The minimal amyloid accumulation (MAA) in cognitively unimpaired individuals that predicts the onset of cognitive impairment remains unknown. In a multi-center amyloid positron emission tomography (PET) study of 1834 cognitively unimpaired participants with longitudinal clinical/cognitive assessments for up to 20.3 years, we found that 48.7% of the amyloid-negative participants with MAA starting from an amyloid PET centiloid of 1.03 had a higher risk of cognitive impairment than those with the lowest centiloid values (<1.03; hazards ratio (HR)=1.40, p=0.0046), although their risk was clearly lower than amyloid-positive participants (centiloid>20; HR=0.47, p<0.0001). Amyloid positivity was also associated with the fastest longitudinal amyloid accumulation and cognitive decline, followed by the MAA, and finally by the lowest amyloid. These findings suggest that current thresholds of amyloid positivity used for Alzheimer disease diagnosis may be overly restrictive, potentially excluding a large portion of amyloid-negative participants at elevated risk of developing cognitive impairment from prevention trials.

Anti-amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN-TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study. This double-blind, phase 2/3 trial (2012-2019), followed by open-label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005]. We report long-term amyloid-plaque removal by PET and findings for metabolic FDG PET and tau PET, and additionally changes of atrophy on volumetric MRI. Imaging measures were secondary outcome analyses. Comparison is made between the treatment cohort and controls (DB placebo participants who didn’t enter OLE, plus external controls from the DIAN OBS). Estimated years to onset was included as a covariate. The gap period of ∼1 year is specifically analyzed to estimate any “rebound” effect on amyloid or tau accumulation or neurodegeneration. Volumetric MRI measures include hippocampal volumes, lateral ventricular volumes, and white matter hyperintensities. In participants who were asymptomatic at baseline and treated with gantenerumab (n = 53), amyloid-plaque removal measured by PIB-PET in Centiloids was dose-dependent. Few participants had reached completely negative levels (below 24). No statistical significance was found for FDG PET, tau PET, or volumetric MRI, including hippocampal volumes. Impact of the gap period of ∼1 year (gap in treatment) on the rate of amyloid accumulation compared to the rate of accumulation predicted in observational studies of this cohort is under evaluation, as are the other imaging measures. While no overall effect was observed in the total group for non-amyloid measures, results suggest dose dependent clearance of amyloid plaque in asymptomatic DIAD mutation carriers following long-term, high-dose gantenerumab. The potential “rebound effect” of elevated amyloid accumulation for participants for whom there was a significant gap in therapy between the trial and the OLE is under evaluation and will be presented, as will the variables for FDG PET, tau PET, and volumetric MRI.

Alzheimer disease (AD) remains a significant global public health challenge, requiring robust multimodal datasets to elucidate its prolonged preclinical phase, improve early detection, advance understanding of disease trajectories, and guide intervention strategies. To address this, the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) at Washington University in St. Louis established the Knight Alzheimer Research Imaging (KARI) dataset. This paper characterizes this dataset emphasizing its phenotypical depth and longitudinal scope, detailing comprehensive multimodal neuroimaging from 1,645 participants (aged 42-97) across 6,217 acquisitions. Spanning the AD spectrum from healthy aging to symptomatic disease, the cohort undergoes extensive longitudinal imaging using structural and functional magnetic resonance imaging (MRI) alongside positron emission tomography (PET) tracers for amyloid and tau pathology. This is complemented by rich clinical, cognitive, genetic, and biomarker data. In addition to raw imaging, the dataset provides quality-controlled processed outputs, including anatomical segmentations and biomarker quantification. By making this data accessible to researchers, the Knight ADRC aims to accelerate discoveries in pathophysiology, biomarker identification, and therapeutic development.

INTRODUCTION:Monoclonal anti-amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS:In the DIAN-TU-001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [11C]-Pittsburgh compound-B (PiB) positron emission tomography (PET), [18F]-fluoro-2-deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS:Gantenerumab significantly reduced PiB-PET uptake overall and in most regions and showed no changes in FDG-PET or MRI measures. Drug effects were associated with baseline PiB-PET uptake, and the largest effects occurred in medial regions. DISCUSSION:Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB-PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. HIGHLIGHTS:Gantenerumab unevenly decreased Aβ burden as measured by PiB-PET across brain regions. The strongest decrease in PiB-PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG-PET metabolism or MRI volumetrics after 4 years.

