Joshua D. Grill

INTRODUCTION: Plasma p-tau217 is associated with Alzheimer’s disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory. METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtype×p-tau217 interactions for memory, adjusting for age, sex, education, APOE ε 4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change. RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p =0.002) and was stronger in MTL-sparing ( B =-0.191, p B =-0.07, p =0.002) and posterior-predominant participants ( B =-0.07, p p =0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma Aβ42/40; none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p =0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p =0.016). DISCUSSION: Tau-PET subtype modified the p-tau217–memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.

Interventions to delay or prevent Alzheimer disease dementia hold the promise of sizable personal and public benefit. The nomenclature, research designs, and interpretation of results for studies a...

INTRODUCTION: APOE genotype shows well-established dose-dependent associations with higher amyloid in cognitively unimpaired (CU) adults. In contrast, associations with tau burden and cognition are less well characterized. METHODS: We performed a cross-sectional analysis of harmonized multi-cohort ADSP-PHC data from 4,380 CU participants across 4 cohorts with APOE genotype, amyloid PET, and cognitive data from four domains of memory, language, executive, and visuospatial function, including a subset of 758 with tau PET imaging. RESULTS: APOE ε4 showed a strong dose-dependent association with amyloid burden and amyloid positivity, with the highest levels observed among ε4 homozygotes. Associations between APOE and global tau burden were more modest and appeared to be driven mainly by ε4 homozygotes, while regional analyses showed localized APOE ε4-related associations in medial temporal regions. Independently, higher tau burden was associated with lower memory and language performance. CONCLUSIONS: In CU older adults, APOE ε4 was most strongly associated with amyloid burden, with more modest associations observed for medial temporal tau burden. Highlights: APOE ε4 showed dose-dependent associations with amyloid burden and age-related amyloid differences APOE-related global tau associations were modest, mainly in ε44 group, with stronger medial temporal effects among ε4 carriers Higher tau burden was associated with lower memory and language performance, regardless APOE status RESEARCH IN CONTEXT: Systematic review: The authors reviewed the literature using PubMed and Google Scholar to examine relationships among APOE genotype, amyloid pathology, tau pathology, and cognition in cognitively unimpaired individuals. Previous studies from A4, ADNI, A4/LEARN, and large multicohort tau PET datasets have consistently shown strong APOE-related effects on amyloid burden and more modest regional effects on tau. The present study extends this literature using a large harmonized ADSP-PHC dataset with amyloid PET, tau PET, and harmonized cognitive measures. Interpretation: The findings suggest that amyloid abnormalities remain the main pathological feature linked to APOE genotype in cognitively unimpaired individuals. APOE-related effects on tau were smaller and were concentrated mainly in medial temporal regions. APOE genotype was not consistently related to cognition, while higher tau burden was associated with lower memory and language performance. Future directions: These findings support the use of APOE genotype as a stratification factor in studies of cognitively unimpaired individuals. Longitudinal studies will be important to clarify how APOE-related differences in amyloid and regional tau burden evolve over time and whether they are linked to later cognitive decline and progression to Alzheimer’s disease.

Importance: Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population. Objectives: To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E ( APOE ) genotypes. Design, Setting, and Participants: This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024. Exposure: Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote. Main outcomes and measures: Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure. Results: Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (−1.1 [4.2]). Conclusions and Relevance: In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk.

INTRODUCTION: Alzheimer’s disease (AD) prevention trials have multiple screening steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in underrepresented groups, thereby impacting trial eligibility. METHODS: 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined. RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between groups excluded for impaired cognition/function, suggesting test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities. DISCUSSION: Biases in cognitive/functional screening tests may disproportionately exclude ethnoracial minorities in AD prevention trials.

BACKGROUND: First held in 2020, the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) is a program to train the next generation of Alzheimer's disease (AD) and related dementias (AD/ADRD) clinical trialists. METHODS: IMPACT‐AD includes didactic, workshop, and small group components. RESULTS: IMPACT‐AD has trained 18 alumni–scholars (accepted from 424 applicants), of whom 67% were female. Forty‐eight (26%) were the first in their family to attend college. Scholars included individuals from all racial and ethnic groups. Each year, participants demonstrated increased learning about AD/ADRD clinical trials through a pre/post‐test model of knowledge assessments. Among those completing annual follow‐up surveys, >84% remain in AD/ADRD trials careers, and 80% have experienced career advances or milestones. In the latter group, > 90% indicated that participating in IMPACT‐AD contributed to this career growth. DISCUSSION: IMPACT‐AD is a novel educational program that is achieving its goals. Highlights: Over 5 years, the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) has trained 188 scholars. The course has been accessible to a broad range of trainees who were diverse in professional and demographic backgrounds. Objective assessments indicate that participants gain knowledge through participation. Eighty‐four percent of trainees have remained in Alzheimer's disease and related dementias (ADRD) trials careers. Eighty percent of alumni have experienced career advances; nearly all indicated that participating in the course contributed to their success.

This Viewpoint discusses a recent book that alleges scientific misconduct in Alzheimer disease (AD) research; summarizes actual progress made in the field; suggests that the book contributes to a narrative that jeopardizes momentum in AD research; and calls for increased transparency and public engagement with science to minimize misinformation.

INTRODUCTION: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) communities are among the fastest growing segments of older adults in the United States yet remain underrepresented in aging, dementia, and caregiving research.METHODS: The Collaborative Approach for AANHPI Research & Education (CARE), a recruitment registry, aims to improve the representation of AANHPI older adults in research. We describe activity to date, as well as planned expansions in cultural groups, language capacity, and data collection in the registry.RESULTS: Between October 15, 2020, and November 4, 2024, 10,367 total AANHPI adults enrolled in the CARE registry, including 50.0% with limited English proficiency, 35.1% age ≥ 65, and 80.2% with no prior participation in research. CARE has made more than 13,954 referrals of 6868 unique registrants to at least one study.DISCUSSION: Through collaborative partnerships with AANHPI communities and researchers, the CARE Registry is achieving its goal of increasing AANHPI representation in research.Highlights: The CARE registry has enrolled 10,367 AANHPI adults. More than 80% of those enrolled had no prior research experience. As of November 4, 2024, CARE had referred 6868 unique participants to at least one study. In total, CARE has made 13,954 referrals to requesting studies.

INTRODUCTION: The long‐term implications of disclosing Alzheimer's disease (AD) biomarker information to cognitively unimpaired individuals are unknown. METHODS: We compared participants who disclosed their elevated amyloid imaging result in a preclinical AD trial to those who disclosed a not elevated result and enrolled in an observational cohort that underwent parallel assessments. Our primary outcome was a score > 0 on the Columbia Suicidality Severity Rating Scale (CSSRS) at any visit; we also considered suicidal behaviors (CSSRS > 5). RESULTS: Among 1707 total participants (68% elevated amyloid, mean [standard deviation] age 71.5 [4.7], 60% female, 90% non‐Hispanic White), followed for a mean 218 (74.1) weeks, there were no suicides and few indications of suicidal thoughts ( n = 124 [7%]) or behaviors ( n = 13 [ 0 (odds ratio = 1.6, 95% confidence interval = 0.76, 3.37). DISCUSSION: With a structured approach, brain amyloid results can be returned safely. Highlights: The Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study was among the first and largest studies to include biomarker disclosure in a population without cognitive impairment. Routine psychological assessment provided a novel assessment of the impact of disclosure in this sample. Learning an elevated brain amyloid result through a protocolized approach was not associated with suicidal thoughts or behaviors compared to a matched cohort who learned they did not have elevated brain amyloid. Future research will be needed to ensure similar safety in more real‐world settings.