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The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.

Background and purposeSporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease caused by an abnormal isoform of the human prion protein. Structural magnetic resonance imaging in patients with pathologically confirmed sCJD was compared with cognitively normal individuals to identify a cortical thickness signature of sCJD.MethodsThis retrospective cross-sectional study compared patients with autopsy-confirmed sCJD with dementia (n = 11) with age- and sex-matched cognitively normal individuals (n = 22). We identified regions of interest (ROIs) in which cortical thickness was most affected by sCJD. Within patients with sCJD, the relationship between ROI cortical thickness and clinical measures (disease duration, cerebrospinal fluid tau and diffusion-weighted imaging abnormalities) was evaluated.ResultsCompared with cognitively normal individuals, patients with sCJD had significantly reduced cortical thickness in multiple ROIs, including the fusiform gyrus, precentral gyrus, precuneus and superior temporal gyrus bilaterally; the caudal middle frontal gyrus, superior frontal gyrus, postcentral gyrus, inferior temporal gyrus and transverse temporal gyrus in the left hemisphere; and the superior parietal lobule in the right hemisphere. Only one patient with sCJD had co-pathology consistent with Alzheimer's disease. Reduced cortical thickness did not correlate with disease duration, presence of diffusion restriction or elevated cerebrospinal fluid tau.ConclusionCortical signature changes in sCJD may reflect brain changes not captured by standard clinical measures. This information may be used with clinical measures to inform the progression of sCJD and patterns of prion protein spread throughout the brain. These results may have implications for prediction of symptomatic progression and plausibly for development of therapeutic strategies.

Background and Objectives: It remains unknown whether the associations between protective lifestyles and sporadic dementia risk reported in observational studies also affect age at symptom onset (AAO) in autosomal dominant Alzheimer disease (ADAD) with predominant genetic influences. We investigated the associations between resilience-related life experiences and interindividual AAO variability in ADAD., Methods: We performed a longitudinal and confirmatory analysis of the Dominantly Inherited Alzheimer Network prospective observational cohort (January 2009-June 2018, follow-up duration 2.13 ± 2.22 years), involving clinical, CSF, and lifestyle/behavioral assessments. We performed a 2-pronged comprehensive resilience assessment in each cohort. Cohort 1, incorporating the general resilience definition (cognitive maintenance [Clinical Dementia Rating = 0] despite high pathology), included carriers during the periods of significant CSF p-tau181 variability and grouped into resilience/resistance outcome bins according to the dichotomous pathologic and cognitive statuses, subcategorized by the estimated years from expected symptom onset (EYO). Cohort 2, focused on ADAD-specific genetically determined time frame characterizing the onset predictability, included asymptomatic participants with available preclinical lifestyle data and AAO outcomes and grouped into delayed or earlier AAO relative to the parental AAO. Associations of cognitive, CSF p-tau181 , and lifestyle/behavioral predictors with binary outcomes were investigated using logistic regression., Results: Of 320 carriers (age 38.19 ± 10.94 years, female 56.25%), cohort 1 included 218 participants (39.00 ± 9.37 years, 57.34%) and cohort 2 included 28 participants (43.34 ± 7.40 years, 71.43%). In cohort 1, 218 carriers after -20 EYO, when the interindividual variability (SD) of CSF p-tau181 first became more than twice greater in carriers than in noncarriers, were grouped into low-risk control (asymptomatic, low pathology, n = 103), high-resilience (asymptomatic despite high pathology, n = 60), low-resilience (symptomatic despite low pathology, n = 15), and susceptible control (symptomatic, high pathology, n = 40) groups. Multivariable predictors of high resilience, controlling for age and depression, included higher conscientiousness (odds ratio 1.051 [95% CI 1.016-1.086], p = 0.004), openness to experience (1.068 [1.005-1.135], p = 0.03) (vs. susceptible controls), and agreeableness (1.082 [1.015-1.153], p = 0.02) (vs. low resilience). From 1 to 3 years before parental AAO (cohort 2), the multivariable predictor of delayed AAO, controlling for CSF p-tau181 , was higher conscientiousness (0.916 [0.845-0.994], p = 0.036)., Discussion: Among the cognitively and socially integrated life experiences associated with resilience, measures of conscientiousness were useful indicators for evaluating resilience and predicting future dementia onset in late preclinical ADAD.

