Recent research suggests that hippocampal-cerebellar (Hp-CB) functional connectivity may be altered early in the course of Alzheimer's disease (AD), given the early accumulation of AD pathology in the hippocampi and emerging evidence of cerebellar changes in early AD. This study analyzed the role of AD genetic risk (via APOE ε4 carrier status) and cerebrospinal fluid (CSF) biomarkers of AD pathology (ratio of phosphorylated tau (p-tau181) to amyloid beta (Aβ42/Aβ40)) on the relationship between age and functional Hp-CB resting state fMRI connectivity in 161 cognitively unimpaired older adults (M age =67.3; SD =9.0; 37 % APOE ε4 +). In multiple regression analyses with Hp-CB connectivity as the outcome, there were significant interactions between age and APOE ε4 status, and between age and CSF AD biomarkers. Older age was associated with greater Hp-CB connectivity in APOE ε4 non-carriers and participants with less abnormal CSF AD biomarkers. In contrast, Hp-CB connectivity was marginally lower with older age in ε4 carriers and those with more abnormal AD biomarkers. Furthermore, greater Hp-CB connectivity was associated with better episodic memory performance across all groups. These findings suggest that age-related increases in Hp-CB connectivity among APOE ε4 non-carriers and those with low AD biomarker levels reflect age-related changes that are largely unrelated to AD, while age-related decreases in Hp-CB connectivity in APOE ε4 carriers may reflect AD-related alterations. These findings also highlight the importance of cerebellar contributions to cognitive performance among older adults and suggest that Hp-CB connectivity may be altered in preclinical AD.

In the current study, a novel route was established for the synthesis of hybrid benzothiazole derived thiazole bearing bis-thiazolidinone-chalcone (1-15) scaffolds. These compounds were screened for their biological potential as anti-Alzheimer therapeutic agents by inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. The biological evaluation and molecular docking studies revealed that most of the synthesized compounds exhibited significant inhibitory activity against both enzymes, outperforming the standard drug, donepezil. Among them, Analog 15 demonstrated remarkable therapeutic potential, with IC₅₀ values of 3.30 ± 0.70 µM and 3.80 ± 0.90 µM, as well as strong binding affinities/docking scores of - 8.97 and - 12.84 kcal/mol for AChE and BuChE, respectively. Additionally, enzyme kinetics analysis using Lineweaver-Burk plots confirmed the mode of inhibition of the synthesized analogs. Pharmacokinetic predictions further supported the drug-like properties of these compounds, highlighting favorable pharmacological profiles, including good water solubility, non-carcinogenicity, and biological safety. The findings presented in this study provide compelling evidence for the anti-Alzheimer potential of these novel scaffolds, warranting further investigation through in vivo studies and clinical exploration to assess their full therapeutic applicability.

The online version contains supplementary material available at 10.1007/s13205-025-04313-6.

Plasma biomarkers of Alzheimer's disease (AD) change during preclinical stages, indicating potential for detecting amyloid-β (Aβ) pathology in cognitively unimpaired (CU) individuals. Given the need for accurate, scalable biomarkers, we evaluated a fully automated plasma panel to detect and monitor longitudinal Aβ accumulation in CU individuals.

In this longitudinal study, we examined a plasma panel (Aβ42/40, p-tau181, GFAP, NfL, p-tau217 and ApoE4) in CU participants at risk for AD. We assessed the biomarkers' performance to detect Aβ pathology and the cross-sectional and longitudinal relationships between the biomarkers and Aβ accumulation, neurodegeneration and cognition.

We included 400 middle-aged CU participants, of whom 135 (33.8%) were CSF Aβ-positive. All plasma biomarkers differed between Aβ-positive and -negative individuals, with plasma Aβ42/40, p-tau217, p-tau181/Aβ42, and p-tau217/Aβ42 showing the best performance in detecting A+ CU individuals. However, plasma Aβ42/40 was sensitive to random variability. Plasma p-tau217/Aβ42 had the highest performance in detecting PET A+ individuals (AUC = 0.94). All baseline plasma biomarkers were associated with longitudinal increases in Aβ deposition (mean follow-up [SD]: 3.27 ± 0.5). Longitudinal changes in plasma p-tau217 and p-tau217/Aβ42 were associated with concurrent changes in Aβ (both CSF and PET) and soluble tau pathology.

In CU individuals, several plasma biomarkers at baseline detect Aβ accumulation and are associated with its short-term change. Plasma p-tau217, and p-tau217/Aβ42 longitudinal changes reflect concurrent Aβ accumulation during this period. These findings help enrich studies in CU individuals at risk of progressing to AD.

ERC-2020-STG (Grant agreement No. 948677); ERA PerMed-ERA NET and the Generalitat de Catalunya (SLD077/21/000001); PI19/00155; PI22/00456, LCF/BQ/PR21/11840004.

The interaction of amyloid and tau in neurodegenerative diseases is a central feature of AD pathophysiology. While experimental studies point to various interaction mechanisms, their causal direction and mode (local, remote or network-mediated) remain unknown in human subjects. The aim of this study was to compare mathematical reaction-diffusion models encoding distinct cross-species couplings to identify which interactions were key to model success.

We tested competing mathematical models of network spread, aggregation, and amyloid-tau interactions on publicly available data from ADNI.

Although network spread models captured the spatiotemporal evolution of tau and amyloid in human subjects, the model including a one-way amyloid-to-tau aggregation interaction performed best.

This mathematical exposition of the "pas de deux" of co-evolving proteins provides quantitative, whole-brain support to the concept of amyloid-facilitated-tauopathy rather than the classic amyloid-cascade or pure-tau hypotheses, and helps explain certain known but poorly understood aspects of AD.

With the advent of disease-modifying therapies for early Alzheimer's disease (AD), a comprehensive characterization of patients initiating lecanemab in the USA is needed to understand its use in real-world settings.

