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BackgroundThe Apolipoprotein E ε4 allele (i.e. ApoE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). TREM2 (i.e. Triggering receptor expressed on myeloid cells 2) is a microglial transmembrane protein brain that plays a central role in microglia activation in response to AD brain pathologies. Whether higher TREM2-related microglia activity modulates the risk to develop clinical AD is an open question. Thus, the aim of the current study was to assess whether higher sTREM2 attenuates the effects of ApoE4-effects on future cognitive decline and neurodegeneration.MethodsWe included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer's disease Neuroimaging Initiative. We used linear regression to test the interaction between ApoE4-carriage by CSF-assessed sTREM2 levels as a predictor of longitudinally assessed cognitive decline and MRI-assessed changes in hippocampal volume changes (mean follow-up of 4 years, range of 1.7-7 years).ResultsAcross the entire sample, we found that higher CSF sTREM2 at baseline was associated with attenuated effects of ApoE4-carriage (i.e. sTREM2 x ApoE4 interaction) on longitudinal global cognitive (p = 0.001, Cohen's f2 = 0.137) and memory decline (p = 0.006, Cohen's f2 = 0.104) as well as longitudinally assessed hippocampal atrophy (p = 0.046, Cohen's f2 = 0.089), independent of CSF markers of primary AD pathology (i.e. Aβ1-42, p-tau181). While overall effects of sTREM2 were small, exploratory subanalyses stratified by diagnostic groups showed that beneficial effects of sTREM2 were pronounced in the MCI group.ConclusionOur results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate Alzheimer's disease from other neurodegenerative diseases and controls was investigated using receiver operating characteristic analyses. The p-tau217 levels measured by the two techniques demonstrated a strong correlation, showing a consistent relationship with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating Alzheimer's disease from other neurodegenerative diseases [area under the curve (AUC) 0.952, 95% confidence interval (CI) 0.927-0.978 versus 0.955, 95% CI 0.928-0.982, respectively] and healthy controls (AUC 0.938, 95% CI 0.910-0.966 and 0.937, 95% CI 0.907-0.967 for both assays). This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using fully automated or semi-automated techniques., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau 181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau 181 . To determine effects of microglial activation on p-tau 181 , we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau 181 levels. Higher sTREM2 was associated with elevated p-tau 181 , with stronger associations in women. Similarly, ApoE4 was related to higher p-tau 181 levels and faster p-tau 181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women., Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests., (© 2025. The Author(s).)

Background: Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet., Methods: Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ 42 , Aβ 40 , p-tau 181 , p-tau 217, p-tau 231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated., Results: Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ 42/40  + compared with Aβ 42/40  - . Furthermore, Aβ 42/40  - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ 42/40  + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ 42/40  + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time., Conclusions: Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts., Competing Interests: Declarations. Ethics approval and consent to participate: The ALFA + study (ALFA-FPM-0311) was approved by the Independent Ethics Committee “Parc de Salut Mar,” Barcelona, and registered at Clinicaltrials.gov (identifier: NCT02485730) on June 10, 2015. All participants signed the informed consent form that had also been approved by the Independent Ethics Committee “Parc de Salut Mar,” Barcelona. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments and comparable ethical standards. Consent for publication: NA. Competing interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, 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). G.K. is a full‑time employee of Roche Diagnostics GmbH. C.Q.-R. is a full‑time employee of Roche Diagnostics International Ltd. O.G-R. has given lectures in symposia sponsored by Roche Diagnostics, and receives support for research (to the institution) from F- Hoffmann La Roche. M.S.-C. has given lectures in symposia sponsored by Roche Diagnostics, S.L.U, Roche Farma, S.A and Amirall. He has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L. He was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). He received in-kind support for research (to the institution) from Roche Diagnostics International Ltd, Avid Radiopharmaceuticals, Inc., Eli Lilly and Janssen Research & Development., (© 2024. The Author(s).)

CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E ( APOE )-ɛ4 allele, in a priori defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and APOE -ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials., Competing Interests: H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Passage Bio, Pinteon Therapeutics, Red Abbey Labs, reMYND, 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). K.B. has served as a consultant, at advisory boards or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics and Siemens Healthineers and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. M.S.-C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A. M.S.-C. was granted with the project ‘Sex and gender role in pre-clinical Alzheimer’s disease: from pathophysiology to clinical trials inclusion’, funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

β-blockers that easily cross the blood-brain barrier (BBB) seem to diminish the risk of Alzheimer's disease (AD), hypothetically facilitating waste clearance. However, their effect on AD pathophysiological markers is unknown. We compared cerebrospinal fluid (CSF) AD biomarker levels among non-demented individuals taking low, intermediate, or high BBB permeable β-blockers in two samples (ADNI: n  = 216; EPAD: n  = 79). We found that CSF amyloid-β levels were higher in individuals taking highly permeable β-blockers in the ADNI sample. This result was not replicated in EPAD, in which diminished levels of pTau181 and tTau were observed. These data suggest that β-blockers may impact AD pathophysiology., 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 Gonzalo Sánchez-Benavides worked as a consultant for Roche Farma, S.A. Marc Suárez-Calvet has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and has given lectures in symposia sponsored by Roche Diagnostics, S.L.U, Roche Farma, S.A and Roche Sistemas de Diagnosticos, Sociedade Unipessoal, Lda.Gonzalo Sánchez-Benavides is Editorial Board Member of this journal but was not involved in the peer-review process nor had access to any information regarding its peer-review. All other authors have no conflict of interest to report.

Recently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing., Competing Interests: Competing interests J.T. has served as a consultant for the Neurotorium educational platform, outside of the scope of the submitted work. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, 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, which is a part of the GU Ventures Incubator Program (outside submitted work). O.H. 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 AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.C.P. has consulted for Roche, Genentech, Eli Lilly, Eisai and Nestle, all outside the scope of the current work. M.S.-C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L.; has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A.; and was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). A.P.P. has served at advisory boards for Schwabe Farma Iberica. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). S. Johnson has served at scientific advisory boards or as a consultant for ALZpath, Prothena, Roche Diagnostics, and Enigma. M.M.M. has served as a consultant and at advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers. P.R.-N. has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. A.A.-S. has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics and Siemens Healthineers. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: While numerous studies have identified blood proteins that modulate brain aging in mice, the direct translation of these findings to human health remains a substantial challenge. Bridging this gap is critical for developing interventions that can effectively target human brain aging and associated diseases., Methods: We first identified 12 proteins with aging or rejuvenating properties in murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we developed polygenic scores to predict plasma protein levels, which we then validated in two independent human cohorts. We employed association models to explore the association between these genetically predicted protein levels and cognitive performance, focusing specifically on their interaction with key genetic markers such as sex, APOE- ε4 and Aβ42 status., Results: Predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans, also when the models were stratified by sex, APOE- ε4, and Aβ42 status., Conclusions: This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans., Competing Interests: Conflicts of interest CC has received research support from: GSK and EISAI. CC is a member of the scientific advisory board of Circular Genomics and owns stocks. CC is a member of the scientific advisory board of ADmit. MS-C has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics, and Roche Farma; received consultancy fees (paid to the institution) from Roche Diagnostics; and served on advisory boards of Roche Diagnostics and Grifols. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, and Roche Diagnostics. The remaining co-authors have no conflicts to disclose.

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.)

Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ 42/40 , p-tau 181 , sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [ 18 F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, using False Discovery Rate to correct for multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau 181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials., (© 2024. The Author(s).)

Competing Interests: MS-C has received speaker fees (paid to the institution) from by Almirall, Eli Lilly, Novo Nordisk, and Roche Diagnostics in the past 36 months. He has received consultancy fees (paid to the institution) from Roche Diagnostics; and served on advisory boards of Eli Lilly, Grifols and Roche Diagnostics. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, ALZPath, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, Meso Scale Discovery, and Roche Diagnostics; MS-C did not receive any personal compensation from these organizations or any other for-profit organization.

