Differences in alcohol-related variables between individuals who engage in food and alcohol disturbance (FAD) behaviors and those who only use alcohol: The role of FAD motives.

OBJECTIVE: Food and alcohol disturbance (FAD) is the use of any compensatory behavior (e.g., skipping meals) within the context of a drinking episode. FAD has two underlying motives: to enhance the effects of alcohol (FAD-AE) and/or compensate for calories consumed from alcohol (FAD-CC). Prior work finds that FAD is positively associated with alcohol-related outcomes; however, it is unclear whether FAD confers increased risk above alcohol use alone, and whether there are differences in alcohol outcomes by FAD motive. Thus, the present study evaluated alcohol use patterns (i.e., past-month quantity/frequency, binge use, consequences, and drinking motives) by FAD status and FAD motives. METHOD: Data were from the Stimulant Norms and Prevalence 2 (SNAP2) study, which included 5,809 undergraduates from six US universities. Participants were grouped into four categories: Alcohol-Only, FAD-AE, FAD-CC, and FAD-both (i.e., both FAD-AE and FAD-CC motives). Ordinary least squares regression was used for drinking motives and quasi-Poisson regressions were used for other outcomes. RESULTS: Alcohol use quantity, frequency, binge use, and consequences were all greatest in the FAD-both group and lowest in the alcohol-only group, with the FAD-AE and FAD-CC groups intermediate and not significantly different from each other. To illustrate, the FAD-both group had 47%, 33%, and 25% greater alcohol-related consequences than the Alcohol-Only, FAD-CC, and FAD-AE groups, respectively. This stepwise pattern held for drinking motives, with fewer significant differences. CONCLUSIONS: Engagement in FAD is linked to increased likelihood of poor alcohol outcomes versus alcohol use alone, and FAD for both motives represents the highest risk group.

Pathways to personalized medicine-Embracing heterogeneity for progress in clinical therapeutics research in Alzheimer's disease.

Biological and clinical heterogeneity is a major challenge in research for developing new treatments for Alzheimer's disease (AD). AD may be defined by its amyloid beta and tau pathologies, but we recognize that mixed pathologies are common, and that diverse genetics, central nervous system (CNS) and systemic pathophysiological processes, and environmental/experiential factors contribute to AD's diverse clinical and neuropathological features. All these factors are rational targets for therapeutic development; indeed, there are hundreds of candidate pharmacological, dietary, neurostimulation, and lifestyle interventions that show benefits in homogeneous laboratory models. Conventional clinical trial designs accommodate heterogeneity poorly, and this may be one reason that progress in translating candidate interventions has been so difficult. We review the challenges of AD's heterogeneity for the clinical trials enterprise. We then discuss how advances in repeatable biomarkers and digital phenotyping enable novel "single-case" and adaptive trial designs to accelerate therapeutics development, moving us closer to personalized research and medicine for AD. HIGHLIGHTS: Alzheimer's disease is diverse in its clinical features, course, risks, and biology. Typical randomized controlled trials are exclusive and necessarily large to attain arm comparability with broad outcomes. Repeated blood biomarkers and digital tracking can improve outcome measure precision and sensitivity. This enables the use of novel "single-case" and adaptive trial designs for inclusivity, rigor, and efficiency.

Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.

Aqueous extractable nonfibrillar and sarkosyl extractable fibrillar Alzheimer's disease tau seeds have distinct properties.

Pathological tau fibrils in progressive supranuclear palsy, frontotemporal dementia, chronic traumatic encephalopathy, and Alzheimer's disease each have unique conformations, and post-translational modifications that correlate with unique disease characteristics. However, within Alzheimer's disease (AD), both fibrillar (sarkosyl insoluble (AD SARK tau)), and nonfibrillar (aqueous extractable high molecular weight (AD HMW tau)) preparations have been suggested to be seed-competent. We now explore if these preparations are similar or distinct in their in vivo seeding characteristics. Using an in vivo amplification and time-course paradigm we demonstrate that, for AD HMW and AD SARK tau species, the amplified material is biochemically similar to the original sample. The HMW and SARK materials also show different clearance, propagation kinetics, and propagation patterns. These data indicate the surprising co-occurrence of multiple distinct tau species within the same AD brain, supporting the idea that multiple tau conformers - both fibrillar and nonfibrillar- can impact phenotype in AD.

Neurofibrillary tangle-bearing neurons have reduced risk of cell death in mice with Alzheimer's pathology.

