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Importance: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology., Objective: To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia., Design, Setting, and Participants: Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024., Main Outcomes and Measures: Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms., Results: In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI., Conclusions and Relevance: Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

Importance: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels., Objective: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age., Design, Setting, and Participants: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024., Main Outcomes and Measures: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating)., Results: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impairment (cognitive unimpairment [CU]), and 1107 had mild cognitive impairment (MCI) or AD dementia (ADD). One thousand five hundred and thirteen participants (37.1%) had amyloid pathology, 1368 of 3599 (38.0%) with data available were APOE ε4 carriers, and 648 (15.9%) had CMBs. In the CU group, amyloid pathology and APOE ε4 copy number were not associated with presence of any, no more than 4, or fewer than 2 CMBs but were associated with increased odds of lobar CMBs (odds ratio [OR] for amyloid, 1.42 [95% CI, 1.20-1.69], P < .001; OR for 2 vs 0 alleles, 1.81 [95% CI, 1.19-2.74], P = .006; OR for 1 vs 0 alleles, 1.10 [95% CI, 0.83-1.46], P = .49; and OR for 2 vs 1 allele, 1.64 [95% CI, 0.90-2.97], P = .11; overall P = .02). In the MCI-ADD group, amyloid pathology was associated with presence of any CMBs (OR, 1.51 [95% CI, 1.17-1.96], P = .002), no more than 4 CMBs (OR, 1.44 [95% CI, 1.18-1.82], P = .002), and fewer than 2 CMBs (OR 1.34 [95% CI, 1.03-1.74], P = .03) but not lobar CMBs. APOE ε4 copy number was associated with presence of any (OR for 2 vs 0 alleles, 1.72 [95% CI, 0.88-3.35], P = .11; OR for 1 vs 0 alleles, 0.78 [95% CI, 0.59-1.04], P = .09; and OR for 2 vs 1 allele, 2.20 [95% CI, 1.32-3.67], P = .002; overall P < .001) and no more than 4 CMBs (OR for 2 vs 0 alleles, 1.31 [95% CI, 0.64-2.68], P = .45; OR for 1 vs 0 alleles, 0.75 [95% CI, 0.54-1.04], P = .08; and OR for 2 vs 1 allele, 1.76 [95% CI, 0.97-3.19], P = .06; overall P = .03) but not with fewer than 2 or lobar CMBs. Prevalence estimates of CMBs ranged from 6% at 50 years of age in a non-APOE ε4 allele carrier with no amyloid pathology and no cognitive impairment to 52% at 90 years of age in an APOE ε4 homozygote carrier with amyloid pathology and cognitive impairment., Conclusions and Relevance: In this cross-sectional study of 4080 participants, prevalence estimates of CMBs were associated with amyloid status, APOE ε4 copy number, and age. CMB prevalence estimates may help inform safety evaluations for antiamyloid clinical trials.

Introduction: Physical function and cognition seem to be interrelated, especially in the oldest-old. However, the temporal order in which they are related and the role of brain health remain uncertain., Methods: We included 338 participants (mean age 93.1 years) from two longitudinal cohorts: the UCI 90+ Study and EMIF-AD 90+ Study. We tested the association between physical function (Short Physical Performance Battery, gait speed, and handgrip strength) at baseline with cognitive decline (MMSE, memory tests, animal fluency, Trail Making Test (TMT-) A, and digit span backward) and the association between cognition at baseline with physical decline (mean follow-up 3.3 years). We also tested whether measures for brain health (hippocampal, white matter lesion, and gray matter volume) were related to physical function and cognition and whether brain health was a common driver of the association between physical function and cognition by adding it as confounder (if applicable)., Results: Better performance on all physical tests at baseline was associated with less decline on MMSE, memory, and TMT-A. Conversely, fewer associations were significant, but better scores on memory, TMT-A, and digit span backward were associated with less physical decline. When adding measures for brain health as confounder, all associations stayed significant except for memory with gait speed decline., Conclusion: In the oldest-old, physical function and cognition are strongly related, independently of brain health. Also, the association between physical function and cognitive decline is more pronounced than the other way around, suggesting a potential for slowing cognitive decline by optimizing physical function., Introduction: Physical function and cognition seem to be interrelated, especially in the oldest-old. However, the temporal order in which they are related and the role of brain health remain uncertain., Methods: We included 338 participants (mean age 93.1 years) from two longitudinal cohorts: the UCI 90+ Study and EMIF-AD 90+ Study. We tested the association between physical function (Short Physical Performance Battery, gait speed, and handgrip strength) at baseline with cognitive decline (MMSE, memory tests, animal fluency, Trail Making Test (TMT-) A, and digit span backward) and the association between cognition at baseline with physical decline (mean follow-up 3.3 years). We also tested whether measures for brain health (hippocampal, white matter lesion, and gray matter volume) were related to physical function and cognition and whether brain health was a common driver of the association between physical function and cognition by adding it as confounder (if applicable)., Results: Better performance on all physical tests at baseline was associated with less decline on MMSE, memory, and TMT-A. Conversely, fewer associations were significant, but better scores on memory, TMT-A, and digit span backward were associated with less physical decline. When adding measures for brain health as confounder, all associations stayed significant except for memory with gait speed decline., Conclusion: In the oldest-old, physical function and cognition are strongly related, independently of brain health. Also, the association between physical function and cognitive decline is more pronounced than the other way around, suggesting a potential for slowing cognitive decline by optimizing physical function., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer's disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits., Competing Interests: Competing interests: C.C. has received research support from GSK and Eisai. 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. C.C. is a member of the advisory board of Circular Genomics and owns stocks in this company. D.J.P. is an employee of GSK and holds stock in GSK. M.d.C.M. has been an invited speaker at Eisai. M.d.C.M. is an associate editor at Alzheimer’s Research and Therapy. B.T. and P.J.V. are inventors on a patent (WO2020197399A1, owned by Stichting VUmc). C.E.T. has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly and performed contract research or received grants from AC Immune, Axon Neuroscience, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama and Vivoryon. She serves on editorial boards of Medidact Neurologie–Springer, Alzheimer’s Research and Therapy and Neurology: Neuroimmunology and Neuroinflammation and is an editor of the Neuromethods book (Springer). She had speaker contracts for Roche, Grifols and Novo Nordisk. The rest of the authors declare no competing interest., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