Introduction: Biomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease-modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non-AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential., Methods: We conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases., Results: Clinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co-pathologies., Discussion: These results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co-pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non-AD neuropathologies. The ADNI NPC supports this mission with well-characterized tissue samples (available through ADNI and the National Institute on Aging) and "gold-standard" diagnostic information (soon to include digital histology)., Highlights: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases. ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging. Digitized slide files from the ADNI NPC will be available in 2025. Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation. Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology. Neuropathology is essential for the development of novel AD/ADRD biomarkers., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and employed machine learning to develop and validate predictive models. Our study identified 137 proteins with distinct trajectories between MCs and NCs, including eight that changed before traditional AD biomarkers. These proteins are grouped into three stages: early stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle stage (neuronal death, apoptosis), and late presymptomatic stage (microglial changes, cell communication). The predictive model revealed a six-protein subset that more effectively differentiated MCs from NCs, compared with conventional biomarkers., Competing Interests: Declaration of interests C.C. has received research support from GSK and EISAI. C.C. is a member of the advisory board of Circular Genomics and owns stocks in these companies. C.C. is on the advisory board of ADmit. J.L. reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Merck, and Roche; consulting fees from Axon Neuroscience, EISAI, and Biogen; author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers; and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6). He receives compensation for serving as chief medical officer for MODAG GmbH and is a beneficiary of the phantom share program of MODAG GmbH. E.M. reports research support received from NIA (U01AG059798), Anonymous Foundation, GHR, Alzheimer Association, Eli Lilly Eisai, and Hoffmann-La Roche and paid consulting for Eli Lilly, Alector, Alzamend, Sanofi, AstraZeneca, Hoffmann-La Roche, Grifols, and Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid β. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid β production., Methods: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [ 11 C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [ 18 F] fluorodeoxyglucose (FDG)-PET, CSF Aβ42-to-Aβ40 ratio (Aβ42/40), CSF log 10 (phosphorylated tau 181), CSF log 10 (phosphorylated tau 217), and MRI-based hippocampal volume., Findings: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (β=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003)., Interpretation: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid β production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset., Funding: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III., Competing Interests: Declaration of interests SAS receives research funding from the Alzheimer's Association and the US National Institutes of Health (NIH). LL receives research funding from the US NIH; consulting fees from Korro Bio; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Biogen and Cell Signaling Technology. NJ-M receives research funding from the Alzheimer's Association and the US NIH. RJB receives research funding from the US NIH, Biogen, AbbVie, Bristol Myers Squibb, Novartis, the US National Intelligence Authority, US National Institute of Neurological Disorders and Stroke, Centene, the Rainwater Foundation, the BrightFocus Foundation, the Association for Frontotemporal Degeneration Biomarkers Initiative, Coins for Alzheimer's Research Trust Fund, the Good Ventures Foundation, Hoffman–La Roche, CogState, Signant, the Cure Alzheimer's Research Trust Fund, Eisai, and C2N Diagnostics; receives royalties or licences from C2N Diagnosticsf payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Korean Dementia Association, the American Neurological Association, Fondazione Prada, Weill Cornell Medical College, Harvard University, Beeson, and Adler Symposium. ZS receives research funding from the BrightFocus Foundation, the Foundation for Barnes-Jewish Hospital, Eli Lilly, the Health Equity Scholars Program, and the Alzheimer's Society of Canada. RAS receives research funding from the US NIH, the Gerald and Henrietta Rauenhorst Foundation, Eli Lilly, the Alzheimer's Assocation, and Eisai and receives consulting fees from AbbVie, Bristol Myers Squibb, Eisai, Eli Lilly, Roche, Prothena, AC Immune, Acumen, Alector, Alnylam, Biohaven, Genentech, Janssen, the Japanese Organization for Medical Device Development, Nervgen, Neuraly, Neurocentria, Oligomerix, Renew, Shionogi, Vigil Neuroscience, Ionis, and Vaxxinity. GSD receives research funcing from the US NIH, the Alzheimer's Association, and the Chan–Zuckerberg Initiative; consulting fees from Parabon Nanolabs and Arialysis Therapeutics; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from PeerView Media, Continuing Education, Eli Lilly, DynaMed, and SixSense Concierge. EM receives research funding from the US National Intelligence Authority, Eisai, Eli Lilly, Roche, and the Gerald and Henrietta Rauenhorst Foundation; consulting fees from AstraZeneca, Sanofi, and Merck; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the Alzheimer Association, Projects in Knowledge, and Neurology Live. JPC receives research funding from the US NIH. RJP receives grants from the US NIH. JL is a consultant for and receives grants, contracts, and royalties from Eisai, Eli Lilly, the German Center of Neurodegenerative Diseases, the German Ministry for Research and Education, the Anton and Petra Ehrmann Foundation, the Luneburg Foundation, Innovationsfonds, the Michael J Fox Foundation, CurePSP, the Jerome LeJeune Foundation, the Alzheimer Forschungs Initiative, Deutsche Stiftung Down Syndrom, Else Kroner Fresenius Stiftung, and MODAG. DJS receives consulting fees from Prothena Biosciences and Eisai. CX receives research funding from the US NIH and consulting fees from Diadem. PRS receives research funding from the the US NIH, the Roth Charitable Foundation, the Australian National Health and Medical Research Council, and the Australian Medical Research Future Fund and receives consulting fees from Outside Opinion and Moira Clay Consulting. JJL receives research funding from the German Center for Neurodegenerative Diseases, the German Ministry for Research and Education, the Anton and Petra Ehrmann Foundation, the Lüneburg Foundation, Innovationsfonds, the Michael J Fox Foundation for Parkinson's Research, CurePSP, the Jerome LeJeune Foundation, the Alzheimer Forschungs Initiative, Deutsche Stiftung Down Syndrom, and Else Kröner Fresenius Stiftung; consulting fees from Eisai and Biogen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Vital, Biogen, Eisai, Teva, Roche, and Zambon. MJ receives payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Eisai. TLSB receives research funding from the US NIH and Siemens; consulting fees from Biogen, Eli Lilly, Eisai, Bristol Myers Squibb, and Johnson & Johnson; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Medscape and PeerView. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

