About

William Jagust is the Principal Investigator and holds the MD Endowed Chair in Geriatric Medicine. He is a Professor of Public Health and Neuroscience. His research focuses on brain aging and Alzheimer’s disease, utilizing neuroimaging biomarkers such as PET and MRI to study disease progression and early detection. As a leading figure in the field, he directs the Jagust Lab, which investigates various aspects of neurodegeneration, including amyloid, tau, and neurodegeneration pathologies, within frameworks like ATN. His work involves developing and applying advanced neuroimaging techniques to better understand the biological underpinnings of Alzheimer’s disease and to identify early biomarkers for diagnosis and intervention.

Research topics

• Computer Science
• Psychology
• Artificial Intelligence
• Neuroscience
• Medicine
• Radiology
• Chemistry
• Pathology
• Internal medicine
• Database
• Biochemistry
• Chromatography

Selected publications

• <i>APOE, ABCA7</i> , and <i>RASGEF1C</i> are associated with earlier onset of amyloid deposition from more than 4000 harmonized positron emission tomography images

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  INTRODUCTION: New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS: Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. RESULTS: Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. DISCUSSION: APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. HIGHLIGHTS: Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses.

  PublisherOA PDFDOI

• Cognitive aging outcomes are related to both tau pathology and maintenance of cingulate cortex structure

  Alzheimer s & Dementia · 2025-01-14 · 9 citations

  articleOpen accessSenior author

  INTRODUCTION: Successful cognitive aging is related to both maintaining brain structure and avoiding Alzheimer's disease (AD) pathology, but how these factors interplay is unclear. METHODS: A total of 109 cognitively normal older adults (70+ years old) underwent amyloid beta (Aβ) and tau positron emission tomography (PET) imaging, structural magnetic resonance imaging (MRI), and cognitive testing. Cognitive aging was quantified using the cognitive age gap (CAG), subtracting chronological age from predicted cognitive age. RESULTS: Lower CAG (younger cognitive age) was related to slower decline in episodic memory, multi-domain cognition, and atrophy of the midcingulate cortex (MCC). Lower entorhinal cortical tau was linked to slower decline in episodic memory, multi-domain cognition, and hippocampal atrophy. DISCUSSION: These results suggest that aging outcomes may be influenced by two independent pathways: one associated with tau accumulation, affecting primarily memory and hippocampal atrophy, and another involving tau-independent structural preservation of the MCC, benefiting multi-domain cognition over time. HIGHLIGHTS: Younger cognitive age (lower cognitive age gap [CAG]) is related to slower cognitive decline. Lower CAG is linked to slower midcingulate cortex (MCC) atrophy. Reduced tau in the entorhinal cortex is related to less hippocampal atrophy and cognitive decline. Structural preservation of the MCC benefits multi-domain cognition over time. Two independent pathways influence cognitive aging: tau accumulation and MCC preservation.

  PublisherOA PDFDOI

• Evaluation of the Revised Criteria for Biological and Clinical Staging of Alzheimer Disease

  JAMA Neurology · 2025-05-19 · 34 citations

  articleOpen access

  Importance: While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau-positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies. Objective: To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics. Design, Setting, and Participants: Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic-based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included. Exposures: The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria. Main Outcomes and Measures: Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics. Results: There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical > biological) and 11.0% had the opposite (biological > clinical). The main differences were between the reference group and the clinical > biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43-like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P < .05). The only difference between the biological > clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P < .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of participants had biological and clinical stages; 36.1% were in the category clinical > biological, and 7.9% in biological > clinical. Conclusions and Relevance: Copathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment. These results highlight the importance of measuring non-AD biomarkers in patients with AD with worse cognitive impairment than expected based on their biological stage, which could impact the clinical diagnosis and prognosis.

