BACKGROUND:The study aim is to investigate whether blood biomarkers (BBMs) of Alzheimer's disease (AD) pathology are associated with postoperative cognitive dysfunction (POCD) after cardiac surgery. METHODS:Cognitive performance was assessed before and 12 months postoperatively using the Montreal Cognitive Assessment (MoCA) and categorized into stages-minimal (1), notable (2), and substantial (3) decline-in the FIND DElirium RIsk factors (FINDERI) study of patients undergoing cardiac surgery. BBMs were measured preoperatively (amyloid beta [Aβ]1-42, Aβ1-40, phosphorylated tau 181 [p-tau181], p-tau217, apolipoprotein E ε4 [apoE4] and apoE). RESULTS:A total of 394 patients completed follow-up investigations. POCD Stage 1 was observed in 105 (26.6%), POCD Stage 2 in 52 patients (13.2%), and POCD Stage 3 in 30 patients (7.6%). The AT217term (ratio Aβ1-40/1-42 * p-tau217) was significantly associated with POCD stages in multiple logistic regression. DISCUSSION:Early Alzheimer's BBMs are associated with POCD in patients, suggesting that our exploratory findings assessing BBMs may support risk stratification, inform decision-making, and contribute to strategies aimed at preventing POCD.

Extracellular deposition of amyloid-β (Aβ) peptides in the form of plaques is the most prominent pathological hallmark of Alzheimer’s disease (AD). The postulated central pathophysiological role of fibrillary Aβ plaques has, however, been questioned, and small, soluble, pre-fibrillar Aβ aggregates (oligomers) have been implicated as the crucial neurotoxic species in AD etiology. While the relationship between insoluble amyloid plaques and soluble Aβ oligomers remains unclear, it has been hypothesized that plaques may serve as reservoirs, sequestering toxic Aβ oligomers in the initial stages of the disease. Next to the canonical “full-length” Aβ1-40 and Aβ1-42 peptides, a variety of N-terminally truncated Aβ variants are present in AD brain tissue, with Aβ4-42 peptides showing high abundance. The detrimental effects of these N-terminally truncated peptides have been previously studied using the Tg4-42hom mouse line, which displays neuron loss and cognitive deficits and accumulates Aβ4-42 peptides in the CA1 region of the hippocampus albeit without amyloid plaque formation. This study aimed to investigate the relationship between soluble Aβ4-42 peptides and insoluble extracellular Aβ deposits by crossing the Tg4-42hom line with the plaque-bearing 5XFAD mouse model. We found that extracellular amyloid deposits in the hippocampus did not aggravate spatial memory deficits in Tg4-42hom mice but rescued recognition memory deficits. Moreover, while proximal CA1 pyramidal neuron loss in the hippocampus of Tg4-42hom mice was not affected by crossing with the 5XFAD line, a reduced loss of distal pyramidal neurons was observed in the filial line. Biochemically, 5XFAD/Tg4-42hom mice showed a trend towards increased levels of insoluble Aβ4-x peptides in the hippocampus. Taken together, these findings support the importance of soluble Aβ oligomers in the pathogenesis of AD and provide evidence for the hypothesis that amyloid plaques provide buffering capacity.

Abstract INTRODUCTION Carriers of the ε4 allele of the apolipoprotein E (APOE) gene have an increased risk for Alzheimer's disease (AD) and amyloid‐related imaging abnormalities (ARIAs) upon anti‐amyloid beta (Αβ) immunotherapy. Measuring apoE4 and pan‐apoE proteins in blood plasma for apoE4 proteotyping may offer an alternative to APOE genotyping. METHODS We assessed apoE4 proteotyping accuracy in 479 participants of the prospective FINd DElirium RIsk factors (FINDERI) study in patients undergoing cardiac surgery and compared results to quantitative polymerase chain reaction (qPCR) genotyping. RESULTS Proteotype–genotype discordance occurred in 8 of 479 participants (1.67%). Five of 17 proteotype homozygotes were genotypically heterozygous. Replacing manufacturer provided cut points with custom data‐driven thresholds substantially improved classification performance. DISCUSSION We confirm the reported overall high classification performance of apoE4 proteotyping but underscore the need to re‐evaluate the generalizability of the cut points provided with the assay kits. Misclassification of heterozygous APOE ε4 carriers as homozygous could erroneously exclude eligible patients from anti‐amyloid therapies.