Introduction: Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed., Methods: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories., Results: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive., Discussion: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression., Highlights: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease., (© 2024. The Author(s).)

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.

Introduction: Amyloid 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., Methods: Using 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., Results: No 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., Discussion: Results 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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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, 11 C-labelled Pittsburgh Compound B-PET and structural MRI. 18 F-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 (PIB 50-70 cerebellar grey reference and FDG 30-60 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 18 F-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 18 F-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 18 F-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., Competing Interests: Y.L., E.T., B.G., and G.W. report no conflict of interest relevant to this manuscript. J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415, SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Janssen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC; Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Carlos Cruchaga, PhD, receives research support from Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Dr. Cruchaga is a member of the advisory board of Vivid Genetics, Halia Therapeutics and Adx Healthcare. G.S.D.’s research is supported by NIH (K23AG064029, U01AG057195 and U19AG032438), the Alzheimer’s Association and the Chan Zuckerberg Initiative. He serves as a consultant for Parabon NanoLabs, Inc., as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the clinical director of the Anti-NMDA Receptor Encephalitis Foundation, Inc. (Canada; uncompensated). He is the co-project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc., and Continuing Education, Inc. He owns stock in ANI Pharmaceuticals. R.J.B., MD, is the director and principal investigator of the DIAN and DIAN-TU-001. He receives research support from the National Institute on Aging of the National Institutes of Health, DIAN-TU Trial Pharmaceutical Partners (Eli Lilly and Company, F. Hoffman-La Roche, Ltd. and Avid Radiopharmaceuticals), Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech, United Neuroscience. Previous: AbbVie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). He has been an invited speaker and consultant for AC Immune, F. Hoffman La Roche, Ltd. and Janssen and a consultant for Amgen and Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01 AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE HealthCare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE HealthCare, Roche, Johnson & Johnson and Merck. He serves as an associate editor for JAMA Neurology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Eteleeb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn., (© 2024. The Author(s).)

