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All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Amyloidogenesis: What Do We Know So Far?

The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Discovery of Proteoforms Associated With Alzheimer's Disease Through Quantitative Top-Down Proteomics

The complex nature of Alzheimer's disease (AD) and its heterogenous clinical presentation has prompted numerous large-scale - omic analyses aimed at providing a global understanding of the pathophysiological processes involved. AD involves isoforms, proteolytic products, and posttranslationally modified proteins such as amyloid beta (Aβ) and microtubule-associated protein tau. Top-down proteomics directly measures these species and thus, offers a comprehensive view of pathologically relevant proteoforms that are difficult to analyze using traditional proteomic techniques. Here, we broadly explored associations between proteoforms and clinicopathological traits of AD by deploying a quantitative top-down proteomics approach across frontal cortex of 103 subjects selected from the ROS and MAP cohorts. The approach identified 1213 proteins and 11,782 proteoforms, of which 154 proteoforms had at least one significant association with a clinicopathological phenotype. One important finding included identifying Aβ C-terminal truncation state as the key property for differential association between amyloid plaques and cerebral amyloid angiopathy. Furthermore, various N-terminally truncated forms of Aβ had noticeably stronger association with amyloid plaques and global cognitive function. Additionally, we discovered six VGF neuropeptides that were positively associated with cognitive function independent of pathological burden. The database of brain cortex proteoforms provides a valuable context for functional characterization of the proteins involved in AD and other late-onset brain pathologies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Design of amyloidogenic peptide traps

Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in β-strand and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities. The crystal structure of a designed protein–peptide complex is close to the design model, and NMR characterization reveals how the peptide-binding cleft is protected in the apo state. We use the approach to design binders to the amyloid-forming proteins transthyretin, tau, serum amyloid A1 and amyloid β 1–42 (Aβ42). The Aβ binders block the assembly of Aβ fibrils as effectively as the most potent of the clinically tested antibodies to date and protect cells from toxic Aβ42 species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Quantum-enhanced photoprotection in neuroprotein architectures emerges from collective light-matter interactions

Background Superradiance is the phenomenon of many identical quantum systems absorbing and/or emitting photons collectively at a higher rate than any one system can individually. This phenomenon has been studied analytically in idealized distributions of electronic two-level systems (TLSs), each with a ground and excited state, as well as numerically in realistic photosynthetic nanotubes and cytoskeletal architectures. Methods Superradiant effects are studied here in idealized toy model systems and realistic biological mega-networks of tryptophan (Trp) molecules, which are strongly fluorescent amino acids found in many proteins. Each Trp molecule acts as a chromophore absorbing in the ultraviolet spectrum and can be treated approximately as a TLS, with its 1 L a excited singlet state; thus, organized Trp networks can exhibit superradiance. Such networks are found, for example, in microtubules, actin filaments, and amyloid fibrils. Microtubules and actin filaments are spiral-cylindrical protein polymers that play significant biological roles as primary constituents of the eukaryotic cytoskeleton, while amyloid fibrils have been targeted in a variety of neurodegenerative diseases. We treat these proteinaceous Trp networks as open quantum systems, using a non-Hermitian Hamiltonian to describe interactions of the chromophore network with the electromagnetic field. We numerically diagonalize the Hamiltonian to obtain its complex eigenvalues, where the real part is the energy and the imaginary part is its associated enhancement rate. We also consider multiple realizations of increasing static disorder in either the site energies or the decay rates. Results We obtained the energies and enhancement rates for realistic microtubules, actin filament bundles, and amyloid fibrils of differing lengths, and we use these values to calculate the quantum yield, which is the ratio of the number of photons emitted to the number of photons absorbed. We find that all three of these structures exhibit highly superradiant states near the low-energy portion of the spectrum, which enhances the magnitude and robustness of the quantum yield to static disorder and thermal noise. Conclusion The high quantum yield and stable superradiant states in these biological architectures may play a photoprotective rolein vivo, downconverting energetic ultraviolet photons—absorbed from those emitted by reactive free radical species—to longer, safer wavelengths and thereby mitigating biochemical stress and photophysical damage. Contrary to conventional assumptions that quantum effects cannot survive in large biosystems at high temperatures, our results suggest that macropolymeric collectives of TLSs in microtubules, actin filaments, and amyloid fibrils exhibit increasingly observable and robust effects with increasing length, up to the micron scale, due to quantum coherent interactions in the single-photon limit. Superradiant enhancement and high quantum yield exhibited in neuroprotein polymers could thus play a crucial role in information processing in the brain, the development of neurodegenerative diseases such as Alzheimer’s and related dementias, and a wide array of other pathologies characterized by anomalous protein aggregates.