This preclinical AD CSF proteome study identified a panel of 12-CSF markers detecting amyloid positivity and clinical progression to AD with high accuracy; some of these CSF proteins related to immune function, neurotrophic processes, energy metabolism and endolysosomal functioning (e.g., ITGB2, CLEC5A, IGFBP-1, CST3) changed before amyloid positivity is established., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Institutional Ethical Review Boards (AD CSF biobank METC number.00–211) and informed consent was obtained from all subjects or their authorized representatives. Consent for publication Not applicable. Competing interests MC has been an invited speaker at Eisai and Novonordisk. She is an associate editor at Alzheimer´s Research & Therapy and has been an invited writer for Springer Healthcare. LV received a grant for CORAL consortium by Olink, and has been invited speaker for Eli Lilly, and consultant for Roche. IV received a TKI Health ~ Holland grant for a collaborative project with OLINK and Quanterix. IV has been an invited speaker by Quanterix, funding is paid to her institution. WvF has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. WF is member of steering cie of NovoNordisk evoke/evoke + . WvF participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. WvF is member of the steering committee of PAVE, and Think Brain Health. WvF was associate editor of Alzheimer, Research & Therapy in 2020/2021. WvF is associate editor at Brain. CET has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. She had speaker contracts for Roche, Grifols, Novo Nordisk. The rest of the authors declare no competing interest., (© 2024. The Author(s).)

Positional information is key for particles to adapt their behavior based on their position in external concentration gradients, and thereby self-organize into complex patterns. Here, position-dependent behavior of floating surfactant droplets that self-organize in a pH gradient is demonstrated, using the Marangoni effect to translate gradients of surface-active molecules into motion. First, fields of surfactant microliter-droplets are generated, in which droplets floating on water drive local, outbound Marangoni flows upon dissolution of surfactant and concomitantly grow myelin filaments. Next, a competing surfactant based on a hydrolysable amide is introduced, which is more surface active than the myelin surfactant and thereby inhibits the local Marangoni flows and myelin growth from the droplets. Upon introducing a pH gradient, the amide surfactant hydrolyses in the acidic region, so that the local Marangoni flows and myelin growth are reestablished. The resulting combination of local and global surface tension gradients produces a region of myelin-growing droplets and a region where myelin growth is suppressed, separated by a wave front of closely packed droplets, of which the position can be controlled by the pH gradient. Thereby, it is shown how "French flag"-patterns, in synthetic settings typically emerging from reaction-diffusion systems, can also be established via surfactant droplet systems., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

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., Competing Interests: C.C.: receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, interpretation of data; or in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of ADx Healthcare and Vivid Genomics Marty Farlow: Grant/Research Support from AbbVie, ADCS Posiphen, AstraZeneca, Biogen, Eisai, Eli Lilly, Genentech, Novartis, Suven Life Sciences, Ltd., vTv Therapeutics; Consultant/Advisory Boards/DSMB Boards for Allergan, Avanir, AZTherapies, Biogen MA Inc., Cerecin (formerly Accera), Chemigen, Cognition Therapeutics, Cortexyme, Danone, Eisai Inc., Eli Lilly, Longeveron, Green Valley, Medavante, Otsuka Pharmaceutical, Proclara, Neurotrope Bioscience, Samumed, Takeda, vTv Therapeutics, Zhejian Hisun Pharmaceuticals; patent Elan Johannes Levin reports speaker’s fees from Bayer Vital, speaker’s fees from Willi Gross Foundation, consulting fees from Axon Neuroscience, consulting fees from Ionis Pharmaceuticals, non-financial support from Abbvie, MODAG compensation for part time CMO, Thieme medical publishers and W. Kohlhammer GmbH medical publishers author fees, outside the submitted work. E.M.: NIA (research Funding); Eli Lilly-DSMB; ESAI—CMS; Alzamend—scientific advisory board. P.S. is partner at LSP Invester fund and has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham and EIP Pharma. Outside of this manuscript, R.J.B. reports grant/research/clinical trial support: NIH, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, Cure Alzheimer's Fund, the Tau SILK Consortium (AbbVie, Biogen and Eli Lilly), Janssen, and an anonymous foundation. R.J.B. reports consulting fees/honoraria from Janssen, Pfizer, Roche, Eisai, and Merck. R.J.B. reports equity ownership interest/advisory board income from C2N Diagnostics. All other authors report no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ 1-42 ) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau 181 ), atrophy, and cognition., Methods: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ 1-42 , P-tau 181 , gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal)., Results: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ 1-42 (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ 1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ 1-42 (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau 181 (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ 1-42 ., Discussion: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ 1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins [proximity extension-based (PEA) immunoassays] in a deeply-phenotyped mixed memory clinic cohort [n = 502, mean age (standard deviation, SD) = 64.1 (8.7) years, 181 female (35.4%)], including patients with Alzheimer's disease (AD, n = 213), dementia with Lewy bodies (DLB, n = 50) and frontotemporal dementia (FTD, n = 93), and controls (n = 146). Validation was assessed in independent cohorts (n = 99 PEA platform, n = 198, mass reaction monitoring-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P = 1.65 × 10-8), ZCWPW1-PILRB (rs1476679, P = 2.73 × 10-32), CTSH-CTSH (rs3784539, P = 2.88 × 10-24) and HESX1-RETN (rs186108507, P = 8.39 × 10-8), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90 × 10-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for FTD loci, either for the total sample as for analyses performed within FTD only. Protein QTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Type 2 diabetes and glucose metabolism have previously been linked to Alzheimer disease (AD). Yet, findings on the relation of glucose metabolism with amyloid-β and tau pathology later in life remain unclear., Research Design and Methods: We included 288 participants (mean age 43.1 years, SD 10.7, range 20-70 years) without dementia, from the Framingham Heart Study, who had available measures of glucose metabolism (i.e., one-time fasting plasma glucose and insulin) and positron emission tomography (PET) measures of amyloid-β and/or tau 14 years later. We performed linear regression analyses to test associations of plasma glucose (continuously and categorically; elevated defined as >100 mg/dL), plasma insulin, homeostatic model assessment for insulin resistance (HOMA-IR) with amyloid-β or tau load on PET. When significant, we explored whether age, sex, and APOE ε4 allele carriership (AD genetic risk) modified these associations., Results: Our findings indicated that elevated plasma glucose was associated with greater tau load 14 years later (B [95% CI] = 0.03 [0.01-0.05], P = 0.024 after false discovery rate [FDR] correction) but not amyloid-β. APOE ε4 carriership modified this association (B [95% CI] = -0.08 [-0.12 to -0.03], P = 0.001), indicating that the association was only present in APOE ε4 noncarriers (n = 225). Plasma insulin and HOMA-IR were not associated with amyloid-β or tau load 14 years later after FDR correction., Conclusions: Our findings suggest that glucose metabolism is associated with increased future tau but not amyloid-β load. This provides relevant knowledge for prevention strategies and prognostics to improve health care., (© 2024 by the American Diabetes Association.)