This retrospective observational study used administrative claims from the Komodo Research Database (1/1/2023-6/30/2024). Eligible patients had ≥ 1 lecanemab administration (first claim defined the index date) and ≥ 12 months of clinical activity/insurance eligibility before the index date. Patient characteristics, diagnostic process, and AD-related medications were evaluated within 12 months before the index date (baseline), whereas lecanemab treatment patterns and concomitant medications were evaluated on or after the index date (follow-up). Outcomes were reported using descriptive statistics and persistence to lecanemab was evaluated using Kaplan-Meier analysis.

Of 3155 patients included in the study, mean age was 75.0 years, 55.8% were female, 44.2% were male, and most (93.3%) received their index lecanemab administration in an urban setting. Diagnoses of AD (83.8%) and mild cognitive impairment (60.8%) were common at baseline, and 67.6% of patients used AD symptomatic medications. Average time from earliest diagnosis to first lecanemab administration was 4.9 months among patients with a diagnosis in January 2023 (accelerated approval date) or onwards. Over a mean follow-up of 138.8 days, the monthly mean number of administrations of lecanemab was 1.9, with an average of 16.5 days between consecutive administrations and 47.4 days to the first follow-up head magnetic resonance imaging. Persistence to lecanemab was 87.6% at 4 months after treatment initiation.

Lecanemab was utilized in appropriate patient populations according to the prescribing information approved by the US Food and Drug Administration. Findings from our study provide first insights into the real-world use of lecanemab in the USA and shed light on the need for increased and timely lecanemab initiation for the long-term management of early AD.

Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal role of necroptosis in various neurological diseases, including stroke, Alzheimer's disease and multiple sclerosis. A defining hallmark of these conditions is neuroinflammation, a complex inflammatory response that critically influences neuronal survival. This review provides a comprehensive analysis of the mechanistic underpinnings of necroptosis and its intricate interplay with neuroinflammation, exploring the interrelationship between the two processes and their impact on neurological disorders. In addition, we discuss potential therapeutic strategies that target the intervention of necroptosis and neuroinflammation, offering novel avenues for intervention. By deepening our understanding of these interconnected processes, the development of more effective treatments approaches holds significant promise for improving patient outcomes in neurological disorders.

BackgroundAlzheimer's disease (AD) is influenced by a complex interplay of genetic, immune, and metabolic factors. Identifying plasma proteins causally linked to AD could help clarify these pathways and uncover potential therapeutic targets.ObjectiveThis study aims to investigate the causal relationships between AD and plasma proteins.MethodsWe conducted a two-stage, two-sample Mendelian randomization (MR) analysis to explore the causal relationships between plasma protein levels and AD risk. In both stages, we used non-overlapping genome-wide association study datasets for exposures (plasma protein levels) and outcome (AD) to ensure robust and independent analyses. We examined both forward (from plasma proteins to AD risk) and reverse (from AD to plasma protein expression) causal effects to elucidate potential bidirectional relationships.ResultsOur MR analysis identified 25 plasma proteins with causal associations to AD, with many implicated in immune and lipid metabolic pathways. These findings reinforce the roles of inflammation and lipid metabolism in AD pathogenesis and offer novel insights into specific proteins that may serve as biomarkers or therapeutic targets.ConclusionsThis study provides further support for the relationship between immune and lipid metabolic dysregulation and AD, advancing our understanding of the molecular mechanisms underlying disease progression and highlighting key proteins for future research and therapeutic development.

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for preparing amyloid-beta (Aβ) peptides implicated in Alzheimer's disease. While considered relatively non-toxic at low concentrations, DMSO itself may exert biological effects that could confound experimental outcomes, especially for weakly cytotoxic substances like Aβ. Seven brain cell types (BV-2, N2a, SH-SY5Y, U87, neurons, astrocytes, microglia) were treated with varying DMSO concentrations or Aβ1-42 oligomers/protofibrils/fibrils prepared using DMSO. Cell viability was assessed by CCK-8 and LDH assays. Matched DMSO controls were prepared alongside Aβ treatments to delineate solvent effects. Low DMSO concentrations (0.0625-0.015625%) exhibited hormetic cytoprotective and growth-promoting effects, while higher concentrations (≥2%) were cytotoxic. Importantly, these hormetic solvent effects confounded the measurement of Aβ cytotoxicity. By accounting for matched DMSO controls, the study revealed that Aβ fibril toxicity may have been underestimated due to the cytoprotective solvent effects of low DMSO concentrations used in their preparation. In conclusion, DMSO exhibits complex hormetic dose-responses that can significantly influence experimental outcomes, especially for weakly cytotoxic agents like Aβ. Rigorous solvent controls are crucial to delineate genuine substance effects from potential solvent confounds and avoid erroneous interpretations.

The progressive nature of neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, presents substantial problems because current treatments are still obscure. Stem cell-based treatments are emerging as a viable solution to address the significant gaps in treating these severe diseases. This study provides a comprehensive analysis of the latest advancements in stem cell research, focusing on the treatment of NDs. Various types of stem cells, such as adult, induced pluripotent, and embryonic stem cells, and their potential applications in immunomodulation, neurotrophic factor release, and neuronal development are also discussed. Recent clinical studies reveal outcomes, challenges, and solutions, with advancements in disease-specific neural cell production, gene editing, and improved stem cell transplantation transport strategies. The review discussed future perspectives on developing more effective stem cell-based interventions. Biomaterials are being used for cell distribution and personalized medicine techniques to improve treatment outcomes, while exploring stem cell treatments for NDs and identifying areas for further research.

Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, the cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using in vivo two-photon Ca2+ imaging in the visual cortex of AD mouse models, we found that cortical layer 5 neurons displayed abnormally prolonged Ca2+ transients before substantial plaque formation. Neuropixels recordings revealed that these abnormal transients were associated with reduced spiking and impaired visual tuning of parvalbumin (PV)-positive fast-spiking interneurons (FSIs) in layers 5/6, whereas PV-FSIs in superficial layers remained unaffected. These dysfunctions occurred alongside a deep-layer-specific reduction in neuronal pentraxin 2 (NPTX2) within excitatory neurons, decreased GluA4 in PV-FSIs, and fewer excitatory synapses onto PV-FSIs. Notably, NPTX2 overexpression increased excitatory input onto layers 5/6 PV-FSIs and rectified their spiking activity. Thus, our findings reveal an early selective impairment of deep cortical layers 5/6 in AD models and identify deep-layer PV-FSIs as therapeutic targets.

While the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer's disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted 'X' in the ATX(N) framework, remain poorly understood.

Using an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF proteins across the AD continuum in three independent cohorts, finely staged by Aβ/tau positron emission tomography (PET), fluid biomarkers, or brain biopsy. Weighted protein co-expression network analysis identified clusters of proteins robustly correlating in all three cohorts which sequentially changed with AD progression. Obtained protein clusters were correlated with fluid biomarker measurements (phosphorylated tau (p-tau) species including p-tau181, p-tau217, and p-tau205, as well as Aβ), Aβ/tau PET imaging, and clinical parameters to discern disease-relevant clusters which were modelled across the AD continuum.

Neurodegeneration-related proteins (e.g., 14-3-3 proteins, PPIA), derived from different brain cell types, strongly correlated with fluid as well as imaging biomarkers and increased early in the AD continuum. Among them, the proteins SMOC1 and CNN3 were highly associated with Aβ pathology, while the 14-3-3 proteins YWHAZ and YWHAE as well as PPIA demonstrated a strong association with both Aβ and tau pathology as indexed by PET. Endo-lysosomal proteins (e.g., HEXB, TPP1, SIAE) increased early in abundance alongside neurodegeneration-related proteins, and were followed by increases in metabolic proteins such as ALDOA, MDH1, and GOT1 at the mild cognitive impairment (MCI) stage. Finally, later AD stages were characterized by decreases in synaptic/membrane proteins (e.g., NPTX2).

Our study identified proxies of Aβ and tau pathology, indexed by PET, (SMOC1, YWHAE, CNN3) and highlighted the dynamic fluctuations of the CSF proteome over the disease course, identifying candidate biomarkers for disease staging beyond Aβ and tau.

BackgroundPrevious studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer's disease. The exact causality and their mediation relationships remain unclear.ObjectiveOur study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer's disease.MethodsWe leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer's disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer's disease.ResultsOur study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer's disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer's disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer's disease. Axin-1 and IL-6 increased the risk of Alzheimer's disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer's disease with the two-step MR method, accounting for 10.83% of the total effect.ConclusionsOur study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer's disease, offering novel perspectives on its etiology, pathogenesis, and treatment.

Alzheimer's disease (AD) is a neurodegenerative disease primarily manifesting with cognitive decline. This study aimed to investigate the alterations in microRNAs in patients across AD continuum as potential biomarkers.

Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including microRNA levels in the serum and cerebrospinal fluid (CSF) of patients across AD continuum. We analyzed the associations between microRNA levels and previously known AD biomarkers, such as amyloid beta (Aβ) accumulations in the brain and glucose reuptake values using positron emission tomography ([18F]AV45 and FDG PET, respectively).

The study found a significant positive correlation between CSF levels of miR-210-3p and Aβ accumulations in the brain (B = 4.69). Conversely, miR-223-3p levels were significantly lower in APOE-ε4 carriers. Significant negative correlations were also observed between glucose reuptake and several miRNAs in the AD group. Specifically, plasma levels of let-7g-5p, mir-423-5p, and mir-660-5p were negatively associated with glucose reuptake in the brain.

Elevated levels of miR-210-3p correlate with Aβ accumulation, supporting previous findings of increased levels of certain microRNAs in patients with MCI and AD. Our findings highlight the potential of microRNAs as biomarkers of AD.

Elevated intake of omega-3 polyunsaturated fatty acids is linked to a reduced risk of dementia in some prospective studies. However, few studies have examined the relationship between nutrient intake and plasma biomarkers of Alzheimer's disease.

We explored whether omega-3, omega-6, and monounsaturated fat intakes were associated with changes in plasma biomarkers of Alzheimer's disease over time.

The Washington Heights-Inwood Columbia Aging Project is a prospective cohort study (1994-2021); the data set used here includes a mean follow-up of 7.0 years.

Community-based in New York City.

599 dementia-free individuals at baseline who completed a 61-item food frequency questionnaire and had biomarkers measured in plasma from at least two different time points.

Fatty acid intake tertiles were computed from participant-completed 61-item Willett semi-quantitative food frequency questionnaires (Channing Laboratory, Cambridge, Massachusetts) obtained once at their baseline visit. Plasma-based biomarker assays were performed, using the single molecule array technology Quanterix Simoa HD-X platform, at baseline and follow-up visits. Generalized Estimating Equations (GEE) models were used to evaluate the association between baseline nutrient intake tertile and changes in biomarkers including phospho-tau181, amyloid-beta 42/40 ratio, phospho-tau181/amyloid-beta42 ratio, glial fibrillary acidic protein, neurofilament light chain, and two biomarker patterns derived from Principal Component Analysis (PCA1 and PCA2), with higher scores indicating a high level of neurodegeneration and low level of Alzheimer's disease burden, respectively). Models were adjusted for age, sex, race/ethnicity, education, and calculated total energy intake initially, and additionally for cerebrovascular risk factors.