  PublisherOA PDFDOI

• Hemispheric asymmetry of tau pathology is related to asymmetric amyloid deposition in Alzheimer’s Disease

  Nature Communications · 2025-09-05 · 6 citations

  articleOpen access

  The distribution of tau pathology in Alzheimer's disease (AD) shows remarkable inter-individual heterogeneity, including hemispheric asymmetry. However, the factors driving this asymmetry remain poorly understood. Here we explore whether tau asymmetry is linked to i) reduced inter-hemispheric brain connectivity (potentially restricting tau spread), or ii) asymmetry in amyloid-beta (Aβ) distribution (indicating greater hemisphere-specific vulnerability to AD pathology). We include 452 participants from the Swedish BioFINDER-2 cohort with evidence of both Aβ pathology (CSF Aβ42/40 or neocortical Aβ-PET) and tau pathology (temporal tau-PET), categorising them as left asymmetric (n = 102), symmetric (n = 306), or right asymmetric (n = 44) based on temporal lobe tau-PET uptake distribution. We assess edge-wise inter-hemispheric functional (RSfMRI; n = 318) and structural connectivity (dMRI; n = 352) but find no association between tau asymmetry and connectivity. In contrast, we observe a strong association between tau and Aβ laterality patterns based on PET uptake (n = 233; β = 0.632, p < 0.001), which we replicate in three independent cohorts (n = 234; β = 0.535, p < 0.001). In a longitudinal Aβ-positive sample, we show that baseline Aβ asymmetry predicts progression of tau laterality over time (n = 289; β = 0.025, p = 0.028). These findings suggest that tau asymmetry is not associated with a weaker inter-hemispheric connectivity but might reflect hemispheric differences in vulnerability to Aβ pathology, underscoring the role of regional vulnerability in determining the distribution of AD pathology.

  PublisherOA PDFDOI

• Frequency and Clinical Outcomes Associated With Tau Positron Emission Tomography Positivity

  JAMA · 2025-06-16 · 39 citations

  articleOpen access

  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.

  PublisherOA PDFDOI

• Protocol for a Randomized Phase II/III Double-Blind Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Extended-Release Metformin in Amnestic Mild Cognitive Impairment

  Alzheimer Disease & Associated Disorders · 2025-04-01 · 6 citations

  article

  BACKGROUND: Metformin has been suggested as a possible strategy for the prevention of Alzheimer disease (AD) and AD related dementias. An early phase II clinical trial of short acting metformin versus placebo showed preliminary evidence of efficacy and safety in slowing cognitive decline among persons with amnestic mild cognitive impairment (aMCI) without diabetes. OBJECTIVE: To conduct a phase II/III randomized clinical of extended-release metformin versus placebo in participants with aMCI without diabetes. METHODS: Ratio of 1:1 randomized placebo-controlled trial of extended-release metformin in 326 persons with aMCI without diabetes, aged 55 to 90 years, lasting 18 months, with 4 visits every 6 months including baseline. The primary outcome is changes in total recall in the Free and Cued Selective Reminding Test. Secondary outcomes include (1) changes in global cognitive performance, measured with the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC); (2) changes in neurodegeneration, ascertained as cortical thickness in areas affected by AD on brain MRI; (3) changes in cerebrovascular disease, ascertained as white matter hyperintensities (WMH) volume on brain MRI; (4) changes in whole brain amyloid ß (Aß) SUVR and in incident amyloid positivity; (5) changes in tau SUVR in a composite brain region comprising medial and inferolateral temporal cortex; (6) changes in plasma AD biomarkers. CONCLUSION: Observational studies and pilot trials suggest that metformin may help prevent cognitive decline in neurodegenerative disorders. This clinical trial aims to assess metformin's potential in preventing cognitive decline in at-risk individuals and its impact on biomarkers indicative of disease modification.