Introduction: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration., Methods: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array., Results: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development., Discussion: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain., Highlights: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: To investigate if changes in vessel density (VD) and the foveal avascular zone (FAZ) occur in the preclinical phase of Alzheimer's disease (pAD) over time., Methods: Optical coherence tomography angiography (OCTA) was used to image VD and FAZ at baseline and for a follow-up period of 2 years. Positron emission tomography (PET) was used to determine the amyloid beta (Aβ) status of participants., Results: The VD and FAZ of 148 participants (54% female) were analyzed at baseline and follow-up (mean time between measurements, 2.24 ± 0.35 years). The mean age of the participants was 68.3 ± 6.0 years at baseline and 70.3 ± 5.9 years at follow-up. Participants were divided into three groups: control group, participants who had negative Aβ status at both measurements (Aβ-, n = 116); converter group, participants who transitioned from negative to positive between baseline and follow-up (Aβ-+, n = 18); and participants who were consistently positive at both visits (Aβ++, n = 14). The VD of both Aβ+ groups demonstrated non-significant increases over time in both macula and optic nerve head (ONH) regions. The Aβ- group was found to be significantly higher in both ONH and macular regions. The VD of the Aβ++ group was significantly higher in the macula inner and outer rings compared to the Aβ-+ and Aβ- groups. No significant change was found in FAZ values over time., Conclusions: Alterations in VD seem to manifest already in pAD, exhibiting distinct variations between the ONH and macula. Further longitudinal studies with a longer follow-up design and known amyloid pathology should be undertaken to validate these observations.

Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10 -3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia   = 2.59)., Discussion: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk., Highlights: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: Visual interpretation of brain amyloid-β (Aβ) PET can be difficult in individuals with borderline Aβ burden. Coregistration with individual MRI is recommended in these cases, which, however, is not always available. This study evaluated coregistration with the early perfusion frames acquired immediately after tracer injection to support the visual interpretation of the late Aβ-frames in PET with 18F-flutemetamol (FMM)., Patients and Methods: Fifty dual-time-window FMM-PET scans of cognitively normal subjects with 0 to 60 Centiloids were included retrospectively (70.1 ± 6.9 years, 56% female, MMSE score 28.9 ± 1.3, 42% APOE ɛ4 carrier). Regional Aβ load was scored with respect to a 6-point Likert scale by 3 independent raters in the 10 regions of interest recommended for FMM reading using 3 different settings: Aβ image only, Aβ image coregistered with MRI, and Aβ image coregistered with the perfusion image. The impact of setting, within- and between-readers variability, region of interest, and Aβ-status was tested by repeated-measure analysis of variance of the Likert score., Results: The Centiloid scale ranged between 2 and 52 (interquartile range, 7-19). Support of visual scoring by the perfusion image resulted in the best discrimination between Aβ-positive and Aβ-negative cases, mainly by improved certainty of excluding Aβ plaques in Aβ-negative cases (P = 0.030). It also resulted in significantly higher between-rater agreement. The setting effect was most pronounced in the frontal lobe and in the posterior cingulate cortex/precuneus area (P = 0.005)., Conclusions: The early perfusion image is a suitable alternative to T1-weighted MRI to support the visual interpretation of the late Aβ image in FMM-PET., Competing Interests: Conflicts of interest and sources of funding: L.E.C. received research support from GE Healthcare and Spinger Healthcare (funded by Eli Lilly). Both contributions have been paid to the institution. There is no actual or potential conflict of interest for the other authors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD). There has been a recent emergence in plasma biomarkers for AD pathophysiology, such as amyloid-beta (Aβ) and phosphorylated tau (p-tau), as well as for axonal damage (neurofilament light, NfL) and astrocytic activation (glial fibrillary acidic protein, GFAP). Hypothesizing that depressive symptoms may occur along the AD process, we investigated associations between plasma biomarkers of AD with depressive symptoms in individuals without dementia., Methods: A two-stage meta-analysis was performed on 2 clinic-based and 6 population-based cohorts (N = 7210) as part of the Netherlands Consortium of Dementia Cohorts. Plasma markers (Aβ42/40, p-tau181, NfL, and GFAP) were measured using Single Molecular Array (Simoa; Quanterix) assays. Depressive symptoms were measured with validated questionnaires. We estimated the cross-sectional association of each standardized plasma marker (determinants) with standardized depressive symptoms (outcome) using linear regressions, correcting for age, sex, education, and APOE ε4 allele presence, as well as subgrouping by sex and APOE ε4 allele. Effect estimates were entered into a random-effects meta-analysis., Results: Mean age of participants was 71 years. The prevalence of clinically relevant depressive symptoms ranged from 1% to 22%. None of the plasma markers were associated with depressive symptoms in the meta-analyses. However, NfL was associated with depressive symptoms only in APOE ε4 carriers (β 0.11; 95% CI: 0.05-0.17)., Conclusions: Late-life depressive symptoms did not show an association to plasma biomarkers of AD pathology. However, in APOE ε4 allele carriers, a more profound role of neurodegeneration was suggested with depressive symptoms., Competing Interests: DISCLOSURES No disclosures to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine., Methods: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity., Results: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication., Discussion: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies., Highlights: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's disease (AD) using cerebrospinal fluid (CSF) proteomics., Methods: Individuals without dementia were classified as A+ (CSF amyloid beta [Aβ]42), T+ (CSF phosphorylated tau181), and N+ or N- based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance., Results: Only a few individuals were A+T+Ng-. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng- and A+T+NfL-, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV-, A+T+HCV+ showed few proteomic changes, associated with oxidative stress., Discussion: Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology., Highlights: In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Quorum sensing enables unicellular organisms to probe their population density and perform behavior that exclusively occurs above a critical density. Quorum sensing is established in emulsion droplet swarms that float at a water surface and cluster above a critical density. The design involves competition between 1) a surface tension gradient that is generated upon release of a surfactant from the oil droplets, and thereby drives their mutual repulsion, and 2) the release of a surfactant precursor from the droplets, that forms a strong imine surfactant which suppresses the surface tension gradient and thereby causes droplet clustering upon capillary (Cheerios) attraction. The production of the imine-surfactant depends on the population density of the droplets releasing the precursor so that the clustering only occurs above a critical population density. The pH-dependence of the imine-surfactant formation is exploited to trigger quorum sensing upon a base stimulus: dynamic droplet swarms are generated that cluster and spread upon spatiotemporally varying acid and base conditions. Next, the clustering of two droplet subpopulations is coupled to a chemical reaction that generates a fluorescent signal. It is foreseen that quorum sensing enables control mechanisms in droplet-based systems that display collective responses in contexts of, e.g., sensing, optics, or dynamically controlled droplet-reactors., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans., Methods: We used an APP knock-in mouse model, APP NL-G-F , exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD., Results: ChP tissue proteome was dysregulated in APP NL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways., Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD., (© 2024. The Author(s).)

