Susan M. Landau

INTRODUCTION: To examine the generalizability of Alzheimer's disease (AD) biomarker models in real‐world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS: We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community‐recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS: Elevated β‐amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION: The role of Aβ and tau in cognitive performance may be reduced in real world samples compared to academic specialty clinics.

Background: A major limitation of the Alzheimer's Disease Neuroimaging Initiative (ADNI) and most ADRD clinical research is lack of generalizability due to under‐inclusion of low socioeconomic status (LSES) participants. ADNI is planning a sub‐study to explore methods and determine feasibility of engaging and enrolling LSES participants. Method: ADNI plans to use two approaches to identify, engage, enroll LSES participants: (1) Several organizations have large databases with health care and SES indicators (e.g. education, occupation, income) on millions of individuals. These databases can identify LSES individuals in various geographic areas and provide contact information for informational marketing and recruitment efforts. (2) Thousands of Federally Qualified Health Clinics (FQHCs) across the USA provide primary care to LSES communities. Although several networks of FQHCs have enrolled LSES participants in clinical research, to our knowledge such individuals have not been previously included in AD biomarker research. ADNI plans to use these approaches to enroll 100‐200 LSES participants in a sub‐study. ADNI leadership and staff will extensively interact with relevant organizations and members of the FQHC community to understand the needs of clients and clinic staff, and to optimize the engagement and enrollment approach. To enroll LSES participants from diverse geographical regions, including rural areas, participants may be assessed at existing ADNI sites or new assessment sites using remote assessment. Result: Participants will be assessed with a simplified ADNI battery: clinical measures (Clinical Dementia Rating, brief tests of memory and executive function), routine blood screening (HbA1C, cholesterol) and AD plasma biomarkers. A subset will undergo neuroimaging (MRI, amyloid PET, tau PET). Critically, acquisition and analysis of all measurements will be harmonized with existing ADNI procedures to enable direct comparison with decades of legacy ADNI measurements. The first participants are expected to be enrolled in late 2025. Conclusion: This sub‐study will identify the most effective methods to engage and enroll LSES participants into ADRD biomarker research. These methods will also evaluate feasibility for ADNI5, which aims to establish a national cohort of participants over age 55 who approximate the US census for gender, race, ethnicity, socioeconomic status and geographic distribution.

INTRODUCTION: A key goal of the Alzheimer's Disease NeuroImaging Initiative (ADNI) positron emission tomography (PET) Core is to harmonize quantification of β‐amyloid (Aβ) and tau PET image data across multiple scanners and tracers. METHODS: We developed an analysis pipeline (Berkeley PET Imaging Pipeline, B‐PIP) for ADNI Aβ and tau PET images and applied it to PET data from other multisite studies. Steps include image pre‐processing, refacing, magnetic resonance imaging (MRI)/PET co‐registration, visual quality control (QC), quantification of tracer uptake, and standardization of Aβ and tau standardized uptake value ratios (SUVrs) across tracers. RESULTS: Measurements from 10,105 cross‐sectional and longitudinal Aβ and tau PET scans acquired in several studies between 2010 and 2024 can be processed, harmonized, and directly merged across tracers and cohorts. DISCUSSION: The B‐PIP developed in ADNI is a scalable image harmonization approach used in several observational studies and clinical trials that facilitates rigorous Aβ and tau PET quantification and data sharing. Highlights: Quantitative results from ADNI Aβ and tau PET data are generated using a rigorous, scalable image processing pipeline This pipeline has been applied to PET data from several other large, multisite studies and trials Quantitative outcomes are harmonizable across studies and are shared with the scientific community

INTRODUCTION: Abnormal amyloid‐beta (Aβ) and tau deposition define Alzheimer's Disease (AD), but non‐elevated tau is relatively frequent in patients on the AD pathway.METHODS: We examined characteristics and regional patterns of 397 Aβ+ unimpaired and impaired individuals with low tau (A+T−) in relation to their higher tau counterparts (A+T+).RESULTS: Seventy‐one percent of Aβ+ unimpaired and 42% of impaired Aβ+ individuals were categorized as A+T− based on global tau. In impaired individuals only, A+T− status was associated with older age, male sex, and greater cardiovascular risk. α‐synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T− status.DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aβ‐ and tau‐modifying therapies.

