGHTS: Phosphorylation of the translational factor eukaryotic elongation factor 2 (eEF2) is increased in the Down syndrome (DS) brain. Suppression of the eEF2 kinase (eEF2K) alleviates cognitive deficits in DS models. Suppression of eEF2K improves synaptic dysregulation in DS models. Cognitive and synaptic impairments in DS models are rescued by eEF2K inhibitors.

Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. METHODS: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. RESULTS: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). DISCUSSION: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. HIGHLIGHTS: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.

Sex-specific genetic architecture of late-life memory performance.

BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales  = 11,942; Nfemales  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. HIGHLIGHTS: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.

INTRODUCTION: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. METHODS: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. RESULTS: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. DISCUSSION: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. HIGHLIGHTS: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-ß pathology but causes hyperexcitability and seizures.

Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-ß (Aß) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aß. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aß1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aß internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Functional excitatory to inhibitory synaptic imbalance and loss of cognitive performance in people with Alzheimer's disease neuropathologic change.

Individuals at distinct stages of Alzheimer's disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes at the synaptic level are observed in brain areas affected early in AD, and if they are emergent in MCI, is not clearly known. Equally important, it is not known whether global synaptic E/I imbalances correlate with the severity of cognitive impairment in the continuum of AD. Measuring the amplitude of ion currents of human excitatory and inhibitory synaptic receptors microtransplanted from the hippocampus and temporal cortex of cognitively normal, mildly cognitively impaired and AD individuals into surrogate cells, we found regional differences in pro-excitatory shifts of the excitatory to inhibitory (E/I) current ratio that correlates positively with toxic proteins and degree of pathology, and impinges negatively on cognitive performance scores. Using these data with electrophysiologically anchored analysis of the synapto-proteome in the same individuals, we identified a group of proteins sustaining synaptic function and those related to synaptic toxicity. We also found an uncoupling between the function and expression of proteins for GABAergic signaling in the temporal cortex underlying larger E/I and worse cognitive performance. Further analysis of transcriptomic and in situ hybridization datasets from an independent cohort across the continuum of AD confirm regional differences in pro-excitatory shifts of the E/I balance that correlate negatively with the most recent calibrated composite scores for memory, executive function, language and visuospatial abilities, as well as overall cognitive performance. These findings indicate that early shifts of E/I balance may contribute to loss of cognitive capabilities in the continuum of AD clinical syndrome.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.