Search

Objective: Although amyloid-beta (Aβ) peptide deposition into insoluble plaques is a pathological hallmark of Alzheimer disease; soluble oligomeric Aβ has been hypothesized to more directly underlie impaired learning and memory in dementia of the Alzheimer type. However, the lack of a sensitive, specific, and quantitative assay for Aβ oligomers has hampered rigorous tests of this hypothesis.Methods: We developed a plate-based single molecule counting fluorescence immunoassay for oligomeric Aβ sensitive to low pg/ml concentrations of synthetic Aβ dimers using the same Aβ-specific monoclonal antibody to both capture and detect Aβ. The Aβ oligomer assay does not recognize monomeric Aβ, amyloid precursor protein, or other non-Aβ peptide oligomers.Results: Aβ oligomers were detected in aqueous cortical lysates from patients with dementia of the Alzheimer type and nondemented patients with Aβ plaque pathology. However, Aβ oligomer concentrations in demented patients' lysates were tightly correlated with Aβ plaque coverage (r = 0.88), but this relationship was weaker in those from nondemented patients (r = 0.30) despite equivalent Aβ plaque pathology. The ratio of Aβ oligomer levels to plaque density fully distinguished demented from nondemented patients, with no overlap between groups in this derived variable. Other Aβ and plaque measures did not distinguish demented from nondemented patients. Aβ oligomers were not detected in cerebrospinal fluid with this assay.Interpretation: The results raise the intriguing hypothesis that the linkage between plaques and oligomers may be a key pathophysiological event underlying dementia of the Alzheimer type. This Aβ oligomer assay may be useful for many tests of the oligomer hypothesis. [ABSTRACT FROM AUTHOR]

The apolipoprotein E ε4 gene is the most important genetic risk factor for sporadic Alzheimer's disease, but the link between this gene and neurodegeneration remains unclear. Using array tomography, we analysed >50000 synapses in brains of 11 patients with Alzheimer's disease and five non-demented control subjects and found that synapse loss around senile plaques in Alzheimer's disease correlates with the burden of oligomeric amyloid-β in the neuropil and that this synaptotoxic oligomerized peptide is present at a subset of synapses. Further analysis reveals apolipoprotein E ε4 patients with Alzheimer's disease have significantly higher oligomeric amyloid-β burden and exacerbated synapse loss around plaques compared with apolipoprotein E ε3 patients. Apolipoprotein E4 protein colocalizes with oligomeric amyloid-β and enhances synaptic localization of oligomeric amyloid-β by >5-fold. Biochemical characterization shows that the amyloid-β enriched at synapses by apolipoprotein E4 includes sodium dodecyl sulphate-stable dimers and trimers. In mouse primary neuronal culture, lipidated apolipoprotein E4 enhances oligomeric amyloid-β association with synapses via a mechanism involving apolipoprotein E receptors. Together, these data suggest that apolipoprotein E4 is a co-factor that enhances the toxicity of oligomeric amyloid-β both by increasing its levels and directing it to synapses, providing a link between apolipoprotein E ε4 genotype and synapse loss, a major correlate of cognitive decline in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing. [ABSTRACT FROM AUTHOR]

Objective: The most common pathogenesis for familial Alzheimer's disease (FAD) involves misprocessing (or alternative processing) of the amyloid precursor protein (APP) by γ-secretase due to mutations of the presenilin 1 (PS1) gene. This misprocessing/alternative processing leads to an increase in the ratio of the level of a minor γ-secretase reaction product (Aβ42) to that of the major reaction product (Aβ40). Although no PS1 mutations are present, altered Aβ42/40 ratios are also observed in sporadic Alzheimer's disease (SAD), and these altered ratios apparently reflect deposition of Aβ42 as amyloid.Methods: Using immunoprecipitation-mass spectrometry with quantitative accuracy, we analyzed in the cerebrospinal fluid (CSF) of various clinical populations the peptide products generated by processing of not only APP but also an unrelated protein, alcadein (Alc). Alc undergoes metabolism by the identical APP α-secretases and γ-secretases, yielding a fragment that we have named p3-Alc(α) because of the parallel genesis of p3-Alc(α) peptides and the p3 fragment of APP. As with Aβ, both major and minor p3-Alc(α) s are generated. We studied the alternative processing of p3-Alc(α) in various clinical populations.Results: We previously reported that changes in the Aβ42/40 ratio showed covariance in a linear relationship with the levels of p3-Alc(α) [minor/major] ratio in media conditioned by cells expressing FAD-linked PS1 mutants. Here we studied the speciation of p3-Alc(α) in the CSF from 3 groups of human subjects (n = 158): elderly nondemented control subjects; mild cognitive impairment (MCI) subjects with a clinical dementia rating (CDR) of 0.5; SAD subjects with CDR of 1.0; and other neurological disease (OND) control subjects. The CSF minor p3-Alc(α) variant, p3-Alc(α) 38, was elevated (p < 0.05) in MCI subjects or SAD subjects, depending upon whether the data were pooled and analyzed as a single cohort or analyzed individually as 3 separate cohorts.Interpretation: These results suggest that some SAD may involve alternative processing of multiple γ-secretase substrates, raising the possibility that the molecular pathogenesis of SAD might involve γ-secretase dysfunction. [ABSTRACT FROM AUTHOR]