Higher baseline omega-3 intake tertile was associated with lesser decline in PCA2 (β = 0.221, p < 0.001) and amyloid-beta 42/40 ratio (β = 0.022, p = 0.003), and a lesser rise in phospho-tau181 (β = -0.037, p = 0.001). Higher omega-6 intake tertile was linked to a lesser rise in phospho-tau181 (β = -0.050, p < 0.001) and glial fibrillary acidic protein (β = -0.028, p = 0.002). Most associations persisted after adjusting for cardiovascular risk factors.

Higher relative baseline intake of omega-3 and omega-6 fatty acids is associated with lesser progression of blood-based biomarkers of Alzheimer's disease. Consuming healthy fatty acids may help prevent accumulation of Alzheimer's disease-related pathological changes.

β-Amyloid (Αβ) imaging revolutionized the in vivo assessment of Alzheimer's disease (AD) Αβ pathology and its changes over time, increasing our insights into Aβ deposition in the brain by providing highly accurate, reliable, and reproducible quantitative statements of regional and global Aβ burden in the brain, proving essential for the differential diagnosis, staging, and evaluation of disease-specific anti-Αβ therapeutic approaches. Longitudinal observations, coupled with different disease-specific biomarkers to assess potential downstream effects of Aβ, have confirmed that Αβ deposition in the brain starts decades before the onset of symptoms. Aβ imaging studies continue to refine our understanding of the role of Αβ deposition in AD, and its relation to other imaging and fluid biomarkers. HIGHLIGHTS: Αβ imaging revolutionized the in vivo assessment of Alzheimer's disease Αβ pathology. Αβ imaging has increased our insights into Aβ deposition in the brain by providing highly accurate, reliable, and reproducible quantitative statements of regional and global Αβ burden in the brain. Αβ imaging is essential for the differential diagnosis, staging, and evaluation of disease-specific anti-Αβ therapeutic approaches. Αβ imaging studies continue to refine our understanding of the role of Αβ deposition in Alzheimer's disease, and its relation to other imaging and fluid biomarkers.

Blood neural cell-derived small extracellular vesicles (sEVs) can directly reflect changes in brain tissue and are easier to obtain than cerebrospinal fluid. This article systematically reviews the alterations of proteins and miRNAs from neural cell-derived sEVs in patients with Alzheimer's disease (AD), and summarizes the biomarkers with clinical diagnostic and predictive value. PubMed, Web of Science, Embase, and Cochrane Library were searched for studies in blood neural cell-derived sEVs in AD patients up to May 2024. According to the inclusion and exclusion criteria, the literature was screened, the information was extracted and the quality was evaluated. Proteins and miRNAs from neural cell-derived sEVs were classified and summarized, focusing on target molecules with high diagnostic and predictive values for AD. A final 34 articles reporting 5601 participants were included. In cross-sectional studies, Aβ- and Tau-related proteins (Aβ42, Aβ42/40, p-S396-Tau, p-Tau181), p-S312-IRS-1, and cathepsin D were increased, conversely, synaptic proteins (neurogranin, synaptotagmin, synaptophysin, synaptopodin, NMDAR2A) and REST were decreased in blood neuron-derived sEVs (NDsEVs) of patients with AD. While miR-29c-3p was increased in blood NDsEVs and glial cell-derived sEVs. Each of these proteins and miRNAs demonstrated high AD diagnostic value. Additionally, blood astrocyte-derived sEVs (ADsEVs) showed increased complement effector proteins and decreased complement regulatory proteins with a moderate diagnostic value. In longitudinal cohort studies, three composite models displayed high predictive efficacy for early AD prediction, and could predict the occurrence of AD within 1-10 years. Therefore, Aβ- and Tau-related proteins, synaptic proteins, and miRNA in blood neural cell-derived sEVs demonstrate high AD diagnostic and predictive values serving as important biomarkers. Especially, synaptic proteins showed significant changes in the early clinical stage, which has early predictive value.

BackgroundAlzheimer's disease (AD) is characterized by cortical atrophy, glutamatergic neuron loss, and cognitive decline. However, large-scale quantitative assessments of cellular changes during AD pathology remain scarce.ObjectiveThis study aims to integrate single-nuclei sequencing data from the Seattle Alzheimer's Disease Cortical Atlas (SEA-AD) with spatial transcriptomics to quantify cellular changes in the prefrontal cortex and temporal gyrus, regions vulnerable to AD neuropathological changes (ADNC).MethodsWe mapped differentially expressed genes (DEGs) and analyzed their interactions with pathological factors such as APOE expression and Lewy bodies. Cellular proportions were assessed, focusing on neurons, glial cells, and immune cells.ResultsRORB-expressing L4-like neurons, though vulnerable to ADNC, exhibited stable cell numbers throughout disease progression. In contrast, astrocytes displayed increased reactivity, with upregulated cytokine signaling and oxidative stress responses, suggesting a role in neuroinflammation. A reduction in synaptic maintenance pathways indicated a decline in astrocytic support functions. Microglia showed heightened immune surveillance and phagocytic activity, indicating their role in maintaining cortical homeostasis.ConclusionsThe study underscores the critical roles of glial cells, particularly astrocytes and microglia, in AD progression. These findings contribute to a better understanding of cellular dynamics and may inform therapeutic strategies targeting glial cell function in AD.

In this scoping review, we examine the role of wearable devices in diagnosing, treating, and monitoring Alzheimer's disease (AD) and mild cognitive impairment (MCI). It identifies various devices, including fitness trackers, smartwatches, electroencephalographic equipment, and sensors, which are used for monitoring physical activity, sleep patterns, and cognitive functions. Our review highlights the potential of these devices for early diagnosis and treatment, improving patient autonomy and quality of life. However, challenges, such as data privacy, device adherence, and technical limitations, remain. Future research should focus on integrating wearable devices with advanced diagnostic tools and validating their effectiveness across diverse populations.

Amyloid PET imaging is capable of measuring brain amyloid load in vivo. The aim of this study is to assess the relationship of the baseline amyloid with its accumulation over time and with cognition in individuals with subjective cognitive decline (SCD), giving a focus on those below Aβ positivity thresholds.