A hallmark of Alzheimer’s disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) targeting specific Aβ variants are essential tools for AD research, diagnostics, and therapy. The monoclonal antibodies Aducanumab, Lecanemab, and Donanemab have recently been approved as the first disease-modifying treatments for early AD, highlighting the clinical importance of their exact binding profiles. In this study, we systematically characterized the binding and modification requirements of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab, and Donanemab, across monomeric, oligomeric, and aggregated Aβ forms. Array-based analysis of 20,000 modified Aβ peptides defined binding epitopes at single-residue resolution and revealed the impact of sequence variation, including familial AD mutations, as well as diverse post-translational modifications (PTMs). Notably, genetic variants, such as H6R, impaired binding of therapeutic Aβ-Abs like Aducanumab. Donanemab showed strong preference for pyroglutamate-modified AβpE3–17, while Lecanemab and Aducanumab exhibited aggregation- and sequence-context-dependent binding requirements. Comparison of peptide binding profiles with binding of full-length and aggregated Aβ via immunoprecipitation-mass spectrometry, capillary immunoassays, Western blotting, and immunohistochemistry on AD brain tissue revealed distinct aggregation-dependent binding behaviours. The valency- and context-dependence of Aducanumab binding, together with its preference for Ser8-phosphorylated Aβ, supports a dimerization-mediated binding mechanism. For Lecanemab, our data suggest that additional structural contributions beyond the minimal N-terminal epitope are required for binding to aggregated Aβ, which remain to be fully resolved. Together, this work provides the most comprehensive dataset to date on aggregation-dependent sequence and modification selectivity of Aβ-Abs. By integrating mutational, PTM, and aggregation contexts in a unified experimental framework, we establish a resource that enables rational selection of antibodies for research and diagnostic applications and offers mechanistic insights that may inform the design and optimization of future therapeutic antibodies in AD.

Obesity, a pandemic, worldwide afflicts almost one billion people. Obesity and ageing share several pathological pathways leading to neurological disorders. However, due to a lack of suitable animal models, the long-term effects of obesity on age-related disorders- cognitive impairment and dementia have not yet been thoroughly investigated. Therefore, the current investigation focuses on developing a suitable model to explore the effects of obese-ageing. It also aims to determine whether obesity affects cognitive abilities in an age-dependent manner, and to identify a potential biomarker(s) for cognitive decline. Cognitive tests were carried out on 6-months and 1-year-old melanocortin-4 receptor (Mc4r)-deficient-obese and lean (wildtype) mice. Additionally, brains and sera were harvested for molecular, histological and serological analyses from 6, 12, and 24-months-old mice. Finally, RT-PCR was carried out after hippocampal mRNA sequencing. The cognitive tests revealed that 1-year-old obese mice have cognitive impairment along with underlying neurodegenerative changes, such as enlarged lateral ventricles. Serum neurofilament light chain (sNfL) levels were also elevated. Lipid accumulation and neuroinflammation were apparent besides, a compromised blood-brain barrier (BBB) indicated by altered junction protein gene expression. Differentially-expressed genes associated with cognitive decline were identified by mRNA sequencing of hippocampi. One such gene, Secreted Phosphoprotein 1 (Spp1) had markedly increased expression in cognitively-impaired obese mice. Our findings present an obese-aged mouse model of cognitive decline with neuroinflammation, reduced BBB-integrity and predisposing neurodegenerative changes. Obese-ageing accelerates the progression of cognitive impairment. Furthermore, Spp1 appears to be a potential biomarker for early diagnosis of neuropathological disorders.