Screening tests for Alzheimer's disease lack sensitivity and specificity. We developed the AD8, a brief dementia screening interview validated against clinical and cognitive evaluations, as an improvement over current screening methods. Because insufficient follow-up has occurred to validate the AD8 against the neuropathologic findings of Alzheimer's disease, we investigated whether AD8 scores correspond to impairment in episodic memory testing and changes in biomarkers of Alzheimer's disease (cerebrospinal fluid and amyloid imaging with Pittsburgh compound B) characteristic of symptomatic Alzheimer's disease. We also compared informant-based assessments with brief performance-based dementia screening measurements such as the Mini Mental State Exam. The sample (n = 257) had a mean age of 75.4 years with 15.1 years of education; 88.7% were Caucasian and 45.5% were male. The sample was divided into two groups based on their AD8 scores: those with a negative dementia screening test (AD8 score 0 or 1, n = 137) and those with a positive dementia screening test (AD8 score ≥2, n = 120). Individuals with positive AD8 scores had abnormal Pittsburgh compound B binding (P < 0.001) and cerebrospinal fluid biomarkers (P < 0.001) compared with individuals with negative AD8 scores. Individuals with positive AD8 tests and positive biomarkers scored in the impaired range on the Wechsler Logical Memory Story A (mean score 7.0 ± 4.5 for Pittsburgh compound B; mean score 7.6 ± 5.3 for cerebrospinal fluid amyloid beta protein 1-42). The AD8 area under the curve for Pittsburgh compound B was 0.737 (95% confidence interval: 0.64-0.83) and for cerebrospinal fluid amyloid beta protein 1-42 was 0.685 (95% confidence interval: 0.60-0.77) suggesting good discrimination. The AD8 had superior sensitivity in detecting early stages of dementia compared with the Mini Mental State Examination. The AD8 had a likelihood ratio of a positive test of 5.8 (95% confidence interval: 5.4-6.3) and likelihood ratio of a negative test of 0.04 (95% confidence interval: 0.03-0.06), increasing the pre-test probability of an individual having symptomatic Alzheimer's disease. Individuals with AD8 scores of ≥2 had a biomarker phenotype consistent with Alzheimer's disease and lower performance on episodic memory tests, supporting a diagnosis of Alzheimer's disease. Informant-based assessments may be superior to performance-based screening measures such as the Mini Mental State Examination in corresponding to underlying Alzheimer's disease pathology, particularly at the earliest stages of decline. The use of a brief test such as the AD8 may improve strategies for detecting dementia in community settings where biomarkers may not be readily available, and may enrich clinical trial recruitment by increasing the likelihood that participants have underlying biomarker abnormalities. [ABSTRACT FROM AUTHOR]

Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-beta (Abeta) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Abeta levels in both brain interstitial fluid and plasma without affecting Abeta elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Abeta, but also decreases in both soluble and deposited Abeta in hippocampus and cortex. Irrespective of caffeine treatment, plasma Abeta levels did not correlate with brain Abeta levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Abeta1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Abeta levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Abeta levels are not an accurate index of brain Abeta levels/deposition or cognitive performance in aged AD mice. [ABSTRACT FROM AUTHOR]

Objective: Accumulation of amyloid-beta (Abeta) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS.Methods: We utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).Results: LY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance.Interpretation: Stable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009. [ABSTRACT FROM AUTHOR]

Objective: For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD.Methods: We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69).Results: Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects.Interpretation: Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression. [ABSTRACT FROM AUTHOR]