A prevailing hypothesis is that neurofibrillary tangles play a causal role in driving cognitive decline in Alzheimer's disease (AD) because tangles correlate anatomically with areas that undergo neuronal loss. We used two-photon longitudinal imaging to directly test this hypothesis and observed the fate of individual neurons in two mouse models. At any time point, neurons without tangles died at >3 times the rate as neurons with tangles. Additionally, prior to dying, they became >20% more distant from neighboring neurons across imaging sessions. Similar microstructural changes were evident in a population of non-tangle-bearing neurons in Alzheimer's donor tissues. Together, these data suggest that nonfibrillar tau puts neurons at high risk of death, and surprisingly, the presence of a tangle reduces this risk. Moreover, cortical microstructure changes appear to be a better predictor of imminent cell death than tangle status is and a promising tool for identifying dying neurons in Alzheimer's.

The big tau splice isoform resists Alzheimer's-related pathological changes.

In Alzheimer's disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus 1-3 . However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.

Amyloid age and tau PET timeline to symptomatic Alzheimer's disease in Down syndrome.

Background: Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD). Recent natural history cohort studies have characterized AD biomarkers, with a focus on PET amyloid-beta (Aß) and PET tau. Leveraging these well-characterized biomarkers, the present study examined the timeline to symptomatic AD based on estimated years since reaching Aß+, referred to as "amyloid age", and in relation to tau in a large cohort of individuals with DS. Methods: In this multicenter cohort study, 25 - 57-year-old adults with DS (n = 167) were assessed twice from 2017 to 2022, with approximately 32 months between visits as part of the Alzheimer Biomarker Consortium - Down Syndrome. Adults with DS completed amyloid and tau PET scans, and were administered the modified Cued Recall Test and the Down Syndrome Mental Status Examination. Study partners completed the National Task Group-Early Detection Screen for Dementia. Findings: Mixed linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and across 32 months. Using broken stick regression models, differences in mCRT scores were detected beginning 2.7 years following Aß+ in cross-sectional models, with an estimated decline of 1.3 points per year. Increases in tau began, on average, 2.7 - 6.1 years following Aß+. On average, participants with mild cognitive impairment were 7.4 years post Aß+ and those with dementia were 12.7 years post Aß+. Interpretation: There is a short timeline to initial cognitive decline and dementia from Aß+ (Centiloid = 18) and tau deposition in DS relative to late onset AD. The established timeline based on amyloid age (or equivalent Centiloid values) is important for clinical practice and informing AD clinical trials, and avoids limitations of timelines based on chronological age. Funding. National Institute on Aging and the National Institute for Child Health and Human Development. Research in Context: Evidence before this study: We searched PubMed for articles published involving the progression of Aß and tau deposition in adults with Down syndrome from database inception to March 1, 2024. Terms included "amyloid", "Down syndrome", "tau", "Alzheimer's disease", "cognitive decline", and "amyloid chronicity," with no language restrictions. One previous study outlined the progression of tau in adults with Down syndrome without consideration of cognitive decline or clinical status. Other studies reported cognitive decline associated with Aß burden and estimated years to AD symptom onset in Down syndrome. Amyloid age estimates have also been created for older neurotypical adults and compared to cognitive performance, but this has not been investigated in Down syndrome.Added value of this study: The timeline to symptomatic Alzheimer's disease in relation to amyloid, expressed as duration of Aß+, and tau has yet to be described in adults with Down syndrome. Our longitudinal study is the first to provide a timeline of cognitive decline and transition to mild cognitive impairment and dementia in relation to Aß+.Implications of all the available evidence: In a cohort study of 167 adults with Down syndrome, cognitive decline began 2.7 - 5.4 years and tau deposition began 2.7 - 6.1 years following Aß+ (Centiloid = 18). Adults with Down syndrome converted to MCI after ~7 years and dementia after ~12-13 years of Aß+. This shortened timeline to AD symptomology from Aß+ and tau deposition in DS based on amyloid age (or corresponding Centiloid values) can inform clinical AD intervention trials and is of use in clinical settings.

Self-reported menses physiology is positively modulated by a well-formulated, energy-controlled ketogenic diet vs. low fat diet in women of reproductive age with overweight/obesity.