Physics↗
DOE OSTI2025

Mass spectrometry structural analysis of intrinsically disordered phosphoproteins

Phosphorylation is a ubiquitous protein modification that is known to play important roles in many biological phenomena including cell signaling, the opening and closing of membrane protein channels, and even triggering of amyloid protein aggregation. Despite the effects phosphorylation has on protein function, the impact phosphorylation has on the structure of proteins is not well understood. Here, to determine how phosphorylation affects the structure of proteins, top-down mass spectrometry (TD-MS) and ion mobility-mass spectrometry (IM-MS) were performed on various phosphorylated proteins and their dephosphorylated proteoforms. TD-MS with collision- and electron-based fragmentation techniques was utilized to locate phosphorylation sites on the intrinsically disordered amyloid proteins β-casein and α-synuclein. TD-MS also provided evidence that alkaline phosphatase dephosphorylates β-casein from the N-terminus to the C-terminus. Furthermore, IM-MS of common phosphorylated proteins such as β-casein, α-casein, ovalbumin, and phosvitin indicates that phosphorylation promotes compaction of protein structure in denaturing as well as native conditions. Increases in abundance of more compact conformers are also observed when the disease related amyloid protein α-synuclein is phosphorylated at serine 129. We interpret the increased abundance of more compact conformers when proteins are phosphorylated as evidence that salt bridges form between negatively charged phosphates and positively charged residues, which alters protein structure. Salt bridge formation due to phosphorylation could be a mechanism for regulating protein function and be responsible for many of the phenomena observed in nature.

Amyloid proteins↗
DOE OSTI2025

Leveraging structure-informed machine learning for fast steric zipper propensity prediction across whole proteomes

Predicting the amyloid fold and the propensity of peptide segments to adopt amyloid-like structures remain a challenge. However, recent progress has facilitated structure-based prediction of steric zipper propensity and the use of machine learning to accelerate the calculation of predictive models across many scientific areas. Leveraging these advances, we have developed a new approach for rapid proteome-wide assessment of zipper profiles that is informed by four million steric zipper predictions collected over ten years. This collection is used to build a machine learning model capable of rapidly predicting steric zipper propensity, and allowing for the assessment of zippers at both the protein and proteome level. Our predictions show enrichment for zipper forming segments in proteins involved in cell wall reorganization in yeast, highlighting a potential category of interest for experimental characterization. Overall, our predictive model allows for the exploration of amyloid formation across the tree of life and provides a tool for assessment of both novel and designed sequences for zipper density.

Biochemistry & Molecular Biology↗
DOE OSTI2025

The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease

Importance The success of recent randomized clinical trials (RCTs) for Alzheimer disease (AD), particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored. Objective To describe temporal changes in the features of RCT design for interventions in AD. Evidence Review PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included. Four assessors independently reviewed full-text articles to capture study characteristics. Main Outcomes and Measures The number of participants and the duration of RCTs as well as the target population, outcomes, and funding were extracted from published reports. These features were analyzed with respect to time using linear regression and χ 2 analyses. Results The study included 203 RCTs with 79 589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]). RCT transparency improved, with more frequent data accessibility statements, registered reports, and better reporting on race and ethnicity. Conclusions and Relevance This methodology research of AD RCTs highlights substantial changes in key features of AD clinical trials from 1992 to 2024. AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.