Objective: Aggregation and deposition of amyloid beta (Abeta) in the brain is thought to be central to the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that cerebrospinal fluid (CSF) Abeta levels are strongly correlated with AD status and progression, and may be a meaningful endophenotype for AD. Mutations in presenilin 1 (PSEN1) are known to cause AD and change Abeta levels. In this study, we have investigated DNA sequence variation in the presenilin (PSEN1) gene using CSF Abeta levels as an endophenotype for AD.Methods: We sequenced the exons and flanking intronic regions of PSEN1 in clinically characterized research subjects with extreme values of CSF Abeta levels.Results: This novel approach led directly to the identification of a disease-causing mutation in a family with late-onset AD.Interpretation: This finding suggests that CSF Abeta may be a useful endophenotype for genetic studies of AD. Our results also suggest that PSEN1 mutations can cause AD with a large range in age of onset, spanning both early- and late-onset AD. [ABSTRACT FROM AUTHOR]

Introduction: In the research setting, obtaining accurate established biomarker measurements and maximizing use of the precious samples is key. Accurate technologies are available for Alzheimer's disease (AD), but no platform can measure all the established and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA) is a technology that requires 15 µL of sample to measure more than 100 analytes., Methods: We compared AD-relevant biomarkers included in the NULISA against validated assays in cerebrospinal fluid (CSF) and plasma., Results: CSF measures of amyloid beta 42/40, and phosphorylated tau (p-tau)217 are highly correlated when measured by immunoassay, mass spectrometry, or NULISA. In plasma, p-tau217 performance is similar to that reported with other technologies when predicting amyloidosis. Other biomarkers show a wide range of correlation values depending on the fluid and the platform., Discussion: The NULISA multiplexed platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional biomarkers using minimal sample volume., Highlights: We tested the novel technology NUcleic acid Linked Immuno-Sandwich Assay (NULISA) in the dementia research setting. NULISA multiplexed platform produces reliable results for established and emerging biomarkers using minimal sample volume. Cerebrospinal fluid measures of amyloid beta 42/40, and phosphorylated tau (p-tau)217 are highly correlated when measured by immunoassay, mass spectrometry, or NULISA. In plasma, p-tau217 performance is similar to that reported with other technologies when predicting amyloidosis. NULISA measures are useful in research settings, with the advantage of measuring additional biomarkers using minimal sample volume., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity., Competing Interests: Competing interests H.Y.Z. cofounded Cajal Neuroscience, is a director of the Regeneron Pharmaceuticals board and is on the scientific advisory board of Cajal Neuroscience, Lyterian and the Column Group. D.M.H. cofounded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Cajal Neuroscience and Genentech, consults for Asteroid Therapeutics, is an inventor of and has a patent on antitau antibodies that was licensed by Washington University to C2N Diagnostics. B.H. owns stock in Novartis; he serves on the scientific advisory board of Dewpoint and has an option for stock. He serves on a scientific advisory board or is a consultant for AbbVie, Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZeneca, Biogen, BMS, Cure Alz Fund, Cell Signaling Technology, Dewpoint, Latus, Novartis, Pfizer, Sanofi, Sofinnova, Vigil, Violet, Voyager and WaveBreak. His laboratory is supported by research grants from the NIH, Cure Alzheimer’s Fund, Tau Consortium and the JPB Foundation, as well as a sponsored research agreement from Abbvie. The other authors declare no competing interests., (© 2024. The Author(s).)