Background and Objectives: Alzheimer disease (AD) is primarily associated with accumulations of amyloid plaques and tau tangles in gray matter, however, it is now acknowledged that neuroinflammation, particularly in white matter (WM), significantly contributes to the development and progression of AD. This study aims to investigate WM neuroinflammation in the continuum of AD and its association with AD pathologies and cognition using diffusion-based neuroinflammation imaging (NII)., Methods: This is a cross-sectional, single-center, retrospective evaluation conducted on an observational study of 310 older research participants who were enrolled in the Knight Alzheimer's Disease Research Center cohort. Hindered water ratio (HR), an index of WM neuroinflammation, was quantified by a noninvasive diffusion MRI method, NII. The alterations of NII-HR were investigated at different AD stages, classified based on CSF concentrations of β-amyloid (Aβ) 42/Aβ40 for amyloid and phosphorylated tau181 (p-tau181) for tau. On the voxel and regional levels, the relationship between NII-HR and CSF markers of amyloid, tau, and neuroinflammation were examined, as well as cognition., Results: This cross-sectional study included 310 participants (mean age 67.1 [±9.1] years), with 52 percent being female. Subgroups included 120 individuals (38.7%) with CSF measures of soluble triggering receptor expressed on myeloid cells 2, 80 participants (25.8%) with CSF measures of chitinase-3-like protein 1, and 110 individuals (35.5%) with longitudinal cognitive measures. The study found that cognitively normal individuals with positive CSF Aβ42/Aβ40 and p-tau181 had higher HR than healthy controls and those with positive CSF Aβ42/Aβ40 but negative p-tau181. WM tracts with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 were primarily located in the posterior brain regions while those with elevated NII-HR in individuals with positive CSF Aβ42/Aβ40 and p-tau181 connected the posterior and anterior brain regions. A significant negative correlation between NII-HR and CSF Aβ42/Aβ40 was found in individuals with positive CSF Aβ42/Aβ40. Baseline NII-HR correlated with baseline cognitive composite score and predicted longitudinal cognitive decline., Discussion: Those findings suggest that WM neuroinflammation undergoes alterations before the onset of AD clinical symptoms and that it interacts with amyloidosis. This highlights the potential value of noninvasive monitoring of WM neuroinflammation in AD progression and treatment.

Introduction: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers., Methods: AD polygenic risk scores (PRS) were tested for association with DS-related traits., Results: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRS APOE , p = 2.84 × 10 -4 ; PRS excluding APOE, PRS nonAPOE , p = 1.60 × 10 -2 ). PRS APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS., Discussion: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits., Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10 -19 ; rs142232675 p.D87N, P=2.71×10 -10 ) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10 -9 ) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10 -8 ), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology., (© 2024. The Author(s).)

Introduction: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD)., Methods: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography ( 11 C-PiB PET) and structural magnetic resonance imaging (MRI)., Results: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences., Discussion: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Biomarkers remain mostly unavailable for non-Alzheimer's disease neuropathological changes (non-ADNC) such as transactive response DNA-binding protein 43 (TDP-43) proteinopathy, Lewy body disease (LBD), and cerebral amyloid angiopathy (CAA)., Methods: A multilabel non-ADNC classifier using magnetic resonance imaging (MRI) signatures was developed for TDP-43, LBD, and CAA in an autopsy-confirmed cohort (N = 214)., Results: A model using demographic, genetic, clinical, MRI, and ADNC variables (amyloid positive [Aβ+] and tau+) in autopsy-confirmed participants showed accuracies of 84% for TDP-43, 81% for LBD, and 81% to 93% for CAA, outperforming reference models without MRI and ADNC biomarkers. In an ADNI cohort (296 cognitively unimpaired, 401 mild cognitive impairment, 188 dementia), Aβ and tau explained 33% to 43% of variance in cognitive decline; imputed non-ADNC explained an additional 16% to 26%. Accounting for non-ADNC decreased the required sample size to detect a 30% effect on cognitive decline by up to 28%., Discussion: Our results lead to a better understanding of the factors that influence cognitive decline and may lead to improvements in AD clinical trial design., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology., Methods: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education., Results: Advanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG., Conclusions: We extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI., (© 2023. The Author(s).)