INTRODUCTION:Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. METHODS:Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS:Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. DISCUSSION:We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. HIGHLIGHTS:Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.

BackgroundNeuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD.Methods445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants.FindingsWe found both tau metrics significantly elevated across increasing disease stages (p < 0.0001) and as a function of increasing amyloid burden for participants with preclinical (p < 0.0001, p = 0.0056) and symptomatic (p = 0.010, p = 0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p = 0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β = 0.59), but then tau burden elevated relative to spread (β = 0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R = 0.83).InterpretationTau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design.FundingThis research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean ( μ ) and standard deviation ( σ ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐ σ and FLAIR‐ σ ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐ μ decreased and T1‐ σ and FLAIR‐ σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients.

OBJECTIVE:Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS:Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS:The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aβ42/40, total tau, p-tau181, and neurofilament light. CSF Aβ42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aβ42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aβ42/40, Aβ42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION:Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

Cognitive decline in Alzheimer Disease (AD) is strongly correlated to the spatiotemporal pattern of tau-protein neurofibrillary tangles (NFTs). Evidence suggests tau seeding spreads transneuronally in a prion-like manner, a biological process distinct from NFT aggregation in previously-affected regions. We previously proposed a method for quantifying global tau spatial spread (TSS) using tau positron emission tomography (PET) which found TSS is particularly informative in preclinical AD. The spread of tau pathology into specific regions may therefore be key to the onset of cognitive decline. 445 older adult and 21 younger control participants were recruited. Cognition was assessed with the Knight ADRC-PACC and Tau-PET images were parcellated using the Schaeffer400 atlas. For each region, TSS was calculated as the proportion of voxels with significant levels of tau. Abnormal voxels were identified by z-scoring tau-PET voxel-wise relative to corresponding voxels in younger controls and then thresholded at z>1.96 for significance. This study predicted participant PACC from regional TSS using random forest regression (trained with 100 repeated 10-folds). Feature importance (FI) was calculated with Mean Decrease in Impurity to identify regions in which tau spread is most significant to cognitive impairment. Regional TSS demonstrated highly saturated regions in the limbic and temporal lobes with progressively lower levels in peripheral regions, largely sparing the frontal lobe (Figure 1). However, the importance of regional spread in predicting cognition did not reflect the same spatial pattern (Figure 2). Four regions emerged with the highest FI in the limbic and default networks, indicating the spread of tau within these brain regions is key to predicting cognitive impairment (Table 1). Our results suggest that tau pathology has spread extensively within medial and temporal regions early in AD. Regional TSS can be used to identify peripheral regions in which tau pathology is currently spreading into. As expected, limbic regions in the temporal lobe were critical to predicting participant cognitive impairment. However, regions in the temporal and parietal lobes belonging to the default network were additionally informative. Spread of tau pathology into new peripheral brain regions should therefore be evaluated when predicting future AD-related cognitive decline.

Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer’s disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies. Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aβ PET imaging. In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results. ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Background: Cerebral small vessel disease (CSVD) as measured by cortical atrophy and white matter hyper -intensities [leukoaraiosis], captured via magnetic resonance imaging (MRI) are increasing in prevalence due to the growth of the aging population and an increase in cardiovascular risk factors in the population. CSVD impacts cognitive function and mobility, but it is unclear if it affects complex, functional activities like driving.Methods: In a cohort of 163 cognitively normal, community-dwelling older adults (age >= 65), we compared naturalistic driving behavior with mild/moderate leukoaraiosis, cortical atrophy, or their combined rating in a clinical composite termed, aging-related changes to those without any, over a two-and-a-half-year period. Results: Older drivers with mild or moderate cortical atrophy and aging-related changes (composite) experienced a greater decrease in the number of monthly trips which was due to a decrease in the number of trips made within a one-to-five-mile diameter from their residence. Older drivers with CSVD experience a larger reduction in daily driving behaviors than drivers without CSVD, which may serve as an early neurobehavioral marker for functional decline. Conclusions: As CSVD markers, leukoaraiosis and cortical atrophy are standard MRI metrics that are widely available and can be used for screening individuals at higher risk for driving safety risk and decline in community mobility.