Introduction: We examined whether baseline glial markers soluble triggering receptor expressed on myeloid cell 2 (sTREM2), chitinase 3-like protein 1 (YKL-40), and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF), and plasma GFAP are associated with cognitive change in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD)., Methods: A total of 353 CU (mean age 60.9 years) participants were included (mean follow-up time 3.28 years). Linear regression models with cognition as outcome were used. We also tested whether amyloid beta (Aβ) status modified these associations., Results: Higher baseline CSF sTREM2 was associated with a positive global cognition (Preclinical Alzheimer's Cognitive Composite) rate of change, and better memory and executive outcomes, independently of AD pathology. Higher baseline plasma GFAP was associated with a decline on attention rate of change. Stratified analyses by Aβ status showed that CSF sTREM2 and YKL-40 were positively associated with executive functioning in amyloid negative (Aβ-) individuals., Discussion: Our results suggest that a TREM2-mediated microglial response may be associated with better longitudinal cognitive performance., Highlights: Higher cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cell 2 (sTREM2) relates to better longitudinal cognitive performance. The association between CSF sTREM2 and cognition is independent of Alzheimer's disease (AD) pathology. Targeting microglial reactivity may be a therapeutic strategy for AD prevention., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time-encoded arterial spin labeling (te-ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals., Methods: We compared te-ASL with single-postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aβ) negative (-), CU Aβ positive (+), and CI Aβ+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants., Results: te-ASL was more sensitive at detecting CBF reduction in the CU Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, tau, synaptic dysfunction, and neurodegeneration., Discussion: CBF reduction occurs early in the AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF changes in AD., Highlights: Lower CBF can be detected in CU subjects in the early AD continuum. te-ASL is more sensitive than single-PLD ASL at detecting CBF alterations in AD. CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Sleep disturbances are prevalent in Alzheimer's disease (AD), affecting individuals during its early stages. We investigated associations between subjective sleep measures and cerebrospinal fluid (CSF) biomarkers of AD in adults with mild cognitive symptoms from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study, considering the influence of memory performance. A total of 442 participants aged >50 years with a Clinical Dementia Rating (CDR) score of 0.5 completed the Pittsburgh Sleep Quality Index questionnaire and underwent neuropsychological assessment, magnetic resonance imaging acquisition, and CSF sampling. We analysed the relationship of sleep quality with CSF AD biomarkers and cognitive performance in separated multivariate linear regression models, adjusting for covariates. Poorer cross-sectional sleep quality was associated with lower CSF levels of phosphorylated tau and total tau alongside better immediate and delayed memory performance. After adjustment for delayed memory scores, associations between CSF biomarkers and sleep quality became non-significant, and further analysis revealed that memory performance mediated this relationship. In post hoc analyses, poorer subjective sleep quality was associated with lesser hippocampal atrophy, with memory performance also mediating this association. In conclusion, worse subjective sleep quality is associated with less altered AD biomarkers in adults with mild cognitive symptoms (CDR score 0.5). These results could be explained by a systematic recall bias affecting subjective sleep assessment in individuals with incipient memory impairment. Caution should therefore be exercised when interpreting subjective sleep quality measures in memory-impaired populations, emphasising the importance of complementing subjective measures with objective assessments., (© 2023 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Introduction: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake., Methods: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)., Results: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants., Discussion: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia., Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD., Competing Interests: MSC has given lectures in symposia sponsored by Roche Diagnostics, S.L.U. Roche Farma, S.A., and Amirall;and he has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L. He was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). He received in‐kind support for research (to the institution) from Roche Diagnostics International Ltd, Avid Radiopharmaceuticals, Inc., Eli Lilly, and Janssen Research & Development. JLM is currently a full‑time employee of H. Lundbeck A/S and previously served as a consultant or on advisory boards for the following for‑profit companies or has given lectures in symposia sponsored by the following for‑profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, and ProMIS Neurosciences. JDG receives research funding from Roche Diagnostics and GE Healthcare and has given lectures at symposia sponsored by Biogen and Philips. AS‐V has received research grant funding through his institution and support to attend professional meetings from the California Walnut Commission. Other authors report no conflicts of interest. Disclosures are available in the supporting information., (© 2024 The Author(s). Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments., (© 2024. Springer Nature Limited.)