Objective: Numerous studies have described the role of STAT3 (signal transducer and activator of transcription 3) in infections, but little is known on whether this transcription factor is linked to negative affectivity (NA) and social inhibition (SI), leading to social withdrawal as a typical symptom of various infections. Methods: In this study, we isolated peripheral blood mononuclear cells (PBMCs) from 63 consecutive depressed patients (mean age 41.4 +/- 16.1 years; 40 females) before and after psychotherapeutic intervention and measured STAT3 tyrosine phosphorylation (pSTAT3) with and without in vitro interleukin-6 (IL-6) stimulation of these cells using flow cytometry. In addition, all study participants were assessed for NA and SI using the German version of the Type D Scale-14 (DS-14) questionnaire with a cut-off level of >= 10 for each subscale. Results: While NA was unrelated to STAT3 activity, PBMCs from SI-positive patients had an increased baseline STAT3 activation level, which made the cells less sensitive to in vitro IL-6 stimulation (11.5% vs. 9.1%, p = 0.036). The stimulatory capacity, defined as the difference in pSTAT3 levels from IL-6-stimulated to unstimulated cells during hospitalization, was significantly lower in PBMCs from SI-positive than from SI-negative patients (-1.7% vs. 6.6%, p = 0.007). The sensitivity of PBMCs to IL-6 stimulation was negatively correlated with the SI score (r = -0.295, p = 0.019). Of note, the altered sensitivity to STAT3 phosphorylation remained stable, when adjusted for clinically relevant confounders in multivariate analysis (Exp((3) = 0.891, 95%-confidence interval = 0.804-0.988, p = 0.029). Conclusion: These findings point towards a possible relationship between STAT3 signaling and social inhibition in depressed patients.

Signal transduction via the Signal Transducer and Activator of Transcription 1 (STAT1) pathway is indispensable for mediating the intracellular effects of interferon-α (IFN-α), interferon-γ (IFN-γ) and other cytokines in the brain and, thereby, crucial for antiviral and antibacterial responses during potential life-threatening CNS infections. However, the role of STAT1 signaling beyond the known IFN-α and IFN-γ effects in immediate antimicrobial defense is highly context-dependent, and studies in the existing literature using STAT1-targeted mouse models under normal physiological conditions remain scarce. Here, we characterized a STAT1 targeted-disruption mouse model in the absence of infectious stimuli by employing established behavioral testing paradigms and immunohistochemical stainings, as well as bulk hippocampal transcriptomic and proteomic analyses. While we found neither overt behavioral alterations nor immunohistochemical changes with respect to microglial phagocytosis or proliferation, significant alterations were detected in gene and protein expression profiles implicated in neuroinflammatory processes and neuroprotection. In summary, this study highlights the complex and context-dependent role of STAT1-mediated signaling even in the absence of any detectable behavioral and neuropathological changes.

A hallmark of Alzheimer's disease (AD), the most common form of dementia, is the progressive accumulation of amyloid-beta (Aβ) peptides across distinct brain regions. Anti-Aβ antibodies (Aβ-Abs) that bind specific Aβ variants are essential research tools. Furthermore, the monoclonal Aβ-Abs Aducanumab, Lecanemab, and Donanemab have recently gained approval as the first disease-modifying therapeutics for early AD. In this study, we systematically determined on peptide microarrays the exact binding epitopes of 20 Aβ-Abs, including biosimilars of Aducanumab, Lecanemab and Donanemab. Precise Aβ-sequence and modification requirements were resolved through deep mutational scans and synthetically modified peptide libraries. To address the potential limitations of peptide microarrays employing short Aβ fragments, the observed monovalent Aβ-Ab reactivities were further studied using biochemical approaches, complementary in vitro analysis of Aβ-Ab binding to oligomeric and aggregated Aβ, as well as immunohistochemical staining of patient-derived AD brain samples. The data identifies Aβ-Abs that preferentially recognize critical truncation and modification variants as well as gain and loss of binding mutants in familial AD. Our work provides insights into the mode of binding of currently available Aβ-Ab biosimilars and further classifies the immunological tools for detecting and discriminating distinct Aβ truncations, mutational variants and post-transcriptionally modified derivatives. We expect that this comprehensive resource on Aβ-Ab sequence and modification selectivity will not only advance fundamental research on AD but potentially also support the development of improved diagnostic tools and therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest.

