Morris, John C

Abstract The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to optimize and validate biomarkers for clinical trials while sharing all data and biofluid samples with the global scientific community. ADNI has been instrumental in standardizing and validating amyloid beta (Aβ) and tau positron emission tomography (PET) imaging. ADNI data were used for the US Food and Drug Administration (FDA) approval of the Fujirebio and Roche Elecsys cerebrospinal fluid diagnostic tests. Additionally, ADNI provided data for the trials of the FDA‐approved treatments aducanumab, lecanemab, and donanemab. More than 6000 scientific papers have been published using ADNI data, reflecting ADNI's promotion of open science and data sharing. Despite its enormous success, ADNI has some limitations, particularly in generalizing its data and findings to the entire US/Canadian population. This introduction provides a historical overview of ADNI and highlights its significant accomplishments and future vision to pioneer “the clinical trial of the future” focusing on demographic inclusivity. Highlights The Alzheimer's Disease Neuroimaging Initiative (ADNI) introduced a novel model for public‐private partnerships and data sharing. It successfully validated amyloid and Tau PET imaging, as well as CSF and plasma biomarkers, for diagnosing Alzheimer's disease. ADNI generated and disseminated vital data for designing AD clinical trials.

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.

Abstract Approximately 5% of Alzheimer’s disease patients develop symptoms before age 65 (early-onset Alzheimer’s disease), with either sporadic (sporadic early-onset Alzheimer’s disease) or dominantly inherited (dominantly inherited Alzheimer’s disease) presentations. Both sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer’s disease and dominantly inherited Alzheimer’s disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer’s disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer’s disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50–70 cerebellar grey reference and FDG30–60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer’s disease, sporadic early-onset Alzheimer’s disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer’s disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer’s disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer’s disease versus sporadic early-onset Alzheimer’s disease. Sporadic early-onset Alzheimer’s disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer’s disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer’s disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer’s disease.

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

AbstractINTRODUCTIONAmyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains.METHODSUsing an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.RESULTSNo asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo.DISCUSSIONResults suggest that in ADAD LBP occurs later than AD pathology and often as amygdala‐ or olfactory‐predominant LBP, for which CSF α‐synuclein SAA has low sensitivity.Highlights Cerebrospinal fluid (CSF) real‐time quaking‐induced conversion (RT‐QuIC) detects misfolded α‐synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT‐QuIC does not detect α‐synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala‐predominant variants. LBP develops late in the disease course in ADAD. CSF α‐synuclein RT‐QuIC has low sensitivity for focal, low‐burden LBP.

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.