Background and Objectives: Discordance between CSF and PET biomarkers of β-amyloid (Aβ) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aβ-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aβ, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories., Methods: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aβ 42 and global Aβ-PET to a hyperbolic regression model, deriving a participant-specific Aβ-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aβ and positive values more aggregated relative to soluble Aβ. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aβ-aggregation scores. With linear mixed models, we assessed whether Aβ-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years)., Results: The imbalance model could be fit (pseudo- R 2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aβ-aggregation scores were associated with larger ventricular volume (β = 0.13, p < 0.001), male sex (β = -0.18, p = 0.019), and homozygous APOE -ε4 carriership (β = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (β = 0.17, p < 0.001) and t-tau (β = 0.16, p < 0.001), better baseline executive functioning (β = 0.12, p < 0.001), and slower global cognitive decline (β = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE -ε4, CSF t-tau, and, although modestly, with cognition., Discussion: We propose a novel continuous model of Aβ CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aβ pools in 2 independent cohorts across the full Aβ continuum. Aβ-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.

Objectives: The implementation of disease-modifying treatments for Alzheimer's Disease (AD) will require cost-effective diagnostic processes. As part of The Precision Medicine In AD consortium (PMI-AD) project, the aim is to analyze the baseline costs of diagnosing early AD at memory clinics in Norway, Slovenia, and the Netherlands., Methods: The costs of cognitive testing and a clinical examination, apolipoprotein E, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), positron emission tomography and blood-based biomarkers (BBM), which are used in different combinations in the three countries, were analyzed. Standardized unit costs, adjusted for GDP per capita and based on Swedish conditions were applied. The costs were expressed in euros (€) as of 2019. A diagnostic set comprising clinical examination, cognitive testing, MRI and CSF was defined as the gold standard, with MRI mainly used as an exclusion filter., Results: Cost data were available for 994 persons in Norway, 169 in Slovenia and 1015 in the Netherlands. The mean diagnostic costs were 1478 (95% confidence interval 1433-1523) € in Norway, 851 (731-970) € in Slovenia and 1184 (1135-1232) € in the Netherlands. Norway had the highest unit costs but also the greatest use of tests. With a uniform diagnostic test set applied, the diagnostic costs were 1264 (1238-1291) €, in Norway, 843 (771-914) € in Slovenia and 1184 (1156-1213) € in the Netherlands. There were no major cost differences between the final set of diagnoses., Conclusions: The total costs for setting a diagnosis of AD varied somewhat in the three countries, depending on unit costs and use of tests. These costs are relatively low in comparison to the societal costs of AD., (© 2024 The Author(s). International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objective: The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is well validated and commonly used to assess difficulties in everyday functioning regarding dementia. To facilitate interpretation and clinical implementation across different European countries, we aim to provide normative data and a diagnostic cutoff for dementia., Methods: Cross-sectional data from Dutch Brain Research Registry ( N = 1,064; mean ( M ) age = 62 ± 11 year; 69.5% female), European Medial Information Framework-Alzheimer's Disease 90 + ( N = 63; Mage = 92 ± 2 year; 52.4% female), and European Prevention of Alzheimer's Dementia Longitudinal Cohort Study ( N = 247; Mage = 63 ± 7 year; 72.1% female) were used. The generalized additive models for location, scale, and shape framework were used to obtain normative values ( Z -scores). The beta distribution was applied, and combinations of age, sex, and educational attainment were modeled. The optimal cutoff for dementia was calculated using area under receiver operating curves (AUC-ROC) and Youden Index, using data from Amsterdam Dementia Cohort ( N = 2,511, Mage = 64 ± 8 year, 44.4% female)., Results: The best normative model accounted for a cubic-like decrease of IADL performance with age that was more pronounced in low compared to medium/high educational attainment. The cutoff for dementia was 1.85 standard deviation below the population mean (AUC = 0.97; 95% CI [0.97-0.98])., Conclusion: We provide regression-based norms for A-IADL-Q and a diagnostic cutoff for dementia, which help improve clinical assessment of IADL performance across European countries.

Introduction: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear., Methods: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269)., Results: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10 -5 ) and higher CSF phosphorylated tau (p-tau) levels (P = 9.28 × 10 -7 ). The rs34294852 minor allele was associated with decreased GPX3 (P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity (P = 2.56 × 10 -6 ) and CSF p-tau levels (P = 4.38 × 10 -9 )., Discussion: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels., Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: There is good evidence that elevated amyloid-β (Aβ) positron emission tomography (PET) signal is associated with cognitive decline in clinically normal (CN) individuals. However, it is less well established whether there is an association between the Aβ burden and decline in daily living activities in this population. Moreover, Aβ-PET Centiloids (CL) thresholds that can optimally predict functional decline have not yet been established., Methods: Cross-sectional and longitudinal analyses over a mean three-year timeframe were performed on the European amyloid-PET imaging AMYPAD-PNHS dataset that phenotypes 1260 individuals, including 1032 CN individuals and 228 participants with questionable functional impairment. Amyloid-PET was assessed continuously on the Centiloid (CL) scale and using Aβ groups (CL < 12 = Aβ-, 12 ≤ CL ≤ 50 = Aβ-intermediate/Aβ± , CL > 50 = Aβ+). Functional abilities were longitudinally assessed using the Clinical Dementia Rating (Global-CDR, CDR-SOB) and the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). The Global-CDR was available for the 1260 participants at baseline, while baseline CDR-SOB and A-IADL-Q scores and longitudinal functional data were available for different subsamples that had similar characteristics to those of the entire sample., Results: Participants included 765 Aβ- (61%, Mdn age  = 66.0, IQR age  = 61.0-71.0; 59% women), 301 Aβ± (24%; Mdn age  = 69.0, IQR age  = 64.0-75.0; 53% women) and 194 Aβ+ individuals (15%, Mdn age  = 73.0, IQR age  = 68.0-78.0; 53% women). Cross-sectionally, CL values were associated with CDR outcomes. Longitudinally, baseline CL values predicted prospective changes in the CDR-SOB (b CL*Time  = 0.001/CL/year, 95% CI [0.0005,0.0024], p = .003) and A-IADL-Q (b CL*Time  = -0.010/CL/year, 95% CI [-0.016,-0.004], p = .002) scores in initially CN participants. Increased clinical progression (Global-CDR > 0) was mainly observed in Aβ+ CN individuals (HR Aβ+ vs Aβ-  = 2.55, 95% CI [1.16,5.60], p = .020). Optimal thresholds for predicting decline were found at 41 CL using the CDR-SOB (b Aβ+ vs Aβ-  = 0.137/year, 95% CI [0.069,0.206], p < .001) and 28 CL using the A-IADL-Q (b Aβ+ vs Aβ-  = -0.693/year, 95% CI [-1.179,-0.208], p = .005)., Conclusions: Amyloid-PET quantification supports the identification of CN individuals at risk of functional decline., Trial Registration: The AMYPAD PNHS is registered at www.clinicaltrialsregister.eu with the EudraCT Number: 2018-002277-22., (© 2024. The Author(s).)