Aims: The aggregation and deposition of amyloid-beta (A beta) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length A beta peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated A beta peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated A beta 4-x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated A beta peptides. Methods: We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated A beta peptide variants. Antibodies against these A beta variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples. Results: In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the A beta peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated A beta-6-x and A beta-3-x peptides, of which the latter serve as a component in a promising A beta-based plasma biomarker. A beta-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of A beta-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated A beta-6/-3-x peptides. Discussion: The current findings implicate ADAMTS4 in both the pathological process of A beta peptide aggregation and in the early detection of amyloid pathology in AD.

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer's disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD prevention and therapeutic strategies.

The Aβ42/40 ratio and the concentration of phosphorylated Tau181 in blood plasma represent attractive biomarkers for Alzheimer's disease. As a means for reducing potential matrix effects, which may interfere with plasma immunoassays, we have previously developed a pre-analytical sample workup by semi-automated immunoprecipitation. Here we test the compatibility of pre-analytical immunoprecipitations with automated Aβ1-40, Aβ1-42 and phosphorylated Tau181 immunoassays on the Lumipulse platform and compare the diagnostic performance of the respective immunoprecipitation immunoassay approaches with direct plasma measurements. 71 participants were dichotomized according to their Aβ42/40 ratios in cerebrospinal fluid into the diagnostic groups amyloid-positive ( n = 32) and amyloid-negative ( n = 39). The plasma Aβ1-42/1-40 ratio and phosphorylated Tau181 levels were determined on the Lumipulse G600II platform (Fujirebio) by direct measurements in EDTA–plasma or after Aβ- or Tau-immunoprecipitation, respectively. Pre-analytical immunoprecipitation of Aβ turned out to be compatible with the Lumipulse Aβ assays and resulted in a numerical, yet statistically not significant increase in the area under the ROC curve for plasma Aβ1-42/1-40. Additionally, we observed a significant increase in the standardised effect size (Cohen’s D). Pre-analytical immunoprecipitation of Tau resulted in increased differences between the diagnostic groups in terms of median and mean phosphorylated Tau 181 levels. Furthermore, we observed a greater Cohen’s d ( p < 0.001) and a larger area under the ROC curve ( p = 0.038) after Tau-IP. Our preliminary findings in a small, preselected sample indicate that pre-analytical immunoprecipitation may have the potential to improve the diagnostic performance of plasma biomarker immunoassays for Aβ1-42/1-40 and phosphorylated Tau181 to predict brain amyloid deposition.

The formation of amyloid-β (Aβ) aggregates in brain is a neuropathological hallmark of Alzheimer’s disease (AD). However, there is mounting evidence that Aβ also plays a pathogenic role in other types of dementia and that specific post-translational Aβ modifications contribute to its pathogenic profile. The objective of this study was to test the hypothesis that distinct types of dementia are characterized by specific patterns of post-translationally modified Aβ variants. We conducted a comparative analysis and quantified Aβ as well as Aβ with pyroglutamate (pGlu3-Aβ and pGlu11-Aβ), N-truncation (Aβ(4-X)), isoaspartate racemization (isoAsp7-Aβ and isoAsp27-Aβ), phosphorylation (pSer8-Aβ and pSer26-Aβ) or nitration (3NTyr10-Aβ) modification in post mortem human brain tissue from non-demented control subjects in comparison to tissue classified as pre-symptomatic AD (Pre-AD), AD, dementia with Lewy bodies and vascular dementia. Aβ modification-specific immunohistochemical labelings of brain sections from the posterior superior temporal gyrus were examined by machine learning-based segmentation protocols and immunoassay analyses in brain tissue after sequential Aβ extraction were carried out. Our findings revealed that AD cases displayed the highest concentrations of all Aβ variants followed by dementia with Lewy bodies, Pre-AD, vascular dementia and non-demented controls. With both analytical methods, we identified the isoAsp7-Aβ variant as a highly abundant Aβ form in all clinical conditions, followed by Aβ(4-X), pGlu3-Aβ, pGlu11-Aβ and pSer8-Aβ. These Aβ variants were detected in distinct plaque types of compact, coarse-grained, cored and diffuse morphologies and, with varying frequencies, in cerebral blood vessels. The 3NTyr10-Aβ, pSer26-Aβ and isoAsp27-Aβ variants were not found to be present in Aβ plaques but were detected intraneuronally. There was a strong positive correlation between isoAsp7-Aβ and Thal phase and a moderate negative correlation between isoAsp7-Aβ and performance on the Mini Mental State Examination. Furthermore, the abundance of all Aβ variants was highest in APOE 3/4 carriers. In aggregation assays, the isoAsp7-Aβ, pGlu3-Aβ and pGlu11-Aβ variants showed instant fibril formation without lag phase, whereas Aβ(4-X), pSer26-Aβ and isoAsp27-Aβ did not form fibrils. We conclude that targeting Aβ post-translational modifications, and in particular the highly abundant isoAsp7-Aβ variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. Hence, our findings might have implications for current antibody-based therapies of AD.

