Benzinger, Tammie L.S.

Abstract We present a comprehensive global analysis of genetic variants associated with autosomal-dominant Alzheimer’s disease (ADAD). A total of 550 variants in the APP, PSEN1 and PSEN2 genes were identified, of which 279 were classified as pathogenic or likely pathogenic based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria, utilizing data from the Dominantly Inherited Alzheimer Network (DIAN), literature and public databases. Symptomatic age at onset (AAO) data were estimated for 227 of these variants, allowing detailed characterization of their frequency, pathogenicity and AAO. Importantly, 226 variants met eligibility criteria for inclusion in disease-modifying clinical trials. Furthermore, we demonstrated the predictive value of mean variant AAO and parental AAO in predicting symptomatic AAO, validated against converters who became symptomatic during follow-up in the DIAN Observational Study. This dataset provides critical insights into the global landscape of ADAD and reveals the genetic and AAO heterogeneity of ADAD variants while refining variant trial eligibility criteria.

AbstractBackgroundAnti‐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.MethodThis 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.ResultIn 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.ConclusionWhile 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.

AbstractBackgroundAutosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta‐amyloid (Aβ) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics. Omics approaches can inform NVU changes and their disease associations.MethodsCSF proteomic data using the Somalogic® platform was generated from 485 participants in the DIAN study, who also had PiB‐PET and MRI assessing Aβ burden, white matter hyperintensity (WMH), and cerebral microhemorrhage (CMH). From previously published AD studies, we identified 33 NVU‐associated proteins with corresponding Somalogic aptamers (Figure 1). We used Principal Component Analysis (PCA) on participants with complete data (n=262, 166 mutation‐carriers and 96 non‐carriers) to find groups of proteins associated with mutation status and disease stage as measured with estimated year to symptom onset (EYO), PiB‐PET, and clinical status. Linear‐mixed effect models and two‐part zero‐inflated negative binomial mixed models further evaluated the link between significant principal components (PCs) and WMH and CMH, respectively. Models accounted for age, APOE‐e4 status, sex, and education.ResultsThe first ten PCs explained >60% of the variance in NVU‐related protein levels (Figure 2A) with only PC5 (4.8%) associated with mutation*EYO, suggesting relationship with ADAD‐specific disease progression (***p<0.0001, Figure 2B). While asymptomatic PiB‐negative individuals were not significantly different from non‐carriers, asymptomatic PiB‐positive individuals had higher PC5 scores than non‐carriers and symptomatic individuals scored still higher (**p<0.005, ***p<0.0001, Figure 2C). The main proteins composing PC5 were: neurofilament light‐chain, angiopoietin‐2, SMOC1, LRP1, E‐selectin, and sTREM2, suggesting strong association with proinflammatory glial response from neuronal injury (Figure 2D). PC5 was also associated with WMH volumes (*p<0.05, Figure 3A) and with CMH count in participants with CMH (**p<0.005, Figure 3B).ConclusionsThis PCA approach indicates that some groups of NVU‐associated proteins are related with mutation status and disease stage, and that they are differentially associated with features of ADAD such as white matter integrity as measured by WMH volume. Weighted Correlation Network Analysis will be of interest to further understand these associations.Funding: K01AG080123, RF1‐AG044546, UF1AG032438

AbstractBackgroundAlzheimer disease (AD) related cognitive decline occurs at relatively young ages in individuals with Down syndrome (DS, early‐mid 50s) and in those with autosomal dominant mutations (ADAD, 40‐50s). Both groups show similar patterns of amyloid accumulation. We examined if brain volumes are similarly affected by AD pathology in individuals with DS and ADAD.MethodData for cognitively stable and declining participants was obtained from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS) and the Dominantly Inherited Alzheimer Network (DIAN). Stability/decline was identified based on cognitive testing and interview of individuals and caregivers by trained assessors. Cognitively stable family members without DS/ADAD mutations were recruited as controls from both studies. Participants underwent MRI and amyloid positron emission tomography (PET) scans from which brain volumes and amyloid (centiloids) were derived, respectively. Participants from DIAN had Pittsburgh Compound‐B (PIB) scans, ABC‐DS had PIB or florbetapir. Nonlinear cross‐sectional associations between regional brain volumes and estimated years to onset of cognitive decline (EYO, negative values before onset, positive after) and centiloid were evaluated using generalized additive models while controlling for sex and random effects of family. EYO was set to 52 for all participants with DS and based on parental decline/mutation type for participants with ADAD. EYO for controls was based on the EYO of their family member.ResultData from 239 participants with DS (47 declining), and 340 participants with ADAD (122 declining), and 263 familial controls were included. Higher EYO and centiloid values were associated with lower brain volumes in almost all regions. At earlier EYOs, individuals with DS typically had smaller regional volumes than ADAD or sibling controls, with volume declining linearly across the EYO range. By contrast, ADAD mutation carriers had similar volumes to non‐carriers at early EYOs, with volumes diverging as early as 10 years before decline. Brain volumes and centiloid values were inversely related in ADAD and DSAD. Volume in key cortical regions were similar by the expected year of onset in both groups.ConclusionADAD and DSAD demonstrated different temporal patterns of regional neurodegeneration prior to cognitive change despite being similarly affected by early onset amyloid.

