Craft, Suzanne

Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Alzheimer’s disease (AD) is characterized by profound metabolic dysfunction and disturbances in gut–brain axis signaling. Ketogenic diet (KD) has demonstrated metabolic and cognitive benefits in both preclinical and clinical studies. However, factors that determine individual responsiveness or non-responsiveness to KD interventions remain poorly understood. Emerging evidence suggests that gut microbiome composition plays a critical role in modulating these factors. This study examined how KD responsiveness, determined by fecal microbiota transplantation (FMT) derived from human KD responders (RES) or non-responders (nRES)- influences cognition, gut barrier function, neuroinflammation, and microbial structure in 3xTg-AD mice. We further evaluated whether supplementing KD with a novel Synbiotic Yogurt (SY) formulated by our team could augment or restore responsiveness. We hypothesized that RES microbiota would confer superior KD-driven benefits and that KD-SY would synergistically improve metabolic and neurobiological outcomes, particularly among nRES recipients. Adult 3xTg-AD mice were antibiotic-cleansed and randomized to receive Control-, RES-, or nRES – FMT, while maintained on KD for four weeks. A second cohort received KD supplemented with SY or non-fat milk along with RES- or nRES-FMT. Behavioral tests, gut permeability assay, serum inflammatory markers, brain amyloid beta (Aβ), intestinal morphology, gene expression, and 16S rRNA microbial profiling were measured. RES-FMT recipients showed early improvements in spatial memory (Y-maze and novel object recognition) and consistently lower Aβ accumulation in cortex and hippocampus. They also showed higher synaptophysin and IL-10 expression. In contrast, nRES-FMT mice exhibited distinct microbiome clustering, lower microbial diversity, enrichment of Proteobacteria, and impaired gut barrier function relative to RES-FMT recipients. Functionally, specific taxa like Enterococcus, Enterobacter, and Paenibacillus were associated with greater vulnerability to AD-related pathology, while Akkermansia, Bifidobacterium, and Muribaculum were linked with lower vulnerability. SY supplementation improved metabolic and gut barrier indices across groups characterized by increased circulating ketone levels, lowered fasting glucose and glucose-ketone index, and decreased gut permeability. nRES-SY mice showed the strongest gains in recognition memory and reductions in brain Aβ1–42 burden. SY increased expression of barrier- and inflammation-modulating genes, including occludin, APLP2, and IL-10. Microbiome analysis demonstrated higher microbial diversity and enrichment of beneficial genera such as Paralactobacillus, Eubacterium, and Muribaculum. These findings show that KD responsiveness is strongly determined by gut microbiota composition and that SY supplementation can enhance or rescue metabolic, cognitive, and microbial outcomes, particularly in nonresponders. This supports a precision-microbiome strategy combining metabolic and Synbiotic interventions to improve gut–brain axis function in AD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder with significant environmental factors, including diet, that influence its onset and progression. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored the KD’s molecular impact for markers of AD therapeutic potential. The BEAM diet study simultaneously profiled the KD’s effect on the lipidome, blood and cerebrospinal metabolome, and microbiome of both cognitively impaired and cognitively normal individuals. The findings summarized here assess the biological impact of a Modified Mediterranean KD in the context of Alzheimer’s disease treatment and prevention.MethodBEAM involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean‐ketogenic diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6‐week washout period. We employed HPLC‐MS/MS lipidomics profiling in plasma, nuclear magnetic resonance (NMR)‐based metabolomics to profile serum and CSF, and metagenomics profiling on fecal samples before and after each diet to assess dietary‐induced changes.ResultThe MMKD led to significant alterations in the blood, CSF, and microbiome. These changes included a global elevation across all plasmanyl and plasmenyl ether lipid species, improved modifiable risk factors, like increased HDL‐C and reduced BMI, the reversal of serum metabolic disturbances linked to AD such as an increase in valine levels, and a reduction in systemic inflammation. Leveraging prior clinical studies on AD (n = 1,912), we found that MMKD was inversely associated with the peripheral lipidomic signature of prevalent and incident AD. In the CSF, the MMKD was linked to modified amino acid levels and the breakdown of branched‐chain amino acids (BCAAs). Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. In addition, participants with MCI on the MMKD had lower levels of GABA‐producing microbes and GABA, and higher levels of GABA‐regulating microbes.ConclusionOur findings highlight that MMKD can improve AD‐related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood‐CSF barrier.Funding: Alzheimer’s Gut Microbiome Project, NIA U19AG063744

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Abstract Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.