118 of 197 individuals with SCD from the Fundació ACE Healthy Brain Initiative underwent three [18F]florbetaben scans and the remaining 79 underwent two scans in a 5-year span. Individuals were categorised based on baseline Centiloid values (CL) into amyloid positive (Aβ+; CL > 35.7), Grey Zone (GZ; 20 < CL ≤ 35.7), and amyloid negative (Aβ-; CL ≤ 20). Relationship between conversion to mild cognitive decline (MCI) and baseline amyloid levels was assessed. Then, to focus on sub-threshold individuals with amyloid accumulation, the Aβ- group was split into two groups (N1 (CL ≤ 13.5) and N2 (13.5 < CL ≤ 20)), Aβ accumulation was determined, and a parametric image analysis of the Aβ accumulators in the N1 group was performed.

At baseline, 20 individuals were Aβ+, 8 GZ, 160 N1, and 9 N2. Higher Aβ load, older and less educated individuals presented increased risk of MCI-conversion. Longitudinally, 19% of N1 individuals were accumulators despite very low Aβ burden at baseline. Meanwhile, 89% of the N2 group accumulated Aβ as well as all GZ individuals (which had the highest rate of amyloid accumulation, 5.1 CL/year). In the parametric image analysis of N1 accumulators, a region within the precuneus was linked to increased Aβ over time.

Baseline amyloid levels differentiate individuals who accumulate amyloid over time and that are at risk for cognitive decline, including those at sub-threshold levels of Aβ. This can be valuable to identify pre-clinical AD in a SCD population.

Presently approved Alzheimer's Disease (AD) therapeutics are designed for targeted removal of the AD-related toxic protein aggregate amyloid-β (Aβ) and have only shown moderate efficacy at slowing disease progression. Reversal of cognitive decline requires both removal of toxic aggregates and repair of the cellular systems damaged by decades of exposure to these aggregates. Adult hippocampal neurogenesis (AHN) is one such system that is known to be affected early and severely in the development of AD. Moreover, preserved AHN is associated with cognitive resilience to AD neuropathology. Therefore, targeted therapies to improve or enhance neurogenesis should be considered in addition to the removal of toxic protein aggregates. Photobiomodulation (PBM) using 670 nm LED light has been shown to induce synaptic resilience to and removal of AD-related toxic protein aggregates. In this study, we aimed to assess the effect of PBM on a mouse model of advanced AD neuropathology. Transgenic 3xTg-AD mice (15- to 17-month old) were randomized to receive PBM or SHAM therapy for one month, followed by neuropathological assessments. Our results show that one month of PBM therapy reduces hyperphosphorylated tau burden and partially rescues AHN in aged 3xTg-AD mice as compared to SHAM-treated transgenic mice. These data support the notion that PBM has the potential to be an effective non-invasive therapy to help preserve AHN and reduce cognitive dysfunction in moderate to advanced AD.

Alzheimer's disease (AD) is a non-communicable disease with global impact. Inhibitors of acetylcholinesterase (AChE) are suitable therapies for AD. In this work, we report the isolation of antiacetylcholinesterase compounds from the methylene chloride (DCM) extract of the medical fungus Ganoderma applanatum (Pers.) Pat (Ganodermataceae). Chemical evaluation of this extract using chromatographic technics led to the isolation of a (1:1) mixture of ergosterol (1) and stellasterol (2), palmitic acid (3), ganodermanondiol (4), lucidumol B (5) and lupeol (6). Structures of these compounds were determined using spectroscopic analysis such as IR, MS, 1D & 2D NMR and literature. The acetylation reaction has been performed on the mixture (1 + 2) and compound 4, leading to the obtention the mixture of 3-acetyl-ergosterol (7) and 3-acetylstellasterol (8) along with 24-acetyl-ganodermanondiol (9) respectively. Total phenolic content was determined for DCM, Ethyl acetate and n-butanol extracts. To assess their antiradical scavenging potential, DPPH was used as free radical. The Inhibition power of acetylcholinesterase was evaluated in vitro using the Ellman reagent. Amongst all tested extracts, the DCM extract showed the high amount of total phenolic compounds with a value of 133.9512 mg EAG/g EX. The same extract showed a very good antiradical scavenging potential with an IC50 of 0.0021 mg/mL. The mixture (1 + 2) showed the highest antiradical scavenging activity with IC50 of 0.0770 mg/mL. The results obtained demonstrated that the acetylation has reduced the antiradical scavenging potential. Concerning the acetylcholinesterase inhibition power, the DCM extract and the mixture (1 + 2) showed a very good power with an inhibition percentage of 89%. The acetylation has also reduced the activity of the obtained derivative. The results provide insights into the potential efficacy of these compounds as acetylcholinesterase inhibitors. The binding interactions of the isolated and acetylated derivatives against acetylcholinesterase protein (PBP 3i6m) of Torpedo californica were studied using Autodock software. Ergosterol (-11.9 kcal/mol) binds better to the protein biding site through significant pi-sigma interactions.

To effectively address Alzheimer's disease, it is crucial to understand its earliest manifestations, underlying mechanisms and early markers of progression. Recent findings of very early brain activation anomalies highlight their potential for early disease characterization and predicting future cognitive decline. Our objective was to evaluate the value of brain activation-both individually and in combination with structural and neuropsychological measures-for predicting cognitive change. The study included 105 individuals from the Consortium for the Early Identification of Alzheimer's Disease-Quebec cohort who exhibited subjective cognitive decline or mild cognitive impairment. Cognitive decline was assessed by calculating the slope of Montreal Cognitive Assessment scores using regression models across successive assessments, and individuals were characterized as either decliners or stable based on clinically reliable change. We evaluated cognitive decline predictions using unimodal models for each class of predictors and multimodal models that combined these predictors. Functional activation emerged as a strong predictor of cognitive change (R²=52.5%), with 87.6% accuracy and 98.7% specificity, performing comparably to structural and neuropsychological measures. Although the unimodal functional model exhibited high specificity, indicating that functional abnormalities frequently predict future decline, it had low sensitivity (60%), meaning that the absence of abnormalities does not rule out future decline. Multimodal models provided greater explanatory power than unimodal models and greater sensitivity than the functional model. These findings highlight the potential role of early brain activation anomalies in the early detection of future cognitive changes, offering valuable insights for clinicians and researchers in assessing cognitive decline risk and refining clinical trial criteria.