General & Internal Medicine↗
DOE OSTI2023

Cognitively defined Alzheimer's dementia subgroups have distinct atrophy patterns

We sought to determine structural magnetic resonance imaging (MRI) characteristics across subgroups defined based on relative cognitive domain impairments using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and to compare cognitively defined to imaging-defined subgroups. We used data from 584 people with Alzheimer's disease (AD) (461 amyloid positive, 123 unknown amyloid status) and 118 amyloid-negative controls. We used voxel-based morphometry to compare gray matter volume (GMV) for each group compared to controls and to AD-Memory. There was pronounced bilateral lower medial temporal lobe atrophy with relative cortical sparing for AD-Memory, lower left hemisphere GMV for AD-Language, anterior lower GMV for AD-Executive, and posterior lower GMV for AD-Visuospatial. Formal asymmetry comparisons showed substantially more asymmetry in the AD-Language group than any other group (p = 1.15 × 10 -10 ). For overlap between imaging-defined and cognitively defined subgroups, AD-Memory matched up with an imaging-defined limbic predominant group. MRI findings differ across cognitively defined AD subgroups.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

The POINTER Imaging baseline cohort: Associations between multimodal neuroimaging biomarkers, cardiovascular health, and cognition

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory

Neurosciences & Neurology↗
DOE OSTI2020

Evaluation of a visual interpretation method for tau-PET with 18 F-flortaucipir

Introduction: Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed. Methods: In this work, we developed a visual interpretation method for 18 F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted 18 F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern. Results: Global visual scores were reliable, correlated with global cortical 18 F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like 18 F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI. Discussion: This 18 F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Detection of non‐native species formed during fibrillization of the myocilin olfactomedin domain

Abstract Glaucoma is a group of neurodegenerative diseases that together are the leading cause of irreversible blindness worldwide. Myocilin‐associated glaucoma is an inherited form of this disease, caused by intracellular aggregation of misfolded mutant myocilin. In vitro, the myocilin C‐terminal olfactomedin domain (OLF), the relevant domain for glaucoma pathogenesis, can be driven to form amyloid‐like fibrils under mild conditions. Here we characterize a species present during in vitro fibrillization. Purified OLF was subjected to fibrillization at concentrations required for downstream electron microscopy imaging and NMR spectroscopy. Additional biophysical techniques, including analytical ultracentrifugation and X‐ray crystallography, were employed to further characterize the multicomponent mixture. Negative stain transmission electron microscopy (TEM) shows a non‐native species reminiscent of known prefibrillar oligomers from other amyloid systems, NMR indicates a minor population of partially misfolded species is present in solution, and cryo‐EM imaging shows two‐dimensional protein arrays. The predominant soluble species remaining in solution after the fibril reaction is natively folded, as evidenced by X‐ray crystallography. In summary, after incubating OLF under fibrillization‐promoting conditions, there is a heterogeneous mixture consisting of soluble folded protein, mature amyloid‐like fibrils, and partially misfolded intermediate species that at present belie additional molecular detail. The characterization of OLF fibrillar species illustrates the challenges associated with developing a comprehensive understanding of the fibrillization process for large, non‐model amyloidogenic proteins.

Scelsi, Hailee F. [School of Chemistry and Biochem↗
DOE OSTI2024

Uncovering supramolecular chirality codes for the design of tunable biomaterials

In neurodegenerative diseases, polymorphism and supramolecular assembly of β-sheet amyloids are implicated in many different etiologies and may adopt either a left- or right-handed supramolecular chirality. Yet, the underlying principles of how sequence regulates supramolecular chirality remains unknown. Here, we characterize the sequence specificity of the central core of amyloid-β 42 and design derivatives which enable chirality inversion at biologically relevant temperatures. We further find that C-terminal modifications can tune the energy barrier of a left-to-right chiral inversion. Leveraging this design principle, we demonstrate how temperature-triggered chiral inversion of peptides hosting therapeutic payloads modulates the dosed release of an anticancer drug. These results suggest a generalizable approach for fine-tuning supramolecular chirality that can be applied in developing treatments to regulate amyloid morphology in neurodegeneration as well as in other disease states.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Assembly of ordered DNA-curli fibril complexes during Salmonella biofilm formation correlates with strengths of the type I interferon and autoimmune responses