AbstractBackgroundMixed model repeated measures (MMRM) is the most common analysis approach in clinical trials for Alzheimer’s disease. The model treats time as a categorical variable, which can be problematic when assessments occur off‐schedule, as including off‐schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. Since MMRM entails a mean parameter for each group and visit, the model can be inefficient for longer trials of Preclinical Alzheimer’s. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time.MethodWe use model selection techniques to compare the predictive value of spline models to slope models, MMRM, and models that assume a proportional treatment effect using data from several completed trials. These trials include the ADCS trial of donepezil in MCI, trials of intranasal insulin and a fyn kinase inhibitor in mild Alzheimer’s dementia, and the A4 trial of solanezumab in Preclinical Alzheimer’s. Simulation studies assess the power and Type I error of these models for trials in Preclinical Alzheimer’s, MCI, and mild dementia.ResultThe spline model with ADAS‐Cog version effect attained the best predictive value for the trials in mild dementia. The proportional model was preferred for the trial in MCI, but the proportional effect assumption was violated, and the treatment effect estimate was in the wrong direction. Considering that the spline with two degrees of freedom and version effect provide fits that are similar to MMRM in Figure 1, we concluded that two degrees of freedom appear to be sufficient to capture enough of the general trend to assess the treatment effect. AIC results from the A4 Study will be considered and included after the study is completed in Spring 2023.ConclusionThe spline model is shown to have better predictive value and precision in real datasets and has better power and Type I error control in a variety of simulation scenarios.

AbstractBackgroundImpaired glucose utilization is central to the pathogenesis of Alzheimer’s disease. In a hypometabolic state, the brain depends on alternative sources of energy, including amino acids, fatty acids, and ketone bodies (KBs). As KBs can cross the blood‐brain barrier, it is considered that a ketogenic diet could augment the high energetic demand of the central nervous system (CNS). A ketogenic diet is already a part of clinical care in epilepsy a CNS disorder. However, the holistic benefits of this diet for Alzheimer’s remain to be determined.MethodsA randomized crossover pilot trial was conducted where participants consumed either the Modified Mediterranean‐Ketogenic Diet (MMKD) or the American Heart Association Diet (AHAD) for 6 weeks, followed by a 6‐week washout, after which the respective other diet was consumed for 6 weeks. The cohort included both mild cognitively impaired (MCI) and cognitively normal (CN) individuals. Serum and cerebrospinal fluid (CSF) samples of these individuals were profiled using two metabolic platforms: MS‐based and NMR‐based metabolomics. Diet‐related changes in levels of metabolites were determined using linear‐mixed effect models with age and sex as confounders.ResultsWe identified post‐diet changes in the two diet groups (AHAD and MMKD), two cognitive groups (MCI and CN), and two fluids (serum and CSF). AHAD was associated with a decrease in serum levels of only a single metabolite, glutamine. MMKD led to widespread lipidomic and metabolic changes in the serum of mild cognitively impaired individuals. Remarkably, MMKD was associated with the reversal of AD‐related metabolic alterations identified in large cohorts like ADNI, AIBL, ROS/MAP, and signature for incident dementia in large epidemiological studies. The post‐MMKD changes include correcting metabolic dysregulation in branched‐chain amino acids, triglycerides, and plasmalogens a class of lipids implicated in membrane structure and function. Peripheral‐central metabolic correlations will be shared.ConclusionOur findings highlight the potential of dietary interventions, specifically the MMKD, in improving the cognitive and metabolic state of individuals with MCI. Further investigation is needed to capture the entirety of MMKD‐related modulation in metabolic profiles and the resulting benefit for AD.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.