The development of biomarkers for Alzheimer disease (AD) has led to the origin of suspected non-AD pathophysiology (SNAP) - a heterogeneous biomarker-based concept that describes individuals with normal amyloid and abnormal tau and/or neurodegeneration biomarker status. In this Review, we describe the origins of the SNAP construct, along with its prevalence, diagnostic and prognostic implications, and underlying neuropathology. As we discuss, SNAP can be operationalized using different biomarker modalities, which could affect prevalence estimates and reported characteristics of SNAP in ways that are not yet fully understood. Moreover, the underlying aetiologies that lead to a SNAP biomarker profile, and whether SNAP is the same in people with and without cognitive impairment, remains unclear. Improved insight into the clinical characteristics and pathophysiology of SNAP is of major importance for research and clinical practice, as well as for trial design to optimize care and treatment of individuals with SNAP., (© 2024. Springer Nature Limited.)

Background: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed., Method: Here, we propose a machine learning-based approach to detect the key metabolites and proteins involved in MCI progression to AD using data from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Study. Proteins and metabolites were evaluated separately in multiclass models (controls, MCI and AD) and together in MCI conversion models (MCI stable vs converter). Only features selected as relevant by 3/4 algorithms proposed were kept for downstream analysis., Results: Multiclass models of metabolites highlighted nine features further validated in an independent cohort (0.726 mean balanced accuracy). Among these features, one metabolite, oleamide, was selected by all the algorithms. Further in-vitro experiments in rodents showed that disease-associated microglia excreted oleamide in vesicles. Multiclass models of proteins stood out with nine features, validated in an independent cohort (0.720 mean balanced accuracy). However, none of the proteins was selected by all the algorithms. Besides, to distinguish between MCI stable and converters, 14 key features were selected (0.872 AUC), including tTau, alpha-synuclein (SNCA), junctophilin-3 (JPH3), properdin (CFP) and peptidase inhibitor 15 (PI15) among others., Conclusions: This omics integration approach highlighted a set of molecules associated with MCI conversion important in neuronal and glia inflammation pathways., Competing Interests: Declaration of competing interest SL is named as an inventor on biomarker intellectual property protected by Proteome Sciences and Kings College London unrelated to the current study and within the past five years has advised for Optum labs, Merck, SomaLogic and been the recipient of funding from AstraZeneca and other companies via the IMI funding scheme. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). AL has served at scientific advisory boards of Fujirebio Europe, Eli Lilly, Novartis, Nutricia and Otsuka and is the inventor of a patent on synaptic markers in CSF (all unrelated to this study). JP has served at scientific advisory boards of Fujirebio Europe, Eli Lilly and Nestle Institute of Health Sciences, all unrelated to this study. SE has received unrestricted research grants from Janssen Pharmaceutica and ADx Neurosciences and has served at scientific advisory boards of Biogen, Eisai, Novartis, Nutricia/Danone, all unrelated to this study. FB is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD, all unrelated to this study. CLQ has received funding related to this study from Pfizer and via the IMI funding scheme, in the past five years has been the recipient of funding from Novo Nordisk, unrelated to this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-β (Aβ) accumulation based on Centiloids (CL) in pre-dementia populations., Methods: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [ 18 F]flutemetamol, [ 18 F]florbetaben or [ 18 F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95 th percentile of longitudinal measurements in sub-populations (N PNHS  = 101/750, N Insight46  = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models., Results: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aβ-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education., Discussion: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Remote monitoring technologies (RMTs) can measure cognitive and functional decline objectively at-home, and offer opportunities to measure passively and continuously, possibly improving sensitivity and reducing participant burden in clinical trials. However, there is skepticism that age and cognitive or functional impairment may render participants unable or unwilling to comply with complex RMT protocols. We therefore assessed the feasibility and usability of a complex RMT protocol in all syndromic stages of Alzheimer's disease and in healthy control participants., Methods: For 8 weeks, participants (N = 229) used two activity trackers, two interactive apps with either daily or weekly cognitive tasks, and optionally a wearable camera. A subset of participants participated in a 4-week sub-study (N = 45) using fixed at-home sensors, a wearable EEG sleep headband and a driving performance device. Feasibility was assessed by evaluating compliance and drop-out rates. Usability was assessed by problem rates (e.g., understanding instructions, discomfort, forgetting to use the RMT or technical problems) as discussed during bi-weekly semi-structured interviews., Results: Most problems were found for the active apps and EEG sleep headband. Problem rates increased and compliance rates decreased with disease severity, but the study remained feasible., Conclusions: This study shows that a highly complex RMT protocol is feasible, even in a mild-to-moderate AD population, encouraging other researchers to use RMTs in their study designs. We recommend evaluating the design of individual devices carefully before finalizing study protocols, considering RMTs which allow for real-time compliance monitoring, and engaging the partners of study participants in the research., Competing Interests: JC is an employee and shareholder of Novartis. AD is supported by the Welcome Trust [223100/Z/21/Z]. Research of Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Biogen, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, and Roche Diagnostics. IK declares support for this work through the National Institute of Health Research (personal award and Oxford Health Biomedical Research Centre) and the Medical Research Council (Dementias Platform UK grant), and is a paid medical advisor for digital healthcare technology companies (Five Lives SAS and Cognetivity Ltd). All other authors declare that there is no conflict of interest., (© The Author(s) 2024.)

