Ronald C. Petersen’s research while affiliated with Mayo Clinic - Rochester and other places

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.

INTRODUCTION Temporal cortical microstructural changes precede cortical atrophy during memory decline. We used neurite orientation dispersion and density imaging (NODDI) to assess such early microstructural change. METHODS Cognitively unimpaired (CU, n = 725) and mildly cognitively impaired (MCI, n = 111) participants from the Mayo Clinic Study of Aging underwent 3T magnetic resonance imaging (MRI), including NODDI and neuropsychological evaluation for calculation of memory z scores. Linear mixed effects modelling assessed the relationship between temporal cortical Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and both baseline and mean annual change in memory z scores. RESULTS NDI was significantly associated with both baseline memory z scores and mean annual change of memory z scores, in the hippocampi and amygdalae. Similar significant associations with ODI were seen in hippocampi, parahippocampal, and fusiform gyri. DISCUSSION Temporal cortical NDI and ODI are early imaging biomarkers of cortical microstructural integrity that may predict memory decline in CU and MCI individuals. Highlights We imaged 836 participants in the Mayo Clinic Study of Aging, who were either cognitively unimpaired (CU) or suffered from mild cognitive impairment (MCI). Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion magnetic resonance imaging (MRI) technique We found significant associations between new NODDI imaging biomarkers of microstructural integrity and memory function in CU and MCI individuals These relationships were both cross‐sectional in nature and associated with future memory decline Future application of NODDI imaging biomarkers in the setting of anti‐amyloid monoclonal antibody therapy may provide greater insight into memory decline than current cortical atrophy measures.

Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, GRN and C9orf72 carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. In addition, long-read bulk cDNA sequencing data were generated from FCX of 9 FTLD-TDP and 7 controls and human TARDBP wildtype and knock-down iPSC-derived neurons. Publicly available RNAseq data (MayoRNAseq, MSBB and ROSMAP studies) from Alzheimer’s disease patients (AD) was also analyzed. Our DSA revealed extensive splicing alterations in FTLD-TDP patients with 1881 differentially spliced events, in 892 unique genes. When evaluating differences between FTLD-TDP subtypes, we found that C9orf72 repeat expansion carriers carried the most splicing alterations after accounting for differences in cell-type proportions. Focusing on cryptic splicing events, we identified STMN2 and ARHGAP32 as genes with the most abundant and differentially expressed cryptic exons between FTLD-TDP patients and controls in the brain, and we uncovered a set of 17 cryptic events consistently observed across studies, highlighting their potential relevance as biomarkers for TDP-43 proteinopathies. We also identified 16 cryptic events shared between FTLD-TDP and AD brains, suggesting potential common splicing dysregulation pathways in neurodegenerative diseases. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-025-02901-7.

The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti‐amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future. Highlights The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid‐beta Targeted Treatments on Biomarkers and Clinical Endpoints.” The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load. Based on data from multiple phase 2 and 3 clinical trials of anti‐amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near‐normal levels is associated with positive changes in tau biomarkers and clinical endpoints. Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

Meaningful benefit is a much‐debated concept in Alzheimer's disease (AD). Research to date has primarily focused on change thresholds that are anchored in clinicians’ or care partners’ impressions; however, these thresholds are not inherently meaningful to people living with AD (PLWAD) and may not take their perspectives into account. By overlaying the lived experience of AD through the eyes of individual PLWAD and their care partners with clinical outcomes, we offer an important framework in which to consider meaningful benefit in terms of symptoms, functioning, and outcomes. The PLWAD and care partner interviews and surveys of the What Matters Most (WMM) research program have identified treatment‐related needs, preferences, and priorities of people at risk of or living with AD and their care partners across the AD continuum. A WMM conceptual model of disease—created and refined through interviews with PLWAD and care partners across the AD severity spectrum—includes 50 concepts across six domains (social life/activities, thought processing, communication, daily activities, mood/emotion, and general independence) considered important to all PLWAD and care partners. From the PLWAD and care partner perspectives, an increase in time to the onset, development, or worsening of the symptoms in any of these meaningful concepts was considered a meaningful benefit. No single commonly used clinical outcome assessment captures all concepts of importance, nor the importance of time in AD; considering the lived experience and priorities of individuals affected by AD is crucial to put the “meaning” in “meaningful.”

Dementia with Lewy bodies (DLB) frequently coexists with Alzheimer's disease pathology, yet the pattern of cortical microstructural injury and its relationship with amyloid, tau, and cerebrovascular pathologies remains unclear. We applied neurite orientation dispersion and density imaging (NODDI) to assess cortical microstructural integrity in 57 individuals within the DLB spectrum and 57 age- and sex-matched cognitively unimpaired controls by quantifying mean diffusivity (MD), tissue-weighted neurite density index (tNDI), orientation dispersion index (ODI), and free water fraction (FWF). Amyloid and tau levels were measured using PiB and Flortaucipir PET imaging. Compared to controls, DLB exhibited increased MD and FWF, reduced tNDI across multiple regions, and focal ODI reductions in the occipital cortex. Structural equation modeling revealed that APOE genotype influenced amyloid levels, which elevated tau, leading to microstructural injury. These findings highlight the role of AD pathology in DLB neurodegeneration, advocating for multi-target therapeutic approaches addressing both AD and DLB-specific pathologies.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyzes, we further identify genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1 and ANO9, as novel subtype-specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signaling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.