Background. While breast cancer and its treatments may affect cognition, the longitudinal trajectories of cognition among those receiving differing cancer treatment types remain poorly understood. Prior research suggests hippocampal-prefrontal cortex network integrity may influence cognition, although how this network predicts performance over time remains unclear. Methods. We conducted a prospective trial including 69 patients with early-stage breast cancer receiving adjuvant therapy and 12 controls. Longitudinal cognitive testing was conducted at four visits: pretreatment-baseline, 6-7 months, 14-15 months, and 23-24 months. Cognitive composite scores of episodic memory, executive functioning, and processing speed were assessed at each timepoint. Baseline structural MRI was obtained in a subset of these participants, and hippocampal and prefrontal cortex regional volumes were extracted. Results. Longitudinal linear mixed modeling revealed significant group by time interactions on memory performance, controlling for age and education. Post hoc analyses revealed this effect was driven by patients treated with chemotherapy or chemotherapy plus hormone therapy, who demonstrated the least improvement in memory scores over time. Treatment group did not significantly influence the relationship between time and processing speed or executive functioning. Neither pretreatment hippocampal nor prefrontal volume differed between groups, and there were no significant group by time by baseline regional volume effects on cognition. Conclusion. Patients with early-stage breast cancer treated with chemotherapy or chemotherapy plus hormone therapy benefit less from practice effects seen in healthy controls on memory tests. Loss of longitudinal practice effect may be a new and clinically relevant measure for capturing patients experience of cognitive difficulties after treatment.

Background: Positron emission tomography (PET) imaging is an increasingly widespread tool for the identification of Alzheimer’s disease (AD) pathophysiology. PET biomarkers of Aβ and tau pathology, together with fluid biomarkers and ex vivo pathology validation, have enabled detection of early regional changes and identification of individuals who are unimpaired but on the AD pathway. This presentation will address the changing and complementary role of PET biomarkers in relation to fluid biomarkers in AD clinical trials, research, and practice.Method: Recent PET imaging work from natural history studies targeting Aβ and tau pathology will be reviewed, with an emphasis on early detection of dynamic regional changes in unimpaired individuals in relation to fluid biomarkers and cognition. Relationships between Aβ and tau PET measurements to other biomarkers and pathology will be discussed, as well as the status of emerging PET markers of inflammation and synaptic integrity.Result: A key unique feature of PET imaging is that it offers a regionally‐specific view of fibrillar Aβ and paired helical filament (PHF) tau pathology in vivo. Initial Aβ and tau changes are detectable over a decade before the onset of clinically‐relevant cognitive symptoms. There is a predictable time course of Aβ and tau change over the course of disease, and regional tau accumulation predicts local neurodegenerative changes. In symptomatic individuals, inferolateral temporal tau accumulation is sensitive to AD and useful for differential diagnosis. However, tau accumulation is also highly variable even among symptomatic Aβ+ individuals, likely due to co‐pathology and the influence of poorly understood factors such as age, sex, genetics, and cardiovascular risk. There are a number of technical and cost considerations for successful implementation of PET relative to other biomarkers in research, trials, and clinical practice.Conclusion: Early, regionally‐specific Aβ and tau PET measurements predict downstream neurodegeneration and cognitive decline. Such early changes represent an opportunity for therapeutic intervention, but identification of individuals who are unimpaired but at risk remains challenging. Additional longitudinal research and development of PET biomarkers for other disease targets will address open questions about how AD develops.

Alzheimer disease (AD) is the sixth leading cause of death in the US, but existing treatments provide only a modest improvement in symptoms. To our knowledge, no approved treatment exists that improves the course of disease or underlying pathology. Research on disease-modifying AD treatments has proven to be extremely challenging, with a number of major recent clinical trials of drug therapies resulting in negative or ambivalent findings.^1,2 While many alternative ideas for developing a treatment for AD are being pursued, 2 key strategies have emerged: initiating interventions earlier in the course of disease in individuals who are at risk but unimpaired and identifying targets beyond abnormal amyloid and tau proteins, the pathology that defines AD.

Objective: Extensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown.Methods: We examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [¹⁸F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function.Results: Among baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance (p = 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline (p = 0.007).Conclusions: Memory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.