Weight loss can positively alter female physiology; however, whether dietary carbohydrate- or fat- restriction confer unique effects is less studied. Precisely designed, hypocaloric well-formulated ketogenic diets (KD; ~75% energy for weight maintenance) were compared to isocaloric/isonitrogenous low-fat diet (LFD) on self-reported menses in pre-menopausal overweight and obese women (mean ± SD: 34 ± 10 years, BMI: 32.3 ± 2.7 kg/m2). Women received a precisely-weighed and formulated KD with either twice-daily with ketone salts (KS; n = 6) or a flavor-matched placebo (PL; n = 7) daily for six-weeks. An age and BMI-matched cohort (n = 6) was later assigned to the LFD and underwent the same testing procedures as the KD. Self-reported menses fluctuations were assessed bi-weekly along with measures of body weight, body composition, and fasting serum clinical chemistries using repeated measures ANOVA with Bonferroni post-hoc corrections. Both diets elicited clinically-significant weight-loss (Δ: -7.0 ± 0.5 kg; p < 0.001), primarily from fat-mass (Δ: -4.6 ± 0.3 kg; p < 0.001), and improved insulin-sensitivity and serum lipids (all p < 0.05). Fasting plasma glucose and inflammatory markers were not different between diets. Fasting capillary beta-hydroxybutyrate (R-ßHB) increased significantly during the KD, independent of supplementation (Δ: 1.2 ± 0.3 mM R-ßHB; p < 0.001). Women randomized to the KD+KS (30%) and KD+PL (43%) reported subjective increases in menses frequency and intensity after 14 days, whereas another third reported a regain of menses (>1 year since the last period) after 28 days. No LFD participants reported menses changes. Nutrient-dense, whole-food KDs and LFD improved weight, BMI, body composition, and blood parameters in pre-menopausal women after six-weeks. Changes in self-reported menses were described by most of the KD participants, but none of the LFD women suggesting there may be unique effects of nutritional ketosis, independent of weight loss.

Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer's disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.

Employing a switching valve to automate external standard calibration in inductively coupled plasma optical emission spectrometry.

The traditional external standard calibration method (EC) is automated and simplified using a four-port switching valve (SV4) and a multi-signal approach that enables the generation of several calibration points from a single calibration solution. The SV4-EC method is applied to inductively coupled plasma optical emission spectrometry (ICP-OES) and is based on gradient dilution taking place within the instrument's sample introduction tubing. Both the calibration solution and the samples are diluted by a blank solution containing an internal standard species. Forty-five dilution points are collected over time while the solutions are mixed. Instrument responses from the calibration solution are then plotted against those from the samples, and the slope of the calibration curve is used to determine the unknown analyte concentrations in the samples. The method is used to determine Ba, Co, Cr, Cu, Fe, Mn, Ni, V and Zn in coconut water, creek water, green tea, mouthwash, soft drink, vinegar, and vodka. Limits of detection are in the 0.0002-0.009 mg L-1 (n = 10) range, with precision on the order of 0.4 %-3 % RSD. Analyte percent recoveries from a 0.5 mg L-1 spike are in the ranges of 88.4 %-111 %, 88.9 %-111 %, and 88.0 %-111 % for EC, SV4-EC, and the internal-standard-corrected method (SV4-EC/Sc), respectively. No statistically significant difference is observed between EC and SV4-EC recoveries for any of the sample matrices evaluated. Comparable results between EC and SV4-EC were also found for the analysis of two certified reference materials, Bovine Liver and Oyster Tissue. Based on a single calibration solution, the SV4-EC method requires caution when preparing the calibration standard to minimize measurement bias.

Nocturnal Cardiac Arrhythmias in Heart Failure With Obstructive and Central Sleep Apnea.

BACKGROUND: Both OSA and central sleep apnea (CSA) may contribute to nocturnal cardiac arrhythmias (NCAs). Data are scarce regarding the prevalence of clinically important nocturnal atrial and ventricular arrythmias in patients with heart failure with reduced ejection fraction (HFrEF) and OSA or CSA. RESEARCH QUESTION: In a cohort of patients with HFrEF, how does the prevalence of NCA compare among those with OSA, CSA, and those with no to mild sleep apnea? Is the severity of OSA or CSA associated with atrial and ventricular NCAs? STUDY DESIGN AND METHODS: This cross-sectional analysis is an ancillary study of the Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Heart Failure (ADVENT-HF) trial. We compared the prevalence of NCAs (excessive supraventricular ectopic activity [ESVEA], defined as premature atrial complexes ≥30/h or supraventricular tachycardia ≥ 20 beats); atrial fibrillation/flutter [AF]; and > 10 premature ventricular complexes [PVC/h]) on ECGs from polysomnograms of patients with HFrEF between those with OSA (apnea-hypopnea index [AHI ≥ 15 events/h]), those with CSA (AHI ≥ 15 events/h), and those with no to mild sleep apnea (AHI < 15 events/h [control]). RESULTS: The prevalence of ESVEA was higher in patients with OSA (n = 430) and CSA (n = 150) compared with control participants (n = 76): 0%, 9%, and 12%, respectively. The prevalence of AF in the control, OSA, and CSA groups was 9%, 17%, and 27%; the prevalence of > 10 PVC/h was 45%, 59%, and 63%. In multivariable regression analyses, premature atrial complexes/h was associated with OSA severity (obstructive AHI: 22.4% increase per 10 events/h [95% CI, 5.2-42.3; P = .009), although neither obstructive nor central AHI was associated with AF or > 10 PVC/h. INTERPRETATION: In patients with HFrEF, the prevalences of nocturnal ESVEA, AF, and PVC > 10/h were higher in those with OSA or CSA than in those without OSA or CSA, and OSA severity was related to the burden of nocturnal atrial ectopy. Severity of OSA or CSA was not significantly related to AF or > 10 PVC/h. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01128816; URL: www. CLINICALTRIALS: gov.