Over 6 million patients in the United States are affected by Alzheimer's Disease and Related Dementias (ADRD). Early detection of ADRD can significantly improve patient outcomes through timely treatment.

To develop and validate machine learning (ML) models for early ADRD diagnosis and prediction using de-identified EHR data from the University of Missouri (MU) Healthcare.

Retrospective case-control study.

The study used de-identified EHR data provided by the MU NextGen Biomedical Informatics, modeled with the PCORnet Common Data Model (CDM).

An initial cohort of 380,269 patients aged 40 or older with at least two healthcare encounters was narrowed to a final dataset of 4,012 ADRD cases and 119,723 controls.

Six ML classifier models: Gradient-Boosted Trees (GBT), Light Gradient-Boosting Machine (LightGBM), Random Forest (RF), eXtreme Gradient-Boosting (XGBoost), Logistic Regression (LR), and Adaptive Boosting (AdaBoost) were evaluated using Area Under the Receiver Operating Characteristic Curve (AUC-ROC), accuracy, sensitivity, specificity, and F1 score. SHAP (SHapley Additive exPlanations) analysis was applied to interpret predictions.

The GBT model achieved the best AUC-ROC scores of 0.809-0.833 across 1- to 5-year prediction windows. SHAP analysis identified depressive disorder, age groups 80-90 yrs and 70-80 yrs, heart disease, anxiety, and the novel risk factors of sleep apnea, and headache.

This study underscores the potential of ML models for leveraging EHR data to enable early ADRD prediction, supporting timely interventions, and improving patient outcomes. By identifying both established and novel risk factors, these findings offer new opportunities for personalized screening and management strategies, advancing both clinical and informatics science.

Growing interest in the role of the immune response in Alzheimer's Disease and related dementias (ADRD) has led to widespread use of fluid inflammatory markers in research studies. To standardize the use and interpretation of inflammatory markers in AD research, we build upon prior guidelines to develop consensus statements and recommendations to advance application and interpretation of these markers. In this roadmap paper, we propose a glossary of terms related to the immune response in the context of biomarker discovery/validation, discuss current conceptualizations of inflammatory markers in research, and recommend best practices to address key knowledge gaps. We also provide consensus principles to summarize primary conceptual, methodological, and interpretative issues facing the field: (1) a single inflammatory marker is likely insufficient to describe an entire biological cascade, and multiple markers with similar or distinct functions should be simultaneously measured in a panel; (2) association studies in humans are insufficient to infer causal relationships or mechanisms; (3) neuroinflammation displays time-dependent and disease context-dependent patterns; (4) neuroinflammatory mechanisms should not be inferred based solely on blood inflammatory marker changes; and (5) standardized reporting of CSF inflammatory marker assay validation and performance will improve incorporation of inflammatory markers into the biological AD criteria.

Longitudinal investigation of the Apolipoprotein E (APOE) genotype's impact on Alzheimer's disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation ("high Aβ accumulators") were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.

Periodontitis is a chronic infectious inflammatory disease primarily caused by periodontal pathogenic bacteria, which poses a significant threat to human health. The pathogenic mechanisms associated with Porphyromonas gingivalis (P. gingivalis), a principal causative agent of periodontitis, are particularly complex and warrant thorough investigation. The extensive array of virulence factors released by this bacterium during its growth and pathogenesis not only inflicts localized damage to periodontal tissues but is also intricately linked to the development of systemic diseases through various mechanisms. The outer membrane vesicles (OMVs) produced by P. gingivalis play a key role in this process. These OMVs serve as important mediators of communication between bacteria and host cells and other bacteria, carrying and delivering virulence factors to host cells and distant tissues, thereby damaging host cells and exacerbating inflammatory responses. The ability of these OMVs to disseminate and deliver bacterial virulence factors allows P. gingivalis to play a pathogenic role far beyond the confines of the periodontal tissue and has been closely associated with the development of a variety of systemic diseases such as cardiovascular disease, Alzheimer's disease, rheumatoid arthritis, diabetes mellitus, non-alcoholic hepatitis, and cancer. In view of this, it is of great pathophysiological and clinical significance to deeply investigate its pathogenic role and related mechanisms. This will not only help to better understand the pathogenesis of periodontitis and its related systemic diseases but also provide new ideas and more effective and precise strategies for the early diagnosis, prevention, and treatment of these diseases. However, the current research in this field is still insufficient and in-depth, and many key issues and mechanisms need to be further elucidated. This article summarizes the recent research progress on the role of P. gingivalis OMVs (P. g-OMVs) in related diseases, with the aim of providing a theoretical basis and direction for future research and revealing the pathogenic mechanism of P. g-OMVs more comprehensively.

Amyloid-β imaging through positron emission tomography (PET) has significantly transformed Alzheimer's disease (AD) research. [11C]PiB has been widely used for imaging β-amyloid plaques due to its high affinity and selectivity for amyloid deposits. [18F]AZD4694 is a more recently developed amyloid-PET imaging agent, which structurally resembles PiB and has less non-specific binding in the white matter than other 18F-labeled compounds. The purpose of this study is to compare the in vitro binding properties of the amyloid-PET radiotracers [11C]PiB and [18F]AZD4694 in post-mortem human brain tissue. Total binding was assessed by autoradiography in prefrontal, inferior parietal, posterior cingulate cortices and hippocampal sections of healthy control (HC) and AD autopsy-confirmed brain tissues. Furthermore, the displacement of [18F]AZD4694 by unlabeled PiB was evaluated in the above-mentioned sections of AD brain tissues.