AbstractBackgroundAutosomal dominant Alzheimer disease (ADAD) is characterized by genetic mutations affecting the beta‐amyloid (Aß) pathway. However, vascular and immune factors play important roles which are not completely understood. Understanding the function of the neurovascular unit (NVU) comprised of neurons, glial cells, and vasculature, at different disease stages appears ideal to developing and evaluating therapeutics. Omics approaches can inform NVU changes and their disease associations.MethodsCSF proteomic data using the Somalogic® platform was generated from 485 participants in the DIAN study, who also had PiB‐PET and MRI assessing Aß burden, white matter hyperintensity (WMH), and cerebral microhemorrhage (CMH). From previously published AD studies, we identified 33 NVU‐associated proteins with corresponding Somalogic aptamers (Figure 1). We used Principal Component Analysis (PCA) on participants with complete data (n = 262, 166 mutation‐carriers and 96 non‐carriers) to find groups of proteins associated with mutation status and disease stage as measured with estimated year to symptom onset (EYO), PiB‐PET, and clinical status. Linear‐mixed effect models and two‐part zero‐inflated negative binomial mixed models further evaluated the link between significant principal components (PCs) and WMH and CMH, respectively. Models accounted for age, APOE‐e4 status, sex, and education.ResultsThe first ten PCs explained >60% of the variance in NVU‐related protein levels (Figure 2A) with only PC5 (4.8%) associated with mutation*EYO, suggesting relationship with ADAD‐specific disease progression (***p<0.0001, Figure 2B). While asymptomatic PiB‐negative individuals were not significantly different from non‐carriers, asymptomatic PiB‐positive individuals had higher PC5 scores than non‐carriers and symptomatic individuals scored still higher (**p<0.005, ***p<0.0001, Figure 2C). The main proteins composing PC5 were: neurofilament light‐chain, angiopoietin‐2, SMOC1, LRP1, E‐selectin, and sTREM2, suggesting strong association with proinflammatory glial response from neuronal injury (Figure 2D). PC5 was also associated with WMH volumes (*p<0.05, Figure 3A) and with CMH count in participants with CMH (**p<0.005, Figure 3B).ConclusionsThis PCA approach indicates that some groups of NVU‐associated proteins are related with mutation status and disease stage, and that they are differentially associated with features of ADAD such as white matter integrity as measured by WMH volume. Weighted Correlation Network Analysis will be of interest to further understand these associations. Funding: K01AG080123, RF1‐AG044546, UF1AG032438

Abstract INTRODUCTION The Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging convened a multidisciplinary workgroup to update appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. METHODS The workgroup identified key research questions that guided a systematic literature review on clinical amyloid/tau PET. Building on this review, the workgroup developed 17 clinical scenarios in which amyloid or tau PET may be considered. A modified Delphi approach was used to rate each scenario by consensus as “rarely appropriate,” “uncertain,” or “appropriate.” Ratings were performed separately for amyloid and tau PET as stand‐alone modalities. RESULTS For amyloid PET, seven scenarios were rated as appropriate, two as uncertain, and eight as rarely appropriate. For tau PET, five scenarios were rated as appropriate, six as uncertain, and six as rarely appropriate. DISCUSSION AUC for amyloid and tau PET provide expert recommendations for clinical use of these technologies in the evolving landscape of diagnostics and therapeutics for Alzheimer's disease. Highlights A multidisciplinary workgroup convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging updated the appropriate use criteria (AUC) for amyloid positron emission tomography (PET) and to develop AUC for tau PET. The goal of these updated AUC is to assist clinicians in identifying clinical scenarios in which amyloid or tau PET may be useful for guiding the diagnosis and management of patients who have, or are at risk for, cognitive decline These updated AUC are intended for dementia specialists who spend a significant proportion of their clinical effort caring for patients with cognitive complaints, as well as serve as a general reference for a broader audience interested in implementation of amyloid and tau PET in clinical practice.

