Petersen, Ronald C.

Abstract The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently celebrated its 20th anniversary, reflecting two decades of major contributions to Alzheimer's research through open data sharing and longitudinal multimodal assessments. This review synthesizes 122 high‐impact studies using ADNI data or biospecimens from 2023 to mid‐2025 to clarify mechanisms of Alzheimer's disease (AD) progression. Studies describe impairment of glymphatic clearance and the impact of cerebral small vessel disease, trajectories of amyloid beta and tau deposition, inflammation, metabolic disturbances, synaptic dysfunction, and neurodegeneration, leading to cognitive impairment and neuropsychiatric symptoms. Multifactorial contributions from genetic and epigenetic influences, co‐pathologies and comorbidities, and mechanisms of resilience modulate disease progression. Finally, heterogeneity of clinical presentation and disease course is described in the context of multiple contributing factors, highlighting the complexity of AD. By integrating imaging, fluid biomarkers, genetics, and clinical measures, ADNI provides a comprehensive research dataset for unraveling mechanisms underlying AD progression.

Abstract Since 2016, the Alzheimer's Association and the Fondation Alzheimer have hosted Global Alzheimer's Leadership Series (GoALS) global think tanks, with world‐leading experts for innovative discussions to advance Alzheimer's disease (AD) research and care. The second GoALS think tank, held in June 2024 in Paris, focused on the relationship between biological changes and clinical manifestations of AD in the context of the evolving therapeutic landscape. Discussions spanned real‐world experiences of providers, patients, and their families, theoretical considerations, and health system challenges. The lived experience perspective was central to these discussions. The importance of shared decision‐making, clear and transparent communication, and the need for real‐world data to holistically support patients during their experiences were highlighted. This manuscript shares key insights from both the think tank meeting in Paris and a featured research session at the 2024 Alzheimer's Association International Conference that expanded the discussion themes for broader dissemination with the community.

Abstract INTRODUCTION White matter lesions on fluid‐attenuated inversion recovery magnetic resonance imaging (FLAIR‐MRI) reflect small vessel disease (SVD) and aid in identifying vascular contributions to impairment and dementia (VCID). Emerging diffusion MRI (dMRI) biomarkers are sensitive to early SVD but the lack of validated approaches for defining dMRI abnormality has limited their clinical utility. METHODS In 3934 participants (8749 observations) from a population‐based sample, we classified 9% as vascular cognitive impairment versus not (VCI+/VCI−) using abnormal FLAIR‐MRI and cognitive testing. We evaluated four distinct dMRI positivity criteria and assessed performance in an independent clinical sample. RESULTS The young referent criterion performed best and yielded an estimated prevalence of dMRI positivity aligned with pathology literature. About 40% of the population were dMRI positive, and these individuals had lower baseline cognition and faster longitudinal decline. Cutpoints were validated in an independent clinical sample. DISCUSSION The proposed dMRI abnormality framework can detect VCID and aid in identification of individuals at risk of VCI.

Rural populations are underrepresented in cognitive impairment research and have limited resources for education about brain and cognitive health, Alzheimer's disease and related dementias, or caregiving. As our Outreach, Recruitment, and Engagement team aimed to expand activities into more rural communities, we also wanted to better understand the characteristics of the communities surrounding our center and gain insight into the social exposome of the areas. The goal of the manuscript is to reflect on our experience and share measures that were useful in this effort, which can be further enriched and adjusted by other outreach teams.

This cross-sectional study evaluates the performance of the US Food and Drug Administration–cleared phosphorylated tau 217 (p-tau217) to β-amyloid 42 ratio cut points used to detect amyloid pathology associated with Alzheimer disease.

Abstract INTRODUCTION Remote neuropsychological testing can monitor brain health in individuals with or at risk of Alzheimer's disease (AD). We evaluated acceptability and validity of the Cogstate Brief Battery (CBB) for remote administration. METHODS Non‐demented adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) completed the CBB in‐clinic under supervision, then remotely every six months, with annual in‐clinic reassessments. Groups included cognitively unimpaired (CU) adults with normal amyloid (CU Aβ−) or elevated amyloid (CU Aβ+), and individuals with mild cognitive impairment with or without amyloid (MCI Aβ+, MCI Aβ−). Performance was compared across contexts and longitudinal changes were examined. RESULTS At baseline, MCI Aβ+ participants performed worse than CU Aβ−. CBB performance was similar across contexts, with consistent group differences. Over time, MCI Aβ+ participants showed greater decline on remote CBB measures than CU Aβ− adults. DISCUSSION Remote unsupervised CBB assessments are valid, reliable, and sensitive to AD‐related cognitive impairment.