For both radiotracers, we found significant differences (p < 0.0001) between HC and AD tissues binding in the prefrontal cortex ([11C]PiB Cohen's d = 3.424, [18F]AZD4694 Cohen's d = 5.070), inferior parietal cortex ([11C]PiB Cohen's d = 3.156, [18F]AZD4694 Cohen's d = 3.959), posterior cingulate cortex ([11C]PiB Cohen's d = 1.781, [18F]AZD4694 Cohen's d = 3.434), and hippocampus ([11C]PiB Cohen's d = 1.320, [18F]AZD4694 Cohen's d = 3.696). Higher binding was detected for [18F]AZD4694 compared to [11C]PiB in AD prefrontal, inferior parietal and posterior cingulate cortices, while binding in the hippocampus was comparable for both radioligands. Strong correlations between [18]AZD4694 and [11C]PiB were found in the prefrontal (R = 0.959, p < 0.0001), inferior parietal (R = 0.893, p < 0.0001), posterior cingulate (R = 0.838, p = 0.0006) cortices and hippocampus (R = 0.750, p < 0.0001). Bland-Altman analyses revealed strong agreement between [11C]PiB and [18F]AZD4694 in the prefrontal, inferior parietal, and posterior cingulate cortices, but lower agreement in the hippocampus. Displacement studies confirmed high binding affinity of PiB in all tissues, indicating that both amyloid-PET agents compete for the same binding sites.

This head-to-head study provides evidence that while [18F]AZD4694 and [11C]PiB bindings are highly correlated with both tracers competing for the same binding sites, [18F]AZD4694 has a slightly higher effect size when comparing between neuropathologically-confirmed AD and HC brain tissues.

This study was conducted to clarify patterns of cortico-limbic volume abnormalities in late life depression (LLD) relative to non-depressed (ND) adults matched for amyloid β (Aβ) deposition and to evaluate the relationship of volume abnormalities with cognitive performance. Participants included 116 LLD and 226 ND. Classification accuracy of LLD status was estimated using area under the receiver operator characteristic curve. Twenty-one percent of LLD and ND participants were Aβ positive and the groups did not differ on white matter hyperintensity volume (WMH (logscale); β = 0.12, p = 0.28). Compared to ND, the LLD group exhibited significantly lower bilateral volume in the lateral orbitofrontal cortex, hippocampus, accumbens area, superior temporal lobe, temporal pole, and amygdala after multiple comparison correction (p < 0.009 for all). Cortico-limbic volumes significantly improved classification of LLD beyond demographic characteristics, Aβ status, and WMH (AUCVol = 0.71, AUCWMH, Aβ = 0.62, AUC difference, 0.09 [0.03 to 0.15]). LLD exhibited poorer performance on measures of global cognition, set shifting, and verbal learning and memory relative to ND. Cognitive function was positively associated with cortico-limbic volumes and these relationships did not differ by group. Secondary analyses with an ND sample additionally matched for Mild Cognitive Impairment (MCI) diagnosis showed a similar but attenuated pattern of volume abnormalities. Overall, our results support LLD as being associated with cortico-limbic volume abnormalities that are distinct from Aβ and white matter pathologies and that these volume abnormalities are important factors associated with cognitive dysfunction in LLD.

The progressive number of old adults with cognitive impairment worldwide and the lack of effective pharmacologic therapies require the development of non-pharmacologic strategies. The photobiomodulation (PBM) is a promising method in prevention of early or mild age-related cognitive impairments. However, it remains unclear the efficacy of PBM for old patients with significant age-related cognitive dysfunction. In our study on male mice, we show a gradual increase in the brain amyloid beta (Aβ) levels and a decrease in brain drainage with age, which, however, is associated with a decline in cognitive function only in old (24 months of age) mice but not in middle-aged (12 months of age) and young (3 month of age) animals. These age-related features are accompanied by the development of hyperplasia of the meningeal lymphatic vessels (MLVs) in old mice underlying the decrease in brain drainage. PBM improves cognitive training exercises and Aβ clearance only in young and middle-aged mice, while old animals are not sensitive to PBM. These results clearly demonstrate that the PBM effects on cognitive function are correlated with age-mediated changes in the MLV network and may be effective if the MLV function is preserved. These findings expand fundamental knowledge about age differences in the effectiveness of PBM for improvement of cognitive functions and Aβ clearance as well as about the lymphatic mechanisms responsible for age decline in sensitivity to the therapeutic PBM effects.

Statins are long known to be beneficial for neurodegenerative conditions, including Alzheimer's disease (AD). Also, nanoparticle (NP) drugs can better affect the target tissue in various diseases. Therefore, the aim of this study was surveying the effect of rosuvastatin (RZV) coated by nano-chitosan in an Alzheimer's (Alz) induced model of rats. We examined learning, memory, and hippocampal amyloid plaques and evaluate expression levels of calbindin, doublecortin (DCX), NeuroD1, neuronal nuclei (NeuN), and neurofilament. Forty rats were randomly divided into five various groups. AD was induced by injecting bilaterally with 1 μl of amyloid beta (Aβ) into the hippocampus. After confirmation of AD, RZV, or NP, or RZV+NP were administered gavage orally daily in rats for 30 days. Induction of AD significantly raised Aβ plaques and dead cells compared to the control group. Results of Morris water maze in the test day indicated that Alz+NP+RZV group significantly reduced escape latency and travelled distance, also significantly increased spending time compared to the Alz group (P<0.05). RZV significantly decreased Aβ plaque percentage and the number of apoptotic cells compared to the Alz group (P<0.05). In addition, NeuN and neurofilament protein expression and calbindin, DCX, and NeuroD1 genes expression increased in Alz+RZV and Alz+RZV+NP compared to the Alz group. RZV coated by nano-chitosan has good potential for reducing Aβ plaques and dead cells, increasing brain NeuN and neurofilament proteins and calbindin, DCX, and NeuroD1 genes, and improving learning and memory in Alz rats.