Calibration by Proxy.

Calibration by Proxy (CbPx) is a matrix-matched calibration method that utilizes multiple internal standard species to build a calibration curve. The technique requires only two solutions: solution 1 containing a sample solution and a suite of internal standards at known concentrations, and solution 2 identical to solution 1, plus an aliquot of a standard containing all analytes and the internal standards at the same concentration. The calibration curve is prepared by plotting the signal measured for each internal standard in solution 1 divided by the signal arising due to the aliquot of internal standard added to solution 2 on the y-axis. In this ratio, the sensitivity for each element cancels, because the sample matrix is equal between the solutions. Therefore, the y-axis value measured for a specific internal standard is identical to the value that would be measured for any other element present at the same concentrations in the two solutions. Hence, each internal standard serves as a proxy for analyte values. The concentrations of internal standards in solution 1 are plotted on the x-axis, and these correspond to any analytes present in solution 1 at the same concentration. CbPx is applied to the analysis of five certified reference materials by inductively coupled plasma optical emission spectrometry (ICP-OES). Percent recoveries for analytes range from 89 to 106%, with relative standard deviations on the order of 1%. A recommended working range for the method is developed through both theoretical simulation and experimental results and then exhibited through the analysis of off-the-shelf vitamin tablets.

Ketosis Suppression and Ageing (KetoSAge) Part 2: The Effect of Suppressing Ketosis on Biomarkers Associated with Ageing, HOMA-IR, Leptin, Osteocalcin, and GLP-1, in Healthy Females.

Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia.

Interneuron diversity in the human dorsal striatum.

Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangling the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq and spatial transcriptomics of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their inherent transcriptional structure in the human dorsal striatum. We propose a comprehensive taxonomy of striatal interneurons with eight main classes and fourteen subclasses, providing their full transcriptomic identity and spatial expression profile as well as additional quantitative FISH validation for specific populations. We have also delineated the correspondence of our taxonomy with previous standardized classifications and shown the main transcriptomic and class abundance differences between caudate nucleus and putamen. Notably, based on key functional genes such as ion channels and synaptic receptors, we found matching known mouse interneuron populations for the most abundant populations, the recently described PTHLH and TAC3 interneurons. Finally, we were able to integrate other published datasets with ours, supporting the generalizability of this harmonized taxonomy.

DdmABC-dependent death triggered by viral palindromic DNA sequences.

Defense systems that recognize viruses provide important insights into both prokaryotic and eukaryotic innate immunity mechanisms. Such systems that restrict foreign DNA or trigger cell death have recently been recognized, but the molecular signals that activate many of these remain largely unknown. Here, we characterize one such system in pandemic Vibrio cholerae responsible for triggering cell density-dependent death (CDD) of cells in response to the presence of certain genetic elements. We show that the key component is the Lamassu DdmABC anti-phage/plasmid defense system. We demonstrate that signals that trigger CDD were palindromic DNA sequences in phages and plasmids that are predicted to form stem-loop hairpins from single-stranded DNA. Our results suggest that agents that damage DNA also trigger DdmABC activation and inhibit cell growth. Thus, any infectious process that results in damaged DNA, particularly during DNA replication, can in theory trigger DNA restriction and death through the DdmABC abortive infection system.

Limited potexvirus diversity in eastern Gulf of Mexico seagrass meadows.