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation. Lipofuscin increased lysosomal accumulation of tau fibrils and was elevated in the APOE4 mouse brain with exacerbation by tau pathology. Intrahippocampal injection of PUFA-CE-lipApoE4 was sufficient to induce lipofuscinosis in wild-type mice. Finally, the protective Christchurch mutation also reduced LDLR binding and phenocopied ApoE2. Collectively, our data strongly suggest decreased lipApoE-LDLR interactions minimize LOAD risk by reducing the deleterious effects of endolysosomal targeting of ApoE and associated pathogenic lipids., Competing Interests: Declaration of interests All authors, except N.N., A.L., and D.M.H., are full-time employees and/or shareholders of Denali Therapeutics. J.L.G., D.B., G.A.F., Y.-T.H., M. Steffek, and S.J.H. are currently full-time employees and shareholders of NICO Therapeutics. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, Cajal Neuroscience, C2N Diagnostics, and Cell. D.M.H. consults for Asteroid., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal's genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems., Competing Interests: Declaration of interests D.M.H. is on the scientific advisory board of C2N diagnostics and has equity. D.M.H. is on the scientific advisory board of Denali Therapeutics, Genentech, and Cajal Therapeutics and consults for Asteroid Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Alzheimer's disease (AD) and Alzheimer's disease-related dementias (ADRDs) are broad-impact multifactorial neurodegenerative diseases. Their complexity presents unique challenges for developing effective therapies. This review highlights research presented at the 2024 Society for Neuroscience meeting which emphasized the gut microbiome's role in AD pathogenesis by influencing brain function and neurodegeneration through the microbiota-gut-brain axis. This emerging evidence underscores the potential for targeting the gut microbiota to treat AD/ADRD., Competing Interests: The authors declare no competing financial interests. R.K.-D. is an inventor on key patents in the metabolomics field and holds equity in Metabolon and Chymia., (Copyright © 2024 the authors.)

Alzheimer's disease (AD) is a progressive neurological disorder and the most common cause of dementia. Genetic analyses identified apolipoprotein E (APOE) as the strongest genetic risk for late-onset AD. Studies have shown that ApoE modulates AD pathogenesis in part by influencing amyloid-β (Aβ) deposition. However, ApoE also appears to regulate elements of AD via regulation of innate immune response, especially through microglial and astrocyte activation. In model systems, it also regulates changes in T-cells. This review focuses on the key findings that have advanced our understanding of the role of ApoE in the pathogenesis of AD and the current view of innate immune response regulated by ApoE in AD, while discussing open questions and areas for future research., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent discoveries of rare variants of human APOE may shed light on novel therapeutic strategies for Alzheimer's disease (AD). Here, we highlight the newly identified protective variant [APOE3 Christchurch (APOE3ch, R136S)] as an example. We summarize human AD and mouse amyloidosis and tauopathy studies from the past 5 years that have been associated with this R136S variant. We also propose a potential mechanism for how this point mutation might lead to protection against AD pathology, from the molecular level, to cells, to mouse models, and potentially, to humans. Lastly, we extend our discussion of the recent insights gained regarding different APOE variants to putative therapeutic approaches in AD., Competing Interests: Declaration of interests D.M.H. co-founded, and is on the scientific advisory board of, C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid. D.M.H. has a patent on the use of anti-ApoE antibodies, which is licensed by Washington University to NextCure., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary-derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease. A detailed review of the presented cases reveals that they do not have Alzheimer's disease, and there are alternative explanations for the cognitive decline described. In people with progressive cognitive decline, the diagnosis of Alzheimer's disease requires a demonstration of amyloid and tau pathology or amyloid and tau biomarkers. Extensive tau pathology is not demonstrated, and some also lack amyloid beta pathology. The cases described in this paper do not meet the criteria for dementia due to Alzheimer's disease by clinical and pathological standards. HIGHLIGHTS: Creutzfeldt-Jakob disease has been transmitted by cadaveric growth hormone. There is no evidence for the transmission of Alzheimer's disease by cadaveric growth hormone. There is no evidence that Alzheimer's disease is transmissible., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota. We explore both animal and human studies that define causative relationships between the gut microbiome and tauopathy by directly manipulating or transferring gut microbiota. This review highlights future directions into identifying and mechanistically elucidating microbial species causally linked to tauopathies, with an ultimate goal of devising therapeutic targets towards the gut microbiome to treat tauopathies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David M. Holtzman reports financial support was provided by Good Ventures. David M. Holtzman reports financial support was provided by Cure Alzheimer's Fund. David M. Holtzman reports a relationship with C2N Diagnostics, LLC that includes: board membership. David M. Holtzman reports a relationship with Denali Therapeutics Inc that includes: board membership. David M. Holtzman reports a relationship with Genentech that includes: board membership. David M. Holtzman reports a relationship with Cajal Neuroscience that includes: board membership. David M. Holtzman reports a relationship with Asteroid that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The strongest risk factors for late-onset sporadic Alzheimer's disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2 R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk., Competing Interests: Declaration of interests L.G. is founder and equity holder of Aeton Therapeutics, Inc. S.C.S. is an equity holder and a consultant of Aeton Therapeutics, Inc. L.G. is scientific co-founder of Neurovanda and consults for Retro Biosciences. D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)