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., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: Increased 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., Objective: To 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 Participants: This 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 Measures: The 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., Results: Data 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 Relevance: The 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.

Approximately 5% of Alzheimer's disease cases have an early age at onset (<65 years), with 5-10% of these cases attributed to dominantly inherited mutations and the remainder considered as sporadic. The extent to which dominantly inherited and sporadic early-onset Alzheimer's disease overlap is unknown. In this study, we explored the clinical, cognitive and biomarker profiles of early-onset Alzheimer's disease, focusing on commonalities and distinctions between dominantly inherited and sporadic cases. Our analysis included 117 participants with dominantly inherited Alzheimer's disease enrolled in the Dominantly Inherited Alzheimer Network and 118 individuals with sporadic early-onset Alzheimer's disease enrolled at the University of California San Francisco Alzheimer's Disease Research Center. Baseline differences in clinical and biomarker profiles between both groups were compared using t -tests. Differences in the rates of decline were compared using linear mixed-effects models. Individuals with dominantly inherited Alzheimer's disease exhibited an earlier age-at-symptom onset compared with the sporadic group [43.4 (SD ± 8.5) years versus 54.8 (SD ± 5.0) years, respectively, P < 0.001]. Sporadic cases showed a higher frequency of atypical clinical presentations relative to dominantly inherited (56.8% versus 8.5%, respectively) and a higher frequency of APOE-ε4 (50.0% versus 28.2%, P = 0.001). Compared with sporadic early onset, motor manifestations were higher in the dominantly inherited cohort [32.5% versus 16.9% at baseline ( P = 0.006) and 46.1% versus 25.4% at last visit ( P = 0.001)]. At baseline, the sporadic early-onset group performed worse on category fluency ( P < 0.001), Trail Making Test Part B ( P < 0.001) and digit span ( P < 0.001). Longitudinally, both groups demonstrated similar rates of cognitive and functional decline in the early stages. After 10 years from symptom onset, dominantly inherited participants experienced a greater decline as measured by Clinical Dementia Rating Sum of Boxes [3.63 versus 1.82 points ( P = 0.035)]. CSF amyloid beta-42 levels were comparable [244 (SD ± 39.3) pg/ml dominantly inherited versus 296 (SD ± 24.8) pg/ml sporadic early onset, P = 0.06]. CSF phosphorylated tau at threonine 181 levels were higher in the dominantly inherited Alzheimer's disease cohort (87.3 versus 59.7 pg/ml, P = 0.005), but no significant differences were found for t-tau levels ( P = 0.35). In summary, sporadic and inherited Alzheimer's disease differed in baseline profiles; sporadic early onset is best distinguished from dominantly inherited by later age at onset, high frequency of atypical clinical presentations and worse executive performance at baseline. Despite these differences, shared pathways in longitudinal clinical decline and CSF biomarkers suggest potential common therapeutic targets for both populations, offering valuable insights for future research and clinical trial design., Competing Interests: J.J.L.-G.’s research is supported by NIH-NIA (K01AG073526), the Alzheimer’s Association (AARFD-21-851415 and SG-20-690363), the Michael J. Fox Foundation (MJFF-020770), the Foundation for Barnes-Jewish Hospital and the McDonnell Academy. A.M.F., PhD, is the Biomarker Core Leader of the DIAN-TU. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech and AbbVie and also consults for Araclon/Grifols, DiademRes, DiamiR and Otsuka Pharmaceuticals. T.L.S.B., MD, PhD, has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. T.L.S.B. participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen and F. Hoffmann-La Roche, Ltd. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker’s Bureau for Biogen. J.C.M., MD, is the Friedman Distinguished Professor of Neurology, Director, Knight ADRC, Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444, P01AG003991, P01AG026276, U19 AG032438 and U19 AG024904. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. A.J.A., PhD, has served as a consultant for Biogen Inc and H. Lundbeck HS. J.H., PhD, is a paid consultant for F. Hoffmann-La Roche, Ltd., Takeda, and Lundbeck and is on the Data Safety and Monitoring Board for Eisai. J.L., MD, reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen and author fees from Thieme Medical Publishers and W. Kohlhammer GmbH Medical Publishers. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is a beneficiary of the phantom share program of MODAG GmbH and is an inventor in a patent ‘Pharmaceutical Composition and Methods of Use’ (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. L.I. is currently a full-time employee of Eli Lilly and Company/Avid Radiopharmaceuticals and a minor shareholder of Eli Lilly and Company. His contribution to the work presented in this manuscript was performed while he was affiliated with the University of California San Francisco. G.D.R., MD, receives research support from NIA P30-AG062422, U01-AG057195, R35 AG072362, R56-AG075744, NINDS R21-NS120629, Alzheimer’s Association ZEN-21-848216, American College of Radiology, Rainwater Charitable Foundation, Shenandoah Foundation, Avid Radiopharmaceuticals, Life Molecular Imaging, GE Healthcare and Genentech. He has served as a consultant for Alector, Eli Lilly, Genentech, GE Healthcare, Roche, Johnson & Johnson and Merck. He serves as associate editor for JAMA Neurology. All other authors report no conflict of interest relevant to this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau., (© 2023. The Author(s).)