Cortical tau accumulation is a key pathological event that partly defines Alzheimer's disease (AD) onset and is associated with cognitive decline and future disease progression. However, an improved understanding of the timing and pattern of early tau deposition in AD and how this may be tracked in vivo is needed. Data from 59 participants involved in two longitudinal cohort studies of autosomal dominant AD (ADAD) were used to investigate whether tau PET can detect and track presymptomatic change; seven participants were symptomatic, and 52 were asymptomatic but at a 50% risk of carrying a pathogenic mutation. All had baseline flortaucipir (FTP) PET, MRI and clinical assessments; 26 individuals had more than one FTP PET scan. Standardised uptake value ratios (SUVRs) in prespecified regions of interest (ROIs) were obtained using inferior cerebellar grey matter as the reference region. We compared the changes in FTP SUVRs between presymptomatic carriers, symptomatic carriers and non-carriers, adjusting for age, sex and study site. We also investigated the relationship between regional FTP SUVRs and estimated years to/from symptom onset (EYO). Compared to both non-carriers and presymptomatic carriers, FTP SUVRs were significantly higher in symptomatic carriers in all ROIs tested (p < 0.001). There were no significant regional differences between presymptomatic carriers and non-carriers in FTP SUVRs, or their rates of change (p > 0.05), although increased FTP signal uptake was seen posteriorly in some individuals around the time of expected symptom onset. When we examined the relationship of FTP SUVR with respect to EYO, the earliest significant regional difference between mutation carriers and non-carriers was detected within the precuneus prior to estimated symptom onset in some cases. This study supports preliminary studies suggesting that presymptomatic tau tracer uptake is rare in ADAD. In cases where early uptake was seen, there was often a predilection for posterior regions (the precuneus and post-cingulate) as opposed to the medial temporal lobe, highlighting the importance of examining in vivo tau uptake beyond the confines of traditional Braak staging.

The apolipoprotein E (APOE) ε4 allele is the most well‐established genetic risk factor for late‐onset Alzheimer disease (AD). The ε4 allele is strongly linked with cerebral β‐amyloidosis whereas its relationship with tauopathy is less established. Here we investigate the relationship between APOE ε4 carrier status, regional amyloid‐β‐ (Aβ) and tau‐ positron emission topography (PET), APOE mRNA expression patterns, and cerebrospinal fluid phosphorylated tau (CSF ptau).

Ethno-racial factors may influence the multifactorial etiology and heterogeneity of Alzheimer Disease (AD). Given the conflicting reports on racial differences in AD, well-powered cohort studies are needed to identify differences in AD biomarkers between racialized groups. This NIH-funded study aims to determine cross-sectional and longitudinal differences in AD biomarkers between self-reported Black/African Americans (AA) and non-Hispanic Whites. It implements a longitudinal design with centralized and standardized analyses of cerebrospinal fluid (CSF) and plasma samples, MRI and amyloid and tau PET scans, and harmonized clinical/cognitive outcomes. It leverages available retrospective biofluid samples and brain scans, and prospectively collected data from four ADRCs (Washington University (WU), University of Pennsylvania, Emory University, University of Alabama), and the study of African Americans Fighting Alzhiemer’s in Midlife (AA-FAIM)), in addition to the derived data from the Harvard Aging Brain Study and the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) trial. It will further determine the roles of major risk factors and Social and Structural Determinants Influencing Aging and Dementia (SS-DIAD) in racial differences. By 12/31/2021, ∼3114 CSF samples, 4896 MRI scans, 3754 amyloid PET scans, and 998 tau PET scans retrospectively collected across studies were transferred to WU Knight ADRC Fluid Biomarker and Imaging Cores. CSF Aβ42, Aβ40, Tau, pTau181, and NfL were measured from all CSF samples. A subset of 3687 MRI scans and 2336 amyloid PET scans were re-processed. Preliminary analyses on data from 179 AAs and 1180 Whites (all CDR 0 at baseline) indicated that baseline CSF Tau and pTau181 were lower, and Aβ42/Aβ40 was higher, in AAs compared to Whites. Longitudinally, CSF Aβ42/Aβ40 declined more slowly, and amyloid (PET) uptake and CSF Tau (pTau181) increased more slowly, in AAs than Whites. Additionally, a multi-domain battery of SS-DIAD was pilot tested, and revealed high test-retest intraclass correlations (ICC>=0.83) for multiple domains, facilitating a uniform collection of SS-DIAD across sites. It is feasible to harmonize biomarker data and SS-DIAD across multiple studies to understand cross-sectional and longitudinal ethno-racial differences in AD. Preliminary analyses suggest cross-sectional and longitudinal differences in both amyloid and tau biomarkers between self-reported AA and Whites.