Competing Interests: CR is CEO and founder of Scottish Brain Sciences and has been a paid consultant on advisory boards for Actinogen, Biogen, CogState, Eisai, Eli Lilly, Janssen Cilag, Merck, Novo Nordisk, Roche Diagnostics, and Signant Health. KB has served as a consultant at advisory boards or data monitoring committees for Acumen, Alzpath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions (BBS) in Gothenburg AB, which is part of the GU Ventures Incubator Program, outside of the present work. JDG has received research support from GE Healthcare, F. Hoffmann-La Roche, and Roche Diagnostics, and speaker or consultant fees from Biogen, Philips Nederlands, and Roche Diagnostics. SJ has served as a consultant for Alzpath, Merck, and Roche Diagnostics, and has also received equipment grants from Roche Diagnostics. IvM has served as a consultant for Roche Diagnostics, received grants from ZonMW, and received PPP allowance from Health~Holland (Top Sector Life Sciences & Health). LV has served as a consultant for Roche Diagnostics and has received research support from Alzheimer Nederland, OLINK, and ZonMw; all payments were made to her institution. MS-C has served as a consultant and attended advisory boards for, and received project grants from, Roche Diagnostics, and has given lectures in symposia sponsored by Roche Diagnostics, S.L.U., Roche Farma, S.A., and Roche Sistemas de Diagnósticos, Sociedade Unipessoal, Lda; all payments for consultancy, advisory boards, and project grants were made to his institution; payments for giving lectures in symposia were made to MS-C directly and his institution. CPM and MHSC are employees of Gates Ventures LLC and volunteer for the Alzheimer's Disease Data Initiative. CAL is an employee and shareholder of Roche Diagnostics GmbH. F-CQ is a former employee and shareholder (during employment) of Roche Diagnostics International Ltd, and Altoida Inc. MCD and MC are employees and shareholders of Roche Diagnostics International Ltd. AA, ER, and OC are employees of Nagarro. The authors declare that this work received funding from Roche Diagnostics International Ltd. The funder had the following involvement: provided support and resources for the Hackathon event; and funded medical writing support for publication of this article.

Objective: Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD., Methods: This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau 181 and Aβ 1-42 / 1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods., Results: Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau 181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aβ 1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively., Interpretation: We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068., (© 2024 Barcelonabeta Brain Research Center and The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: The lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer's disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer's continuum., Methods: We analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner's report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis., Results: CSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner's SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance., Discussion: These results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed., Competing Interests: GS-B worked as a consultant for Roche Farma, S.A. MS-C has given lectures in symposia sponsored by Almirall, Eli Lilly, Novo Nordisk, Roche Diagnostics, and Roche Farma; received consultancy fees (paid to the institution) from Roche Diagnostics; and served on advisory boards of Roche Diagnostics and Grifols. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, and Roche Diagnostics. JDG has received research support from GE HealthCare, Roche Diagnostics, Hoffman – La Roche, spearer/consultant fees from Biogen, Philips Nederlands, Roche Diagnostics and Life-Molecular Imaging, and serves in the Molecular Neuroimaging Advisory Board of Prothena Biosciences. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, 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). KB has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this manuscript. OG-R receives research funding from Roche Pharma. GK was a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. CQ-R was a full-time employee of Roche Diagnostics International Ltd, Rotkreuz, Switzerland. The rest of coauthors have nothing to disclose. COBAS and ELECSYS are trademarks of Roche. The NeuroToolKit is a panel of exploratory prototype assays designed to robustly evaluate biomarkers associated with key pathologic events characteristic of AD and other neurological disorders, used for research purposes only and not approved for clinical use (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Elecsys Phospho-Tau (181P) CSF and Elecsys Total-Tau CSF assays are approved for clinical use. All other product names and trademarks are the property of their respective owners. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 López-Martos, Suárez-Calvet, Milà-Alomà, Gispert, Minguillon, Quijano-Rubio, Kollmorgen, Zetterberg, Blennow, Grau-Rivera and Sánchez-Benavides.)

Background: Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease (AD). No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and SIMOA ALZpath p-tau217., Aim: To evaluate the diagnostic accuracy of Lumipulse and SIMOA plasma p-tau217 assays for AD., Methods: The study included 392 participants, 162 with AD, 70 with other neurodegenerative diseases (NDD) with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate AD from NDD and controls was investigated using ROC analyses., Results: Both techniques showed high internal consistency of p-tau217 with similar correlation with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating AD from NDD (area under the curve [AUC] 0.952, 95%CI 0.927-0.978 vs 0.955, 95%CI 0.928-0.982, respectively) and HC (AUC 0.938, 95%CI 0.910-0.966 and 0.937, 95% CI0.907-0.967 for both assays)., Conclusions: This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using either fully automated or semi-automated techniques.