Turtlegrass virus X, which infects the seagrass Thalassia testudinum, is the only potexvirus known to infect marine flowering plants. We investigated potexvirus distribution in seagrasses using a degenerate reverse transcription polymerase chain reaction (RT-PCR) assay originally designed to capture potexvirus diversity in terrestrial plants. The assay, which implements Potex-5 and Potex-2RC primers, successfully amplified a 584 nt RNA-dependent RNA polymerase (RdRp) fragment from TVX-infected seagrasses. Following validation, we screened 74 opportunistically collected, apparently healthy seagrass samples for potexviruses using this RT-PCR assay. The survey examined the host species T. testudinum, Halodule wrightii, Halophila stipulacea, Syringodium filiforme, Ruppia maritima, and Zostera marina. Potexvirus PCR products were successfully generated only from T. testudinum samples and phylogenetic analysis of sequenced PCR products revealed five distinct TVX sequence variants. Although the RT-PCR assay revealed limited potexvirus diversity in seagrasses, the expanded geographic distribution of TVX shown here emphasizes the importance of future studies to investigate T. testudinum populations across its native range and understand how the observed fine-scale genetic diversity affects host-virus interactions.

Brain vasculature accumulates tau and is spatially related to tau tangle pathology in Alzheimer's disease.

Insoluble pathogenic proteins accumulate along blood vessels in conditions of cerebral amyloid angiopathy (CAA), exerting a toxic effect on vascular cells and impacting cerebral homeostasis. In this work, we provide new evidence from three-dimensional human brain histology that tau protein, the main component of neurofibrillary tangles, can similarly accumulate along brain vascular segments. We quantitatively assessed n = 6 Alzheimer's disease (AD), and n = 6 normal aging control brains and saw that tau-positive blood vessel segments were present in all AD cases. Tau-positive vessels are enriched for tau at levels higher than the surrounding tissue and appear to affect arterioles across cortical layers (I-V). Further, vessels isolated from these AD tissues were enriched for N-terminal tau and tau phosphorylated at T181 and T217. Importantly, tau-positive vessels are associated with local areas of increased tau neurofibrillary tangles. This suggests that accumulation of tau around blood vessels may reflect a local clearance failure. In sum, these data indicate that tau, like amyloid beta, accumulates along blood vessels and may exert a significant influence on vasculature in the setting of AD.

Multifaceted roles of APOE in Alzheimer disease.

For the past three decades, apolipoprotein E (APOE) has been known as the single greatest genetic modulator of sporadic Alzheimer disease (AD) risk, influencing both the average age of onset and the lifetime risk of developing AD. The APOEε4 allele significantly increases AD risk, whereas the ε2 allele is protective relative to the most common ε3 allele. However, large differences in effect size exist across ethnoracial groups that are likely to depend on both global genetic ancestry and local genetic ancestry, as well as gene-environment interactions. Although early studies linked APOE to amyloid-ß - one of the two culprit aggregation-prone proteins that define AD - in the past decade, mounting work has associated APOE with other neurodegenerative proteinopathies and broader ageing-related brain changes, such as neuroinflammation, energy metabolism failure, loss of myelin integrity and increased blood-brain barrier permeability, with potential implications for longevity and resilience to pathological protein aggregates. Novel mouse models and other technological advances have also enabled a number of therapeutic approaches aimed at either attenuating the APOEε4-linked increased AD risk or enhancing the APOEε2-linked AD protection. This Review summarizes this progress and highlights areas for future research towards the development of APOE-directed therapeutics.

In situ seeding assay: A novel technique for direct tissue localization of bioactive tau.

Proteins exhibiting prion-like properties are implicated in tauopathies. The prion-like traits of tau influence disease progression and correlate with severity. Techniques to measure tau bioactivity such as RT-QuIC and biosensor cells lack spatial specificity. Therefore, we developed a histological probe aimed at detecting and localizing bioactive tau in situ. We first induced the recruitment of a tagged probe by bioactive Tau in human brain tissue slices using biosensor cell lysates containing a fluorescent probe. We then enhanced sensitivity and flexibility by designing a recombinant probe with a myc tag. The probe design aimed to replicate the recruitment process seen in prion-like mechanisms based on the cryo-EM structure of tau aggregates in Alzheimer disease (AD). Using this novel probe, we observed selective staining of misfolded tau in pre- and post-synaptic structures within neurofibrillary tangles and neurites, whether or not associated with neuritic plaques. The probe specifically targeted AD-associated bioactive tau and did not recognize bioactive tau from other neurodegenerative diseases. Electron microscopy and immunolabeling further confirmed the identification of fibrillar and non-fibrillar tau. Finally, we established a correlation between quantifying bioactive tau using this technique and gold standard biosensor cells. This technique presents a robust approach for detecting bioactive tau in AD tissues and has potential applications for deciphering mechanisms of tau propagation and degradation pathways.