Abstract INTRODUCTION We describe the reliability of remote self‐administered digital cognitive measures completed via the Mayo Test Drive (MTD) web‐based platform. METHODS A total of 1846 participants (mean age = 70, SD = 12, range 31–101; 48% male; 96% White; 99% non‐Hispanic; 97% cognitively unimpaired) with two to four complete MTD sessions at ∼7.5‐month intervals were included. Test‐retest reliability was assessed using single‐rating, absolute‐agreement, and two‐way mixed intraclass correlation coefficients (ICCs) with 95% confidence intervals. ICCs for in‐person‐administered traditional neuropsychological measures were compared to MTD for a subset of 244 participants. Analyses also compared reliability across demographic, residential, and session context subgroups. RESULTS Reliability was good for the MTD Composite (total ICC = 0.79 [0.77, 0.80]), and moderate‐to‐good for the primary outcome variables for each MTD subtest (total ICCs 0.70–0.83 for Stricker Learning Span and Symbols). The reliability of the remote self‐administered MTD was similar to in‐person‐administered cognitive measures. DISCUSSION MTD showed moderate‐to‐good reliability, supporting its use in longitudinal monitoring.

Abstract Introduction The relationship between sleep and brain metabolism remains unclear. This study aimed to examine whether overnight sleep features, using a home sleep apnea system based on peripheral arterial tonometry, are associated with regional FDG-PET changes in older adults. Methods We analyzed cognitively unimpaired adults (≥60 years) from the Mayo Clinic Study of Aging (MCSA) cohort who were not receiving sleep apnea treatment. Participants underwent overnight sleep assessment with the WatchPAT system, followed by FDG-PET imaging the next morning. FDG-PET data were co-registered to 3T MRI and automatically segmented into 122 anatomical regions. PET signal was referenced to the pons (SUVR). We computed voxel-weighted median FDG signal across 47 bilateral cortical and subcortical regions of interest (ROIs), excluding brainstem and cerebellum. Associations between sleep architecture and sleep apnea/hypoxemia burden and regional metabolism were assessed using partial Spearman’s rank correlation, adjusting for age. Results Thirty-seven participants were included (70.3% female; median [IQR] age: 72.0 [68.0–78.0] years). Wake after sleep onset (WASO) showed widespread negative associations with FDG uptake in cortical regions (p< 0.05), particularly the ventromedial/ventrolateral (rs=–0.47 to –0.33) prefrontal cortex, lateral temporal (rs=–0.38 to –0.33), and occipital (rs=–0.47 to –0.37) cortices. Total sleep time (TST) was positively associated with medial structures (p< 0.05), including the posterior cingulate (rs=0.39), retrosplenial cortex (rs=0.48), hippocampus/parahippocampal (rs=0.34 to 0.36), calcarine cortex (ρ=0.38), thalamus (rs=0.37), and caudate (rs=0.43). Hypoxic burden was positively associated with medial occipital regions (rs=0.35 to 0.39) and AHI-4% with cuneus (rs=0.33). Regional gray matter volume did not mediate these associations. WASO correlated with Insomnia Severity Index (rs=0.43, p=0.008) and self-reported refreshing sleep (rs=0.046). Conclusion Overnight sleep macrostructure features (WASO and TST) and hypoxic burden are significantly associated with brain metabolism, potentially underlying symptoms of sleep disturbance and cognitive aging. Support (if any) Mayo Clinic Alzheimer’s Disease Research Center Development Award (P30 AG062677), R01 AG056366, U01 AG006786, R01 AG056366, R01 AG034676, R37 AG011378, R01 AG041851, R01 NS097495, R01 AG068206, P30 AG062677, R01 HL065176. CLARA project work with funding from the European Union’s HORIZON EUROPE research and innovation programme (No 101136607).

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.