Variants in the apolipoprotein E ( APOE ) gene represent the greatest genetic risk factor for Alzheimer disease (AD). Carriers of the ε4 allele have an increased risk of developing AD pathology and a lower age of symptom onset. While prior work has focused on the sporadic form of AD, little is known about how the ε4 allele impacts AD-specific pathology in autosomal dominant AD (ADAD). 430 participants from the Charles and Joanne F. Knight Alzheimer Disease Research Center and 276 ADAD mutation-carriers from the Dominantly Inherited Alzheimer Network, were included in these analyses. Participants were classified as ε4-positive or -negative, and further grouped using Clinical Dementia Rating® (CDR®) scores as cognitively impaired or –unimpaired (Table 1). All participants completed magnetic resonance imaging (MRI), beta-amyloid positron emission tomography (Ab-PET), and cognitive testing within a 12-month period. Using regression models, we replicated prior work demonstrating that the ε4 allele is associated with an increase in AD pathology measured by Ab-PET and MRI in a sporadic AD cohort. Furthermore, the ε4 allele was also associated with a decline in cognitive performance. Follow-up pairwise comparisons revealed that within the sporadic-AD cohort, the influence of the ε4 allele was most pronounced in individuals who were cognitively impaired. In contrast, in a cohort of individuals possessing autosomal dominant mutations, the ε4 allele was not associated with increases in pathology measured by Ab-PET and MRI, nor was it associated with a decrease in cognition (Table 1; Figure 1). We present quantitative evidence that the APOE - ε4 allele differentially impacts the pathology and cognitive outcomes of sporadic- and autosomal dominant AD. In those with sporadic AD, possession of at least one copy of the ε4 allele is associated with increased amyloid deposition and cortical thinning, as well as decreased cognition, particularly in individuals who are cognitively impaired. However, in ADAD mutation-carriers, these same patterns are not evident. We propose that this is due to the overwhelming influence of the autosomal dominant genetic mutations that drive this unique and rare form of AD.

The apolipoprotein E ( APOE ) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau 181 ). Three hundred fifty participants underwent imaging, and 270 had ptau 181 . We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau 181 . Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau 181 . This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.

Off-target binding of [18F]flortaucipir (FTP) can complicate quantitative PET analyses. An underdiscussed off-target region is the skull. Here, we characterize how often FTP skull binding occurs, its influence on estimates of Alzheimer disease pathology, its potential drivers, and whether skull uptake is a stable feature across time and tracers. Methods: In 313 cognitively normal and mildly impaired participants, CT scans were used to define a skull mask. This mask was used to quantify FTP skull uptake. Skull uptake of the amyloid-6 PET tracers [18F]florbetapir and [11C]Pittsburgh compound B (n = 152) was also assessed. Gaussian mixture modeling defined abnormal levels of skull binding for each tracer. We examined the relationship of continuous bone uptake to known off-target binding in the basal ganglia and choroid plexus as well as skull density measured from the CT. Finally, we examined the confounding effect of skull binding on pathologic quantification. Results: We found that 50 of 313 (-16%) FTP scans had high levels of skull signal. Most were female (n = 41, 82%), and in women, lower skull density was related to higher FTP skull signal. Visual reads by a neuroradiologist revealed a significant relationship with hyperostosis; however, only 21% of women with high skull binding were diagnosed with hyperostosis. FTP skull signal did not substantiallycorrelate with other known off-target regions. Skull uptake was consistent over longitudinal FTP scans and across tracers. In amyloid-6-negative, but not -positive, individuals, FTP skull binding impacted quantitative estimates in temporal regions. Conclusion: FTP skull binding is a stable, participant-specific phenomenon and is unrelated to known off-target regions. Effects were found primarily in women and were partially related to lower bone density. The presence of [11C]Pittsburgh compound B skull binding suggests that defluorination does not fully explain FTP skull signal. As signal in skull bone can impact quantitative analyses and differs across sex, it should be explicitly addressed in studies of aging and Alzheimer disease.

BACKGROUND:Obesity is an increasingly recognized modifiable risk factor for Alzheimer's disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. OBJECTIVE:We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. METHODS:A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. RESULTS:We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. CONCLUSION:BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

INTRODUCTION As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.