  PublisherDOI

• The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment

  Alzheimer s & Dementia · 2025-11-01

  articleOpen access

  INTRODUCTION: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. HIGHLIGHTS: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

  PublisherOA PDFDOI

• Challenges and best practices when using ComBAT to harmonize diffusion MRI data

  Scientific Reports · 2025-11-24 · 3 citations

  articleOpen access

  Over the years, ComBAT has become the standard method for harmonizing MRI-derived measurements, with its ability to compensate for site-related additive and multiplicative biases while preserving biological variability. However, ComBAT relies on a set of assumptions that, when violated, can result in flawed harmonization. In this paper, we thoroughly review ComBAT's mathematical foundation, outlining these assumptions, and exploring their implications for the demographic composition necessary for optimal results. Through a series of experiments involving a slightly modified version of ComBAT called Pairwise-ComBAT tailored for normative modeling applications, we assess the impact of various population characteristics, including population size, age distribution, the absence of certain covariates, and the magnitude of additive and multiplicative factors. Based on these experiments, we present five essential recommendations that should be carefully considered to enhance consistency and supporting reproducibility, two essential factors for open science, collaborative research, and real-life clinical deployment.

  PublisherOA PDFDOI

• Impact of a White Matter Reference Region on the Relationship between Florbetapir PET Measurements of Amyloid Plaque Deposition and Measurements of Cognitive Decline

  medRxiv · 2025-09-25

  preprintOpen access

  The objective of this study was to systematically investigate both cross-sectional and longitudinal associations between amyloid PET tracer, Florbetapir (FBP), and cognition when different reference regions of interest - whole cerebellum versus white matter - are used for Standardized Uptake Value Ratio (SUVR) semi-quantification of amyloid beta deposition. Baseline and 2.2±0.4 year follow-up Florbetapir PET scans from 1,238 mild AD dementia, mild cognitive impairment (MCI), and cognitively unimpaired (CU) participants from AD Neuroimaging Initiative (ADNI) were used to characterize and compare the impact of using a cerebral white matter versus whole cerebellar reference region on cross-sectional and longitudinal relationships between florbetapir SUVR indicators of amyloid plaque deposition and measurements of cognitive or clinical decline (ADAS-Cog-13, CDR-Sum Boxes, and AVLT-total) after covarying for age and education. In both cross-sectional and longitudinal comparisons, florbetapir PET measurements of amyloid plaque deposition using the cerebral white matter reference region were more closely related to each measure of cognitive or clinical decline in the aggregate mild dementia, MCI and CU group (P<1.3E-06). This study supports the potential use of a cerebral white matter reference region in the detection and tracking of amyloid plaque deposition using florbetapir PET. Additional studies are needed to clarify the generalizability of findings to other amyloid PET ligands.

  PublisherOA PDFDOI

• Relationships of PGRN with sTREM2 in AD continuum and non-AD pathophysiology and their reciprocal roles in modulating amyloid pathology: two population-based study

  Translational Psychiatry · 2025-07-08 · 3 citations

  articleOpen access

  . These proteins are mainly enriched in immune processes and neural plasticity. These findings suggest that the interplay between lysosome function and microglia-related neuroinflammation plays key roles in amyloid metabolism.

  PublisherDOI

Recent grants

• NIH Grant R01AG044292

  NIH · $3.6M · 2019

• NIH Grant R01AG025303

  NIH · $2.3M · 2014

• Neural and Biochemical Mechanisms of Cognitive Aging

  NIH · $9.2M · 2009–2029

• Alzheimer's Disease Neuroimaging Initiative (ADNI4)

  NIH · $191.8M · 2004–2028

• NIH Grant R01AG027859

  NIH · $1.2M · 2011

Frequent coauthors

• Paul Aisen

  University of Southern California

  838 shared

• Michael W. Weiner

  University of California, San Francisco

  646 shared

• Michael Donohue

  Janssen (United States)

  635 shared

• Paul M. Thompson

  University of Southern California

  353 shared

• Michael D. Devous

  319 shared

• Li Shen

  297 shared

• Scott Neu

  University of Southern California

  297 shared

• Michael Borrie

  Ludwig-Maximilians-Universität München

  294 shared

Labs

• The Jagust LabPI