Kaye, Jeffrey

Importance Amyloid positron emission tomography (PET) is increasingly used in research and clinical settings to determine the etiology of cognitive decline and eligibility for amyloid-targeting therapies. To assist with amyloid PET evaluation and to guide clinical decision-making, images can be quantified in a standardized unit called Centiloid, the interpretation of which can vary according to the method and threshold used. Objective To collect Centiloid values from available studies and determine robust positivity cutoffs using data-driven methods and correspondence with visual reads. Data Sources PubMed search (October 2024) identified studies with Centiloid values. Corresponding authors were invited to share individual participant data. Additional data were obtained through access-controlled repositories and conference outreach (July 2024-July 2025). Study Selection Studies were included if they provided Centiloids, radiotracer, age, and sex. Data Extraction and Synthesis Each study was analyzed using a unified statistical pipeline; study estimates were pooled using random-effects meta-analysis. Main Outcomes and Measures Gaussian mixture models (GMMs) were fitted to Centiloid values for each study. In studies with a bimodal distribution (per integrated completed likelihood), single cutoffs for positivity were set as mean plus 2 SDs of the lower gaussian component. Using GMMs, a double-cutoff approach defined a lower certainty range using a 90% posterior probability cutoff for assignment to the low (amyloid-negative) vs high (amyloid-positive) component. An alternative Centiloid cutoff was derived from maximizing the correspondence (Cohen κ) with the binary visual reads when available. Results This meta-analysis included cross-sectional amyloid PET scans acquired with 5 radiotracers from 49 227 participants across 53 studies from 15 countries (mean age, 71 years; 54% female, 62% cognitively impaired). The data-driven GMM approach identified a bimodal distribution in 51 studies (n = 48 786), resulting in a single cutoff for positivity of 18 Centiloids (95% CI,16-19; I 2 = 97%). The double-cutoff approach revealed high confidence for interpreting scans as negative when Centiloid values were lower than 11 (95% CI, 9-13; I 2 = 95%) and interpreting scans as positive if Centiloid values were higher than 26 (95% CI, 24-28; I 2 = 95%). In analyses of correspondence with binary (positive or negative) visual reads of amyloid PET scans (n = 35 045; 36 studies), Centiloids were highly predictive of visual positivity (Cohen κ, 0.86; 95% CI, 0.83-0.89; I 2 = 96%) with a cutoff of 27 Centiloids (95% CI, 24-30; I 2 = 80%). Conclusions and Relevance In this individual participant data meta-analysis, positivity cutoffs converged around 18 Centiloids (data-driven) and 27 Centiloids (visual reads). Findings from a double-cutoff analysis suggest that scans in the 11 to 26 Centiloid range should be interpreted with caution depending on the context of use.

Importance Alzheimer disease (AD) predominates in females at almost twice the rate relative to males. Mounting evidence in adults without AD indicates that females exhibit higher tau deposition than age-matched males, particularly in the setting of elevated β-amyloid (Aβ), but the evidence for sex differences in tau accumulation rates is inconclusive. Objective To examine whether female sex is associated with faster tau accumulation in the setting of high Aβ (as measured with positron emission tomography [PET]) and the moderating influence of sex on the association between APOE ε4 carrier status and tau accumulation. Data Sources This meta-analysis used data from 6 longitudinal aging and AD studies, including the Alzheimer’s Disease Neuroimaging Initiative, Berkeley Aging Cohort Study, BioFINDER 1, Harvard Aging Brain Study, Mayo Clinic Study of Aging, and Wisconsin Registry for Alzheimer Prevention. Longitudinal data were collected between November 2004 and May 2022. Study Selection Included studies required available longitudinal [ 18 F]flortaucipir or [ 18 F]-MK-6240 tau-PET scans, as well as baseline [ 11 C] Pittsburgh Compound B, [ 18 F]flutemetamol or [ 18 F]florbetapir Aβ-PET scans. Recruitment criteria varied across studies. Analyses began on August 7, 2023, and were completed on February 5, 2024. Data Extraction and Synthesis In each study, primary analyses extracted estimates for the sex (female or male) and the sex by baseline Aβ-PET status (high or low) association with longitudinal tau-PET using a series of mixed-effects models. Secondary mixed-effects models extracted the interaction estimate for the association of sex by APOE ε4 carrier status with longitudinal tau-PET. Study-specific estimates for each mixed-effects model were then pooled in a meta-analysis, and the global fixed effect (β) and total heterogeneity ( I 2 ) across studies were estimated. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures Seven tau-PET outcomes that showed cross-sectional sex differences were examined across temporal, parietal, and occipital lobes. Results Among 6 studies assessed, there were 1376 participants (761 [55%] female; mean [range] age at first tau scan, 71.9 [46-93] years; 401 participants [29%] with high baseline Aβ; 412 APOE ε4 carriers [30%]). Among individuals with high baseline Aβ, female sex was associated with faster tau accumulation localized to inferior temporal (β = −0.14; 95% CI, −0.22 to −0.06; P = .009) temporal fusiform (β = −0.13; 95% CI, −0.23 to −0.04; P = .02), and lateral occipital regions (β = −0.15; 95% CI, −0.24 to −0.06; P = .009) compared with male sex. Among APOE ε4 carriers, female sex was associated with faster inferior-temporal tau accumulation (β = −0.10; 95% CI, −0.16 to −0.03; P = .01). Conclusions and Relevance These findings suggest that sex differences in the pathological progression of AD call for sex-specific timing considerations when administrating anti-Aβ and anti-tau treatments.

AbstractBackgroundFrontotemporal Dementia (FTD) patients are geographically dispersed and often have behavioral and/or motor deficits that limit access to in‐person clinical trials and research. To address these participation barriers, we investigated the feasibility of installing in‐home sensor technologies to remotely assess everyday functioning in FTD.MethodWe aimed to recruit 20 FTD participants with a variety of clinical syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). We also aimed to enroll a study partner for each participant that lived in the same home to serve as a control. The Collaborative Aging Research Using Technology (CART) platform was installed in participants’ homes to collect continuous data for up to two years, using motion sensors, physiological monitoring devices (e.g., scales, sleep sensors), electronic pillboxes, and wearable actigraphs. Computer use and driving patterns were also tracked. Technology was installed either via a study coordinator visit or remotely through video and written instructions, based on schedule and logistics. Participants were asked to complete a weekly Qualtrics survey about time away from home, visitors, and health changes.ResultOf the 159 UCSF participants available for recruitment through ALLFTD and other FTD projects, 28% (N = 45) met inclusion criteria. Of those 45, ten were ineligible due to advanced disease severity or relocation to an assisted living facility. A third (36%, N = 17) declined due to overwhelmed study partners (N = 3), declined any subproject participation (N = 7), sensitivity to participant’s diagnosis (N = 2), or lack of response (N = 5). Two additional participants were recruited through UCLA’s ALLFTD cohort. The platform has been installed in 19 homes (bvFTD: n = 10; PPA: n = 5; CBS/PSP: n = 4). Two homes discontinued due to death or relocation to assisted living facility. Mean data collection is 360 days (max = 527). Of 103 reported technological issues, 92% were resolved without additional home visits, either by phone or email. Participants completed 65% of weekly health questionnaires.ConclusionsAlthough there were some recruitment and retention challenges, these findings generally provide preliminary support for the feasibility and sustainability of conducting comprehensive in‐home passive data research in FTD.

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.