Hornbeck, Russ C.

Abstract The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Abstract 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 [ 11 C]‐Pittsburgh compound‐B (PiB) positron emission tomography (PET), [ 18 F]‐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.

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.

Importance Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3–like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = −242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = −0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = −0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = −0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration ClinicalTrials.gov Identifier: NCT04623242

AbstractINTRODUCTIONAmyloidosis, 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.METHODSIndividuals 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.RESULTSPostcodon 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.DISCUSSIONWe 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.

AbstractCarriers 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.

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 Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

AbstractBackgroundTau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.MethodsCross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and sub‐threshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.ResultsThere were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or sub‐threshold levels of amyloid.ConclusionsTau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.

AbstractBackgroundTau PET imaging is an established tool for studying Alzheimer Disease but its sensitivity to primary age‐related tauopathy (PART) as well as sex effects in individuals without abnormal levels of amyloid are unknown.MethodsCross‐sectional data were collected from 2014 to 2019 in 144 cognitively normal younger, middle‐aged, and older adults free from amyloid pathology as quantified using PET. Regional values of tau PET binding were measured using flortaucipir. Statistical models examined the main effects of increasing age, sex, race, and subthreshold levels of amyloid. Secondary analyses also examined the relationship between tau PET binding and iron as measured using T2* weighted imaging and calcification as measured using CT.ResultsThere were significant positive associations between tau binding and age in 19 regions, with the largest effects seen in the inferior temporal cortex (t=4.59), caudate (t=9.58), and putamen (t=12.57). Iron as measured using T2* imaging mediated only a modest (11.9%) amount of the association between age and tau binding. Elevated tracer uptake in females was present in 23 regions in frontal, lateral parietal, and temporal regions including, most prominently the rostral middle frontal gyrus (t=7.48), superior temporal gyrus (t=5.12) and the inferior temporal gyrus (t=4.22). There were no significant effects of race or subthreshold levels of amyloid.ConclusionsTau PET is sensitive to primary effects of age in regions consistent with the neuropathological definition of PART although strong age effects in regions of off‐target binding were also present. There was a robust effect of sex, suggesting prior observations of elevated binding in women is not solely a potentiation of Alzheimer pathology but instead represents an ubiquitous phenomenon. Understand how both sex and age impact tracer binding is critical to understanding the utility of PET tracers as well as interpreting tracer values in the context of disease.