The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.

A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer's disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed.

Background STAT1 is an intracellular signaling molecule that is crucially involved in the regulation of the innate immune system by activation of defense mechanisms against microbial pathogens. Phosphorylation-dependent activation of the STAT1 transcription factor is associated with a conversion from an antiparallel to parallel dimer configuration, which after nuclear import binds to DNA. However, not much is known about the specific intermolecular interactions that stabilize unphosphorylated, antiparallel STAT1 complexes prior to activation. Results In this study, we identified a previously unknown interdimeric interaction site, which is involved in the termination of STAT1 signaling. Introduction of the glutamic acid-to-alanine point mutation E169A in the coiled-coil domain (CCD) by site-directed mutagenesis led to increased tyrosine phosphorylation as well as accelerated and prolonged nuclear accumulation in transiently transfected cells. In addition, DNA-binding affinity and transcriptional activity were strongly enhanced in the substitution mutant compared to the wild-type (WT) protein. Furthermore, we have demonstrated that the E169 residue in the CCD mediates the release of the dimer from the DNA in an auto-inhibitory manner. Conclusion Based on these findings, we propose a novel mechanism for the inactivation of the STAT1 signaling pathway, assigning the interface with the glutamic acid residue 169 in the CCD a crucial role in this process.

Amyloid-β (Aβ) peptides, including post-translationally modified variants thereof, are believed to play a key role in the onset and progression of Alzheimer's disease. Suggested modified Aβ species with potential disease relevance include Aβ peptides phosphorylated at serine in position eight (pSer8-Aβ) or 26 (pSer26-Aβ). However, the published studies on those Aβ peptides essentially relied on antibody-based approaches. Thus, complementary analyses by mass spectrometry, as shown for other modified Aβ variants, will be necessary not only to unambiguously verify the existence of phosphorylated Aβ species in brain samples but also to reveal their exact identity as to phosphorylation sites and potential terminal truncations. With the aim of providing a novel tool for addressing this still-unresolved issue, we developed a customized matrix formulation, referred to as TOPAC, that allows for improved detection of synthetic phosphorylated Aβ species by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. When TOPAC was compared with standard matrices, we observed higher signal intensities but minimal methionine oxidation and phosphate loss for intact pSer8-Aβ(1-40) and pSer26-Aβ(1-40). Similarly, TOPAC also improved the mass spectrometric detection and sequencing of the proteolytic cleavage products pSer8-Aβ(1-16) and pSer26-Aβ(17-28). We expect that TOPAC will facilitate future efforts to detect and characterize endogenous phosphorylated Aβ species in biological samples and that it may also find its use in phospho-proteomic approaches apart from applications in the Aβ field.

The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths 1 , the latter of which is associated with secondary neuroinflammation 2 , 3 . As oligodendrocytes support axonal energy metabolism and neuronal health 4 – 7 , we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.