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Abnormal deposition of Aβ amyloid is an early neuropathological marker of Alzheimer's disease (AD), arising long ahead of clinical symptoms. Non-invasive measures of associated early neurofunctional changes, together with easily accessible behavioral readouts of these changes, could be of great clinical benefit. We pursued this aim by investigating large-scale cortical gradients of functional connectivity with functional MRI, which capture the hierarchical integration of cortical functions, together with acoustic-prosodic features from spontaneous speech, in cognitively unimpaired older adults with and without Aβ positivity (total N = 188). We predicted distortions of the cortical hierarchy associated with prosodic changes in the Aβ + group. Results confirmed substantially altered cortical hierarchies and less variability in these in the Aβ + group, together with an increase in quantitative prosodic measures, which correlated with gradient variability as well as digit span test scores. Overall, these findings confirm that long before the clinical stage and objective cognitive impairment, increased risk of cognitive decline as indexed by Aβ accumulation is marked by neurofunctional changes in the cortical hierarchy, which are related to automatically extractable speech patterns and alterations in working memory functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies., (© 2024. The Author(s).)

Background: Neuroimaging-based brain-age delta has been shown to be a mediator linking cardiovascular risk factors to cognitive function. We aimed to assess the mediating role of brain-age delta in the association between modifiable risk factors of dementia and longitudinal cognitive decline in middle-aged and older individuals who are asymptomatic, stratified by Alzheimer's disease pathology. We also explored whether the mediation effect is specific to cognitive domain., Methods: In this cohort study, we included participants from the ALFA+ cohort aged between 45 years and 65 years who were cognitively unimpaired and who had available structural MRI, cerebrospinal fluid β-amyloid (Aβ)42 and Aβ40 measurements obtained within 1 year of each other, modifiable risk factors assessment, and cognitive evaluation over 3 years. Participants were recruited from the Barcelonaβeta Brain Research Center (Barcelona, Spain). Included individuals underwent a first assessment between Oct 25, 2016, and Jan 28, 2020, and a follow-up cognitive assessment 3·28 (SD 0·27) years later. We computed brain-age delta and composites of different cognitive function domains (preclinical Alzheimer's cognitive composite [PACC], attention, executive function, episodic memory, visual processing, and language). We used partial least squares path modelling to explore mediation effects in the associations between modifiable risk factors (including cardiovascular, mental health, mood, metabolic or endocrine history, and alcohol use) and changes in cognitive composites. To assess the role of Alzheimer's disease pathology, we computed separate models for Aβ-negative and Aβ-positive individuals., Findings: Of the 419 participants enrolled in ALFA+, 302 met our inclusion criteria, of which 108 participants were classified as Aβ-positive and 194 as Aβ-negative. In Aβ-positive individuals, brain-age delta partially mediated (percent mediation proportion 15·73% [95% CI 14·22-16·66]) the association between modifiable risk factors and decline in overall cognition (across cognitive domains). Brain-age delta fully mediated (mediation proportion 28·03% [26·25-29·21]) the effect of modifiable risk factors on the PACC, wherein increased values for risk factors correlated with an older brain-age delta, and, consequently, an older brain-age delta was linked to greater PACC decline. This effect appears to be primarily driven by memory decline. Mediation was not significant in Aβ-negative individuals (3·52% [0·072-4·17]) on PACC, although path coefficients were not significantly different from those in the Aβ-positive group., Interpretation: Our findings suggest that brain-age delta captures the association between modifiable risk factors and longitudinal cognitive decline in middle-aged and older people. In asymptomatic middle-aged and older individuals who are Aβ-positive, the pathology might be the strongest driver of cognitive decline, whereas the effect of risk factors is smaller. Our results highlight the potential of brain-age delta as an objective outcome measure for preventive lifestyle interventions targeting cognitive decline., Funding: La Caixa Foundation, the TriBEKa Imaging Platform, and the Universities and Research Secretariat of the Catalan Government., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests MS-C has served as a consultant and at advisory boards for Roche Diagnostics International and Grifols; has given lectures in symposia sponsored by Roche Diagnostics and Roche Farma; and was granted with a project funded by Roche Diagnostics International. JLM is currently a full-time employee of H Lundbeck and previously has served as a consultant for, served on advisory boards for, or has given lectures in symposia sponsored by Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, Merck & Co, Eisai, Alector, BioCross, GE Healthcare, and ProMIS Neurosciences. JDG receives research funding from Roche Diagnostics and GE Healthcare and has given lectures in symposia sponsored by Biogen and Philips. GS-B has served as a consultant for Roche Farma. OG-R receives research funding from F Hoffmann-La Roche and has given lectures in symposia sponsored by Roche Diagnostics. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions., Methods: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI)., Results: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD., Discussion: It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Existing blood-based biomarkers for Alzheimer's disease (AD) mainly focus on its pathological features. However, studies on blood-based biomarkers associated with other biological processes for a comprehensive evaluation of AD status are limited., Methods: We developed a blood-based, multiplex biomarker assay for AD that measures the levels of 21 proteins involved in multiple biological pathways. We evaluated the assay's performance for classifying AD and indicating AD-related endophenotypes in three independent cohorts from Chinese or European-descent populations., Results: The 21-protein assay accurately classified AD (area under the receiver operating characteristic curve [AUC] = 0.9407 to 0.9867) and mild cognitive impairment (MCI; AUC = 0.8434 to 0.8945) while also indicating brain amyloid pathology. Moreover, the assay simultaneously evaluated the changes of five biological processes in individuals and revealed the ethnic-specific dysregulations of biological processes upon AD progression., Discussion: This study demonstrated the utility of a blood-based, multi-pathway biomarker assay for early screening and staging of AD, providing insights for patient stratification and precision medicine., Highlights: The authors developed a blood-based biomarker assay for Alzheimer's disease. The 21-protein assay classifies AD/MCI and indicates brain amyloid pathology. The 21-protein assay can simultaneously assess activities of five biological processes. Ethnic-specific dysregulations of biological processes in AD were revealed., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited., Methods: We employed a novel p-tau217 immunoassay (University of Gothenburg [UGOT] p-tau217) in four independent cohorts (n = 308) including a cerebrospinal fluid (CSF) biomarker-classified cohort (Discovery), two cohorts consisting mostly of cognitively unimpaired (CU) and mild cognitively impaired (MCI) participants (MYHAT and Pittsburgh), and a population-based cohort of individuals with SCD (Barcelonaβeta Brain Research Center's Alzheimer's At-Risk Cohort [β-AARC])., Results: UGOT p-tau217 showed high accuracy (area under the curve [AUC] = 0.80-0.91) identifying amyloid beta (Aβ) pathology, determined either by Aβ positron emission tomography or CSF Aβ42/40 ratio. In individuals experiencing SCD, UGOT p-tau217 showed high accuracy identifying those with a positive CSF Aβ42/40 ratio (AUC = 0.91)., Discussion: UGOT p-tau217 can be an easily accessible and efficient way to screen and monitor patients with suspected AD pathophysiology, even in the early stages of the continuum., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: This study examined the relationship between blood-brain-barrier permeability (BBBp), measured by cerebrospinal fluid/serum albumin ratio (QAlb), and cognitive decline progression in a clinical cohort., Methods: This prospective observational study included 334 participants from the BIODEGMAR cohort. Cognitive decline progression was defined as an increase in Global Deterioration Scale and/or Clinical Dementia Rating scores. Associations between BBBp, demographics, and clinical factors were explored., Results: Male sex, diabetes mellitus, and cerebrovascular burden were associated with increased log-QAlb. Vascular cognitive impairment patients had the highest log-QAlb levels. Among the 273 participants with valid follow-up data, 154 (56.4%) showed cognitive decline progression. An 8% increase in the hazard of clinical worsening was observed for each 10% increase in log-QAlb., Discussion: These results suggest that increased BBBp in individuals with cognitive decline may contribute to clinical worsening, pointing to potential targeted therapies. QAlb could be a useful biomarker for identifying patients with a worse prognosis., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Poor sleep quality is associated with cognitive outcomes in Alzheimer's disease (AD). We analyzed the associations between self-reported sleep quality and brain structure and function in cognitively unimpaired (CU) individuals., Methods: CU adults (N = 339) underwent structural magnetic resonance imaging, lumbar puncture, and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A subset (N = 295) performed [18F] fluorodeoxyglucose positron emission tomography scans. Voxel-wise associations with gray matter volumes (GMv) and cerebral glucose metabolism (CMRGlu) were performed including interactions with cerebrospinal fluid (CSF) AD biomarkers status., Results: Poorer sleep quality was associated with lower GMv and CMRGlu in the orbitofrontal and cingulate cortices independently of AD pathology. Self-reported sleep quality interacted with altered core AD CSF biomarkers in brain areas known to be affected in preclinical AD stages., Discussion: Poor sleep quality may impact brain structure and function independently from AD pathology. Alternatively, AD-related neurodegeneration in areas involved in sleep-wake regulation may induce or worsen sleep disturbances. Highlights Poor sleep impacts brain structure and function independent of Alzheimer's disease (AD) pathology. Poor sleep exacerbates brain changes observed in preclinical AD. Sleep is an appealing therapeutic strategy for preventing AD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)