Conflicting evidence exists on the relationship between diabetes mellitus (DM) and Alzheimer's disease (AD) biomarkers. Therefore, we conducted a random-effects meta-analysis to evaluate the correlation of glucose metabolism measures (glycated hemoglobin, fasting blood glucose, insulin resistance indices) and DM status with AD biomarkers of amyloid-β and tau measured by positron emission tomography or cerebrospinal fluid. We selected 37 studies from PubMed and Embase, including 11,694 individuals. More impaired glucose metabolism and DM status were associated with higher tau biomarkers (r=0.11[0.03-0.18], p=0.008; I2=68%), but were not associated with amyloid-β biomarkers (r=-0.06[-0.13-0.01], p=0.08; I 2 =81%). Meta-regression revealed that glucose metabolism and DM were specifically associated with tau biomarkers in population settings (p=0.001). Furthermore, more impaired glucose metabolism and DM status were associated with lower amyloid-β biomarkers in memory clinic settings (p=0.004), and in studies with a higher prevalence of dementia (p<0.001) or lower cognitive scores (p=0.04). These findings indicate that DM is associated with biomarkers of tau but not with amyloid-β. This knowledge is valuable for improving dementia and DM diagnostics and treatment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We assessed whether co-morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease., Methods: In 1090 non-demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow-up for cognitive function 3.1 ± 2.4 years)., Results: Thirty-nine percent had neither Aβ nor SVD (A-V-), 21% had SVD only (A-V+), 23% Aβ only (A+V-), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A-V- (reference), A+V- had a faster rate of cognitive decline. Co-morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A-V+ (hazard ratio [95% confidence interval: 1.8 [1.0-3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups., Discussion: In non-demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A-, but did not increase deleterious effects in A+., Highlights: Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality. Small vessel disease (SVD) had no additional deleterious effects in A+. SVD modestly predicted dementia in A-. Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The development of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) has progressed over the last decade, and the first-ever therapies with potential to slow the progression of disease are approved in the United States. AD DMTs could provide life-changing opportunities for people living with this disease, as well as for their caregivers. They could also ease some of the immense societal and economic burden of dementia. However, AD DMTs also come with major challenges due to the large unmet medical need, high prevalence of AD, new costs related to diagnosis, treatment and monitoring, and uncertainty in the therapies' actual clinical value. This perspective article discusses, from the broad perspective of various health systems and stakeholders, how we can overcome these challenges and improve society's readiness for AD DMTs. We propose that innovative payment models such as performance-based payments, in combination with learning healthcare systems, could be the way forward to enable timely patient access to treatments, improve accuracy of cost-effectiveness evaluations and overcome budgetary barriers. Other important considerations include the need for identification of key drivers of patient value, the relevance of different economic perspectives (i.e. healthcare vs. societal) and ethical questions in terms of treatment eligibility criteria., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aβ (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration., Methods and Results: Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume ( b per SD increase=0.16 [95% CI, 0.06-0.26], P =0.015). Higher NfL ( b =-5.63, [95% CI, -8.95 to -2.31], P =0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P =0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P =0.010)., Conclusions: Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer's disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs., Competing Interests: Dr. Zetterberg has served at scientific advisory boards and/or as a consultant for AbbVie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from Amylyx, Alzpath, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens. Dr. Minguillon reported receiving grants from JPND EU-Fingers and from Alzheimer’s Drug Discovery Foundation outside the submitted work. Dr. Middleton reports grants from Janssen, Merck, Takeda, Gates Ventures, Eisai and NIHR, outside the submitted work. Dr Schöll has served on advisory boards for Roche and Novo Nordisk (outside scope of submitted work). Dr. Ferrell has provided consulting services to Gates Ventures, Morningside Technical Advisory, and the ADDF Diagnostics Accelerator, and is a former employee and current shareholder of Eli Lilly and Company. Dr. van der Flier’s research programs have been funded by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences and Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer and Neuropsychiatrie Foundation, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Fujifilm, Eisai, Combinostics. Dr. van der Flier holds the Pasman chair. Dr. van der Flier is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences and Health (PPP-allowance; #LSHM20106). Dr. van der Flier has been an invited speaker at Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, European Brain Council. WF is consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, and Eisai. Dr. van der Flier is member of steering cie of NovoNordisk evoke/evoke+. Dr. van der Flier participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. All funding is paid to her institution. Dr. van der Flier is member of the steering committee of PAVE and Think Brain Health, and was associate editor of Alzheimer, Research and Therapy in 2020/2021, as well as associate editor at Brain. Dr. Krishnan and Dr. Sardi are employees and shareholders of Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187). These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times and anatomical patterns of brain atrophy. These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine., (© 2024. The Author(s).)

Augmented reality (AR) apps, in which the virtual and real world are combined, can recreate instrumental activities of daily living (IADL) and are therefore promising to measure cognition needed for IADL in early Alzheimer's disease (AD) both in the clinic and in the home settings. The primary aim of this study was to distinguish and classify healthy controls (HC) from participants with AD pathology in an early AD stage using an AR app. The secondary aims were to test the association of the app with clinical cognitive and functional tests and investigate the feasibility of at-home testing using AR. We furthermore investigated the test-retest reliability and potential learning effects of the task. The digital score from the AR app could significantly distinguish HC from preclinical AD (preAD) and prodromal AD (proAD), and preAD from proAD, both with in-clinic and at-home tests. For the classification of the proAD group, the digital score (AUC clinic&#95;visit  = 0.84 [0.75-0.93], AUC at&#95;home  = 0.77 [0.61-0.93]) was as good as the cognitive score (AUC = 0.85 [0.78-0.93]), while for classifying the preAD group, the digital score (AUC clinic&#95;visit  = 0.66 [0.53-0.78], AUC at&#95;home  = 0.76 [0.61-0.91]) was superior to the cognitive score (AUC = 0.55 [0.42-0.68]). In-clinic and at-home tests moderately correlated (rho = 0.57, p < 0.001). The digital score was associated with the clinical cognitive score (rho = 0.56, p < 0.001). No learning effects were found. Here we report the AR app distinguishes HC from otherwise healthy Aβ-positive individuals, both in the outpatient setting and at home, which is currently not possible with standard cognitive tests., (© 2023. The Author(s).)

Background: Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles., Methods: We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n = 535) and follow-up (n = 213), between 1 and 6 years from baseline (mean 2.8 years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group., Results: Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p < 0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p < 0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p < 0.001) and MCP-1 (p < 0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p < 0.01)., Conclusions: Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns., (© 2023. The Author(s).)

Background: Alzheimer's disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline., Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population., Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ 42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions., Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ - 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions., Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications., Competing Interests: The authors declare that they have no conflict of interest., (© 2023 – The authors. Published by IOS Press.)