This study aimed to investigate the correlation between mild cognitive impairment and flourishing among Chinese residents.

A total of 527 community residents aged ≥18 years were recruited from December 2023 to April 2024. Based on the results of the Ascertain Dementia 8-Item Informant Questionnaire (AD8), participants were classified into a healthy group (n = 356) and a mild cognitive impairment (MCI) group (n = 171). General demographic data, including age, gender, height, weight, place of residence, education level, marital status, household composition, personal income, occupation, and the flourishing scale (FS) were collected for statistical analysis. The analysis was performed using Statistical Product and Service Solutions software. Chi-square test was used to compare differences between the groups, while Kendall's correlation analysis and multivariate logistic regression were applied to assess the relationship between flourishing and MCI.

Comparisons between the healthy and MCI groups showed that the FS scores in the healthy group were significantly higher than those in the MCI group (p < 0.01). Kendall's correlation analysis revealed that the score of AD8 was negatively correlated with FS (r = -0.237, p < 0.01). Multivariate analysis indicated that age [odds ratio (OR) = 1.451, 95% confidence interval (CI; 1.107-1.902), p = 0.007], place of residence [OR = 5.523, 95% CI (3.572-8.539), p < 0.001], and FS [OR = 0.421, 95%CI (0.311-0.569), p < 0.001] were correlated with MCI.

Flourishing levels are negatively correlated with MCI, and higher levels of flourishing associated with a lower risk of MCI. This suggests that flourishing may serve as a protective factor against cognitive decline. Additionally, age and place of residence are identified as risk factors for MCI.

Cost-effective, noninvasive screening methods for preclinical Alzheimer's disease (AD) and other neurocognitive disorders remain an unmet need. The olfactory neural circuits develop AD pathological changes prior to symptom onset. To probe these vulnerable circuits, we developed the digital remote AROMHA Brain Health Test (ABHT), an at-home odor identification, discrimination, memory, and intensity assessment. The ABHT was self-administered among cognitively normal (CN) English and Spanish speakers (n = 127), participants with subjective cognitive complaints (SCC; n = 34), and mild cognitive impairment (MCI; n = 19). Self-administered tests took place remotely at home under unobserved (among interested CN participants) and observed modalities (CN, SCC, and MCI), as well as in-person with a research assistant present (CN, SCC, and MCI). Olfactory performance was similar across observed and unobserved remote self-administration and between English and Spanish speakers. Odor memory, identification, and discrimination scores decreased with age, and olfactory identification and discrimination were lower in the MCI group compared to CN and SCC groups, independent of age, sex, and education. The ABHT revealed age-related olfactory decline, and discriminated CN older adults from those with cognitive impairment. Replication of our results in other populations would support the use of the ABHT to identify and monitor individuals at risk for developing dementia.

Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).

Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).

Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.

Protein aggregation is a critical factor in the development and progression of several human diseases, including Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and type 2 diabetes. Among these conditions, AD is recognized as the most prevalent progressive neurodegenerative disorder, characterized by the accumulation of amyloid-beta (Aβ) peptides. Neuronal toxicity is likely driven by soluble oligomeric intermediates of the Aβ peptide, which are thought to play a central role in the cascade leading to neuronal dysfunction and cognitive decline. In response, numerous therapeutic strategies have been developed to inhibit Aβ oligomerization, as this is believed to delay the formation of Aβ protofibrils. Traditional research has focused on discovering small molecules or peptides that antagonize Aβ oligomerization. However, recent studies have explored an alternative approach-developing ligands that stabilize the Aβ peptide in its α-helical conformation. This stabilization is thought to alter the peptide's natural aggregation kinetics, shifting it away from toxic oligomer formation and toward less harmful states. Crucially, by maintaining Aβ in this α-helical form, these ligands have been shown to rescue the peptide's associated cytotoxicity, offering a promising mechanism to mitigate the detrimental effects of Aβ in AD. While challenges remain, including treatment costs and side effects like ARIA (amyloid-related imaging abnormalities), anti-Aβ drug development represents a major advancement in Alzheimer's research and therapeutic options. This brief review aims to highlight the development and potential of these α-helix-stabilizing ligands as antagonists of Aβ aggregation, focusing on their interactions with Aβ and how these compounds induce and maintain secondary structural changes in the Aβ peptide. Notably, this innovative strategy holds promise beyond Aβ-related pathology, as the fundamental principles could be applied to other amyloidogenic proteins implicated in various amyloid-related diseases, potentially broadening the scope of therapeutic intervention for multiple neurodegenerative conditions.

Elevated tau is temporally proximal to dementia onset but less is known about factors influencing T+ onset age and time to dementia following T+ in Alzheimer's disease. We used sampled iterative localized approximation (SILA) estimated T+ onset age (ETOA) to investigate factors associated with T+ age and time from T+ to dementia onset in ADNI.

Using SILA-estimated A+ and T+ onset ages derived from 18F-Flortaucipir, 18F-Florbetapir, and 18F-Florbetaben PET and Cox proportional hazards and accelerated failure time models, we analyzed APOE, sex, amyloid burden, age, educational attainment, and literacy associations with ETOA and time from T+ to dementia.

Higher amyloid, APOE-ε4, lower education, and lower literacy associated with younger ETOA. Older ETOA and higher amyloid associated with shorter time from T+ to dementia.

This work highlights the prognostic value of ETOA and the need to better characterize factors contributing to ETOA and dementia onset in AD.