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

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., (© 2023. The Author(s).)

Background and Objectives: White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF β-amyloid (Aβ) 42, Aβ40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aβ with PET using [ 11 C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span., Methods: We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models., Results: A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm 3 per year) more than 13 times faster ( p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm 3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers., Discussion: Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition., (© 2023 American Academy of Neurology.)

Common and rare variants in the LRRK2 locus are associated with Parkinson's disease (PD) risk, but the downstream effects of these variants on protein levels remain unknown. We performed comprehensive proteogenomic analyses using the largest aptamer-based CSF proteomics study to date (7006 aptamers (6138 unique proteins) in 3107 individuals). The dataset comprised six different and independent cohorts (five using the SomaScan7K (ADNI, DIAN, MAP, Barcelona-1 (Pau), and Fundació ACE (Ruiz)) and the PPMI cohort using the SomaScan5K panel). We identified eleven independent SNPs in the LRRK2 locus associated with the levels of 25 proteins as well as PD risk. Of these, only eleven proteins have been previously associated with PD risk (e.g., GRN or GPNMB). Proteome-wide association study (PWAS) analyses suggested that the levels of ten of those proteins were genetically correlated with PD risk, and seven were validated in the PPMI cohort. Mendelian randomization analyses identified GPNMB, LCT, and CD68 causal for PD and nominate one more (ITGB2). These 25 proteins were enriched for microglia-specific proteins and trafficking pathways (both lysosome and intracellular). This study not only demonstrates that protein phenome-wide association studies (PheWAS) and trans-protein quantitative trail loci (pQTL) analyses are powerful for identifying novel protein interactions in an unbiased manner, but also that LRRK2 is linked with the regulation of PD-associated proteins that are enriched in microglial cells and specific lysosomal pathways., (© 2023. The Author(s).)

Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Pittsburgh Compound-B ( 11 C-PiB) and 18 F-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 11 C-PiB and 18 F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies., Methods: 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 11 C-PiB and 18 F-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 11 C-PiB while other sites use 18 F-florbetapir for Aβ PET imaging., Results: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11 C-PiB SUVRs did not differ from that of global cortical 18 F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11 C-PiB SUVRs decreased more rapidly than global cortical 18 F-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 18 F-florbetapir was primarily used versus trials where 11 C-PiB was primarily used., Conclusion: 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., Trial Registration: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain., Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD)., Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration., Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation., Highlights: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser ( http://web.hararilab.org/SNARE/ )., (© 2023. The Author(s).)

Alzheimer's disease (AD) is a looming public health disaster with limited interventions. Alzheimer's is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing., (© 2023. The Author(s).)

Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health's Alzheimer's Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)