Background: Prior studies suggest a changing association between blood pressure (BP) and cognition with aging, however work in the oldest-old has yielded ambiguous results. Potentially, these mixed results can be explained by modifying factors. The aim of this study was to establish whether physical, vascular or brain pathology markers that describe a state of increased vulnerability, affect the association between BP and cognition in the oldest-old. Results may influence clinicians' decisions regarding the use of antihypertensives in this age group., Methods: We included 122 individuals (84 without cognitive impairment and 38 with cognitive impairment) from the EMIF-AD 90 + Study (mean age 92.4 years). First, we tested cross-sectional associations of systolic and diastolic BP with a cognitive composite score. Second, we tested whether these associations were modified by physical markers (waist circumference, muscle mass, gait speed and handgrip strength), vascular markers (history of cardiac disease, carotid intima media thickness as a proxy for atherosclerosis and carotid distensibility coefficient as a proxy for arterial stiffness) or brain pathology markers (white matter hyperintensities and cortical thickness)., Results: In the total sample, there was no association between BP and cognition, however, waist circumference modified this association (p-value for interaction with systolic BP: 0.03, with diastolic BP: 0.01). In individuals with a high waist circumference, higher systolic and diastolic BP tended to be associated with worse cognition, while in individuals with a low waist circumference, higher systolic BP was associated with better cognition. The others physical, vascular and brain pathology markers did not modify the association between BP and cognition., Conclusions: When examining various markers for physical, vascular and brain vulnerability, only waist circumference affected the association between BP and cognition. This warrants further research to evaluate whether waist circumference may be a marker in clinical practice influencing the use of antihypertensives in the oldest-old., (© 2023. The Author(s).)

Background and Objectives: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [ 18 F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables., Methods: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE)., Results: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = -0.52, CI -0.74 to -0.30, p < 0.001) and participants with AD (β = -0.30, CI -0.58 to -0.02, p = 0.04)., Discussion: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population., Classification of Evidence: This study provides Class II evidence that [ 18 F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer's disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies., Methods: Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests., Results: 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β =  - 0.22, OR = 0.80, p < .05), more prior study visits (β =  - 0.93, OR = 0.40, p < .001), and positive family history of dementia (β = 2.08, OR = 8.02, p < .01) resulted in lower odds on study refusal. General study burden was the main enrollment barrier (36.1%), followed by amyloid-PET related burden (PC research  = 27.4%, PC clinical  = 9.0%, X 2  = 10.56, p = .001), and loss of research interest (PC clinical  = 46.3%, PC research  = 16.5%, X 2  = 32.34, p < .001)., Conclusions: The enrollment rate for the AMYPAD-PNHS was relatively high, suggesting an advantage of recruitment via ongoing studies. In this observational cohort, study burden reduction and tailored strategies may potentially improve participant enrollment into trial readiness cohorts such as for phase-3 early anti-amyloid intervention trials. The AMYPAD-PNHS (EudraCT: 2018-002277-22) was approved by the ethical review board of the VU Medical Center (VUmc) as the Sponsor site and in every affiliated site., (© 2023. The Author(s).)

Background: Image harmonization has been proposed to minimize heterogeneity in brain PET scans acquired in multi-center studies. However, standard validated methods and software tools are lacking. Here, we assessed the performance of a framework for the harmonization of brain PET scans in a multi-center European clinical trial., Method: Hoffman 3D brain phantoms were acquired in 28 PET systems and reconstructed using site-specific settings. Full Width at Half Maximum (FWHM) of the Effective Image Resolution (EIR) and harmonization kernels were estimated for each scan. The target EIR was selected as the coarsest EIR in the imaging network. Using "Hoffman 3D brain Analysis tool," indicators of image quality were calculated before and after the harmonization: The Coefficient of Variance (COV%), Gray Matter Recovery Coefficient (GMRC), Contrast, Cold-Spot RC, and left-to-right GMRC ratio. A COV% ≤ 15% and Contrast ≥ 2.2 were set as acceptance criteria. The procedure was repeated to achieve a 6-mm target EIR in a subset of scans. The method's robustness against typical dose-calibrator-based errors was assessed., Results: The EIR across systems ranged from 3.3 to 8.1 mm, and an EIR of 8 mm was selected as the target resolution. After harmonization, all scans met acceptable image quality criteria, while only 13 (39.4%) did before. The harmonization procedure resulted in lower inter-system variability indicators: Mean ± SD COV% (from 16.97 ± 6.03 to 7.86 ± 1.47%), GMRC Inter-Quartile Range (0.040-0.012), and Contrast SD (0.14-0.05). Similar results were obtained with a 6-mm FWHM target EIR. Errors of ± 10% in the DRO activity resulted in differences below 1 mm in the estimated EIR., Conclusion: Harmonizing the EIR of brain PET scans significantly reduced image quality variability while minimally affecting quantitative accuracy. This method can be used prospectively for harmonizing scans to target sharper resolutions and is robust against dose-calibrator errors. Comparable image quality is attainable in brain PET multi-center studies while maintaining quantitative accuracy., (© 2023. The Author(s).)

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences., Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects., Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers., Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aging-related cognitive decline can be accelerated by a combination of genetic factors, cardiovascular and cerebrovascular dysfunction, and amyloid-β burden. Whereas cerebral blood flow (CBF) has been studied as a potential early biomarker of cognitive decline, its normal variability in healthy elderly is less known. In this study, we investigated the contribution of genetic, vascular, and amyloid-β components of CBF in a cognitively unimpaired (CU) population of monozygotic older twins. We included 134 participants who underwent arterial spin labeling (ASL) MRI and [ 18 F]flutemetamol amyloid-PET imaging at baseline and after a four-year follow-up. Generalized estimating equations were used to investigate the associations of amyloid burden and white matter hyperintensities with CBF. We showed that, in CU individuals, CBF: 1) has a genetic component, as within-pair similarities in CBF values were moderate and significant (ICC > 0.40); 2) is negatively associated with cerebrovascular damage; and 3) is positively associated with the interaction between cardiovascular risk scores and early amyloid-β burden, which may reflect a vascular compensatory response of CBF to early amyloid-β accumulation. These findings encourage future studies to account for multiple interactions with CBF in disease trajectory analyses., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BP, LL, DVG, EC, SI, JT, QD, MS, EJCdG, EvG, MK, JP, AdB, and HM have no conflicts of interest related to the current work. LEC has received research support from GE Healthcare (paid to the institution). PV has served as a member of the advisory board of Roche Diagnostics and received non-financial support from GE Healthcare, and research support from Biogen. FB receives payment and honoraria from Bayer Genzyme, Biogen-Idec, TEVA, Merck, Novartis, Roche, IXICO Ltd, GeNeuro, and Apitope Ltd for consulting; payment from the IXICOLtd, and MedScape for educational presentations.