AbstractBackgroundAlzheimer disease (AD) involves neurodegenerative disorders with progressive cognitive decline. Atypical presentations like Posterior Cortical Atrophy (PCA) and Logopenic Variant Primary Progressive Aphasia (lvPPA) exhibit distinct clinical profiles. PCA affects the posterior parietal and occipital lobes, causing visuospatial deficits, while lvPPA manifests as language impairment in the temporoparietal region. Understanding the biological underpinnings of these variants is crucial for deciphering AD’s heterogeneity.MethodParticipants diagnosed with AD dementia (n = 54, female = 25, Age: 75.23±6.52), PCA (n = 9, female = 8, Age: 62.78±7.21), and lvPPA (n = 6, female = 2, Age: 66.33±6.38) from the Knight Alzheimer Disease Research Center (Knight ADRC) underwent 18F‐AV‐1451 tau‐PET imaging. Tau deposition, along with nine biological properties, was mapped to the cortical surface (Figure 1A): gene expression, myelin, cortical thickness, sensorimotor association axis, evolutionary expansion, cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of glucose (CMRglu) (Figure 1B). Correlation matrices and generalized linear models (GLMs) assessed relationships between tau accumulation and biological properties.ResultA correlation matrix (Figure 2A) shows significant positive associations (p<0.05) between evolutionary expansion patterns and tau accumulation in AD (r = 0.53), PCA (r = 0.29), and lvPPA (r = 0.56); and gene expression in PCA (r = 0.51). Conversely, strongest negative associations were observed in AD (r = ‐0.38, r = ‐0.15) and lvPPA (r = ‐0.18, r = ‐0.28) for CBF and myelin mapping, respectively, and in PCA (r = ‐0.25, ‐0.23) for cortical thickness and sensorimotor association axis. GLMs demonstrated significant relationships between cerebrovascular health and evolutionary expansion with tau measures across all groups. AD (r = ‐0.52) and PCA (r = ‐0.19) exhibited negative associations with gene expression and myelin mapping, respectively. Additionally, lvPPA (r = 0.39) displayed positive association with the sensorimotor association cortex.ConclusionResults elucidate distinct tau deposition patterns in AD, PCA, and lvPPA, providing insights into subtype‐specific pathophysiology. The correlation matrix and GLMs highlight the significance of evolutionary expansion and cerebrovascular health in tau accumulation. Associations underscore the complex interplay of gene expression, myelin mapping, and cortical thickness with tau pathology. Findings contribute to understanding heterogeneity within AD spectrum disorders, emphasizing the multifaceted nature of neurodegenerative processes. Further research promises refined diagnostic and therapeutic strategies tailored to distinct neurobiological profiles in AD, PCA, and lvPPA.

Abstract The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer’s disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer’s disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.

AbstractINTRODUCTIONWe investigated longitudinal associations between self‐reported exercise and Alzheimer's disease (AD)‐related biomarkers in individuals with autosomal dominant AD (ADAD) mutations.METHODSParticipants were 308 ADAD mutation carriers aged 39.7 ± 10.8 years from the Dominantly Inherited Alzheimer's Network. Weekly exercise volume was measured via questionnaire and associations with brain volume (magnetic resonance imaging), cerebrospinal fluid biomarkers, and brain amyloid beta (Aβ) measured by positron emission tomography were investigated.RESULTSGreater volume of weekly exercise at baseline was associated with slower accumulation of brain Aβ at preclinical disease stages β = –0.16 [–0.23 to –0.08], and a slower decline in multiple brain regions including hippocampal volume β = 0.06 [0.03 to 0.08].DISCUSSIONExercise is associated with more favorable profiles of AD‐related biomarkers in individuals with ADAD mutations. Exercise may have therapeutic potential for delaying the onset of AD; however, randomized controlled trials are vital to determine a causal relationship before a clinical recommendation of exercise is implemented.Highlights Greater self‐reported weekly exercise predicts slower declines in brain volume in autosomal dominant Alzheimer's disease (ADAD). Greater self‐reported weekly exercise predicts slower accumulation of brain amyloid beta in ADAD. Associations varied depending on closeness to estimated symptom onset.

Abstract This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer’s disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating® (CDR®). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR®. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.