Deposition of human amyloids is associated with complex human diseases such as Alzheimer’s and Parkinson’s. Amyloid proteins are also produced by bacteria. The bacterial amyloid curli, found in the extracellular matrix of both commensal and pathogenic enteric bacterial biofilms, forms complexes with extracellular DNA, and recognition of these complexes by the host immune system may initiate an autoimmune response. Here, we isolated early intermediate, intermediate, and mature curli fibrils that form throughout the biofilm development and investigated the structural and pathogenic properties of each. Early intermediate aggregates were smaller than intermediate and mature curli fibrils, and circular dichroism, tryptophan, and thioflavin T analyses confirmed the establishment of a beta-sheet secondary structure as the curli conformations matured. Intermediate and mature curli fibrils were more immune stimulatory than early intermediate fibrils in vitro . The intermediate curli was cytotoxic to macrophages independent of Toll-like receptor 2. Mature curli fibrils had the highest DNA content and induced the highest levels of Isg15 expression and TNFα production in macrophages. In mice, mature curli fibrils induced the highest levels of anti-double-stranded DNA autoantibodies. The levels of autoantibodies were higher in autoimmune-prone NZBWxF/1 mice than wild-type C57BL/6 mice. Chronic exposure to all curli forms led to significant histopathological changes and synovial proliferation in the joints of autoimmune-prone mice; mature curli was the most detrimental. In conclusion, curli fibrils, generated during biofilm formation, cause pathogenic autoimmune responses that are stronger when curli complexes contain higher levels of DNA and in mice predisposed to autoimmunity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Polyunsaturated Fatty Acids Mend Macrophage Transcriptome, Glycome, and Phenotype in the Patients with Neurodegenerative Diseases, Including Alzheimer’s Disease

Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-β (Aβ) into endosomes, and degrade Aβ, whereas macrophages of patients with Alzheimer’s disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of Aβ. To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte/macrophage (MM) migration in the AD brain, MM transcripts in energy and Aβ degradation, MM glycome, and macrophage clearance of Aβ. We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. MM invade Aβ plaques, upload but do not degrade Aβ, and release Aβ into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and Aβ degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and Aβ phagocytosis (p < 0.001). Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, Aβ phagocytosis, and Aβ degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance Aβ clearance, and benefit the cognition of early-stage AD patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18 F-flortaucipir (FTP) and 11 C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aβ, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages. SIGNIFICANCE STATEMENT Tau and β-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aβ may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aβ, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aβ+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Exploring inflammation‐related protein expression and its relationship with TSPO PET in Alzheimer's disease

Abstract INTRODUCTION To understand the role of neuroinflammation in Alzheimer's disease (AD), we characterized immune‐related proteins in central and peripheral biofluids. METHODS Selection of participants from the Translational Biomarker of Aging and Dementia (TRIAD) cohort with available translocator protein (TSPO) positron emission tomography (PET), cerebrospinal fluid (CSF) (n = 97), and plasma (n = 165). Biofluid samples analyzed with Olink technology (368 inflammation proteins). RESULTS Elevated proteins levels in CSF of TSPO‐positive individuals were identified. Functional enrichment analysis of CSF proteins revealed processes implicated in AD (MAPK, ERK cascades, cytokine, and leukocyte signaling). Selected candidates (CXCL1 and TNFRSF11B) showed high correlation with each other in CSF and with TSPO PET signal, but weaker associations with amyloid and tau PET. No significantly changed proteins in plasma between TSPO groups were found. DISCUSSION This explorative study identified two potential targets in CSF showing correlations with TSPO, amyloid and tau PET, suggesting a direct link between neuroinflammation, expression of these proteins and their potential implication in AD. Highlights Several proteins are elevated in CSF of TSPO PET‐positive individuals, linking them to neuroinflammation. Elevated CSF proteins were enriched in pathways such as MAPK, ERK, and cytokine signaling, linking them to the AD pathophysiology. Candidate proteins (CXCL1 and TNFRSF11B) correlated strongly with TSPO PET, particularly in brain regions known to be affected in AD. Although none of the plasma proteins remained significant after multiple comparisons correction when comparing their expression between TSPO groups, as done for CSF, candidate CSF proteins were found to correlate with plasmatic proteins, highlighting the complexity of the immune system.

Neurosciences & Neurology↗
DOE OSTI2024

Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Mutations that cause familial Alzheimer’s disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the products—of γ-secretase cleavage of substrates in FAD pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