Genomic studies of molecular traits have provided mechanistic insights into complex disease, though these lag behind for brain-related traits due to the inaccessibility of brain tissue. We leveraged cerebrospinal fluid (CSF) to study neurobiological mechanisms in vivo , measuring 5,543 CSF metabolites, the largest panel in CSF to date, in 977 individuals of European ancestry. Individuals originated from two separate cohorts including cognitively healthy subjects (n=490) and a well-characterized memory clinic sample, the Amsterdam Dementia Cohort (ADC, n=487). We performed metabolite quantitative trait loci (mQTL) mapping on CSF metabolomics and found 126 significant mQTLs, representing 65 unique CSF metabolites across 51 independent loci. To better understand the role of CSF mQTLs in brain-related disorders, we performed a metabolome-wide association study (MWAS), identifying 40 associations between CSF metabolites and brain traits. Similarly, over 90% of significant mQTLs demonstrated colocalized associations with brain-specific gene expression, unveiling potential neurobiological pathways.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = -0.37, P = 0.03) and memory functioning (β = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Alzheimer's disease (AD) is the most common cause of dementia, and due to increasing life expectancy the number of patients is expected to grow. The diagnosis of AD involves the use of biomarkers determined by an amyloid PET scan or cerebrospinal fluid analyses that are either invasive or expensive, and not available in each hospital, thus limiting their usage as a front-line screener. The TearAD study aims to use tear fluid as a potential source for AD biomarkers. In previous reports, we demonstrated that AD biomarkers amyloid-beta and tau, are measurable in tear fluid and are associated with disease severity and neurodegeration. This study aims to validate previous results in a larger cohort and evaluate the diagnostic accuracy of tear biomarkers to discriminate between individuals with and without neurodegeneration as determined by hippocampal atrophy., Methods: The TearAD study is an observational longitudinal multi-center study that will enroll 50 cognitively healthy controls, 50 patients with subjective cognitive decline, 50 patients with mild cognitive impairment and 50 patients with AD dementia from the memory clinic. Participants will be examined at baseline, after one year, and after two years follow-up. Study assessments include neuropsychological tests and ophthalmic examination. All participants will receive a MRI scan, and a subset of the study population will undergo cerebral spinal fluid collection and an amyloid PET scan. Tear fluid will be collected with Schirmer strips and levels of Aβ38, Aβ40, Aβ42, t-tau and p-tau in tear fluid will be determined using multiplex immunoassays. Blood samples will be collected from all participants. Images of the retina will be obtained with a standard, hyperspectral and ultra-wide field fundus camera. Additionally, macular pigment optical density will be measured with the macular pigment reflectometer, and cross-sectional images of the retina will be obtained through optical coherence tomography imaging., Discussion: The TearAD study will provide insight into the potential diagnostic use of tear biomarkers as a minimally invasive and low cost tool for the screening and diagnosis of AD., Trial Registration: Retrospectively registered at clinicaltrials.gov (NCT05655793)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD., Methods: Using the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR)., Results: AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform., Discussion: This study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Cerebrospinal fluid (CSF) biomarkers for specific cellular disease processes are lacking for tauopathies. In this translational study we aimed to identify CSF biomarkers reflecting early tau pathology-associated unfolded protein response (UPR) activation., Methods: We employed mass spectrometry proteomics and targeted immunoanalysis in a combination of biomarker discovery in primary mouse neurons in vitro and validation in patient CSF from two independent large multicentre cohorts (EMIF-AD MBD, n = 310; PRIDE, n = 771)., Results: First, we identify members of the protein disulfide isomerase (PDI) family in the neuronal UPR-activated secretome and validate secretion upon tau aggregation in vitro. Next, we demonstrate that PDIA1 and PDIA3 levels correlate with total- and phosphorylated-tau levels in CSF. PDIA1 levels are increased in CSF from AD patients compared to controls and patients with tau-unrelated frontotemporal and Lewy body dementia (LBD)., Highlights: Neuronal unfolded protein response (UPR) activation induces the secretion of protein disulfide isomerases (PDIs) in vitro. PDIA1 is secreted upon tau aggregation in neurons in vitro. PDIA1 and PDIA3 levels correlate with total and phosphorylated tau levels in CSF. PDIA1 levels are increased in CSF from Alzheimer's disease (AD) patients compared to controls. PDIA1 levels are not increased in CSF from tau-unrelated frontotemporal dementia (FTD) and Lewy body dementia (LBD) patients., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Efficient data sharing is hampered by an array of organizational, ethical, behavioral, and technical challenges, slowing research progress and reducing the utility of data generated by clinical research studies on neurodegenerative diseases. There is a particular need to address differences between public and private sector environments for research and data sharing, which have varying standards, expectations, motivations, and interests. The Neuronet data sharing Working Group was set up to understand the existing barriers to data sharing in public-private partnership projects, and to provide guidance to overcome these barriers, by convening data sharing experts from diverse projects in the IMI neurodegeneration portfolio. In this policy and practice review, we outline the challenges and learnings of the WG, providing the neurodegeneration community with examples of good practices and recommendations on how to overcome obstacles to data sharing. These obstacles span organizational issues linked to the unique structure of cross-sectoral, collaborative research initiatives, to technical issues that affect the storage, structure and annotations of individual datasets. We also identify sociotechnical hurdles, such as academic recognition and reward systems that disincentivise data sharing, and legal challenges linked to heightened perceptions of data privacy risk, compounded by a lack of clear guidance on GDPR compliance mechanisms for public-private research. Focusing on real-world, neuroimaging and digital biomarker data, we highlight particular challenges and learnings for data sharing, such as data management planning, development of ethical codes of conduct, and harmonization of protocols and curation processes. Cross-cutting solutions and enablers include the principles of transparency, standardization and co-design - from open, accessible metadata catalogs that enhance findability of data, to measures that increase visibility and trust in data reuse., Competing Interests: NH is an employee of Janssen Pharmaceutica NV and owns stock in Johnson & Johnson, but no product-related aspects. LS is an employee of Janssen Pharmaceutica NV. RB was employed by Aridhia Informatics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bradshaw, Hughes, Vallez-Garcia, Chokoshvili, Owens, Hansen, Emmert, Maetzler, Killin, Barnes, Brookes, Visser, Hofmann-Apitius, Diaz and Steukers.)