Search

This study describes the main characteristics of ongoing observational studies on Alzheimer's disease (AD) to help identify any important research gaps. A search through the WHO International Clinical Trials Registry Platform and on the Primary Registries was conducted on 9 June 2012. The descriptors 'recruiting' or 'open' were used to describe a study's recruitment status. 62 studies are being conducted in 18 countries (Australia, Far-East, Middle-East, North America, and Western Europe). The US and France are involved in 55% of these studies. The studies aimed to recruit 20 to 10,000 participants, lasting 8 months to 24 years; 46% are case-control, whereas 44% are cohort studies; 60% and 34% are longitudinal and cross-sectional, respectively. The majority are sponsored by hospitals, universities, medical centers, or public health systems (63%), and are conducted in single centers (55%). 37 use imaging (MRI, PET, SPECT), 18 conduct lumbar puncture, 21 collect DNA and/or RNA, and 15 collect ApoE genotyping. 17 studies are medium-term prospective disease progression studies, the majority to assess mild cognitive impairment (MCI) or/and AD progression; only 3 are on cognitively normal older people at risk (2 studies, n = 180) or not (1 study, n < 200) of developing MCI. Observational studies are being conducted in few countries, with very few in low and middle-income countries where the majority of AD patients live. There is a remarkable interest in disease progression studies; however, longitudinal, long-term studies, on cognitively normal middle-age individuals, of key importance to try to fully understand the preclinical phase of AD, are lacking. [ABSTRACT FROM AUTHOR]

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).)

Introduction: Leukocyte telomere length (LTL) is an objective biomarker of biological aging, and it is proposed to play a crucial role in Alzheimer's disease (AD) risk. We aimed at evaluating the cross-sectional association between LTL and cognitive performance in middle-aged cognitively unimpaired individuals at increased risk of AD., Methods: A total of 1520 participants from the ALFA cohort were included. Relative telomere length was measured in leukocytes through qPCR. LTL was residualized against age and sex, and associations with cognitive performance were assessed in short and long groups based on residualized LTL (rLTL). Interactions with sex and genetic risk of AD were tested., Results: Non-linear associations were found between LTL and episodic memory (EM). Better EM was associated with longer rLTL among women in the short rLTL group., Discussion: Results suggest a potential role of telomeres in the cognitive aging process with sex-specific patterns., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests JLM is currently a full-time employee of Lundbeck and has previously served as a consultant or at 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, ProMIS Neurosciences. JDG has received speaker’s or consultant's fees from Philips Nederlands, Roche Diagnostics and Biogen and research support from GE Healthcare, Roche Diagnostics and Hoffmann-La Roche. MSC has served as a consultant and at advisory boards for Roche Diagnostics International Ltd, has given lectures in symposia sponsored by Roche Diagnostics, S.L.U, Roche Farma, S.A and Roche Sistemas de Diagnósticos, Sociedade Unipessoal, Lda. and research support from Roche Diagnostics International Ltd. GSB has served as a consultant for Roche Farma, S.A. ASV has received research funding through his institution and support to attend professional meetings from the California Walnut Commission. The remaining authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

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.)

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.)

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.)

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: We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages., Methods: We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade., Results: Cerebrospinal fluid (CSF) amyloid beta (Aβ) 42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau 181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ 42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau 181 , and NfL., Discussion: Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury., Highlights: Lower CSF Aβ 42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury., (© 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.)

Traditional neuropsychological tests accurately describe the current cognitive state but fall short to characterize cognitive change over multiple short time periods. We present an innovative approach to remote monitoring of executive functions on a monthly basis, which leverages the performance indicators from self-administered computerized cognitive training games (NUP-EXE). We evaluated the measurement properties of NUP-EXE in N = 56 individuals (59% women, 60-80 years) at increased risk of Alzheimer's disease ( APOE -ϵ4 carriers with subjective cognitive decline) who completed a 12-month multimodal intervention for preventing cognitive decline. NUP-EXE presented good psychometric properties and greater sensitivity to change than traditional tests. Improvements in NUP-EXE correlated with improvements in functionality and were affected by participants' age and gender. This novel data collection methodology is expected to allow a more accurate characterization of an individual's response to a cognitive decline preventive intervention and to inform development of outcome measures for a new generation of intervention trials., Competing Interests: The authors declare the following competing interests: Carolina Sastre and Íñigo Fernandez De Piérola are employees of the company NeuronUP©. This company did not fund the study, had no role in its design, and did not participate during its execution or in the decision to submit results. Dr. José Luis Molinuevo is currently a full-time employee of H. Lundbeck A/S and previously has served as a consultant or at 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., (© 2023 The Author(s).)

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer's disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD, and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE -ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging in non-demented individuals with abnormal levels of biomarkers of AD and axonal injury., Competing Interests: IC, MG, GO, CF, MS, RC, MM, LL, SI, AM, HM, CM, KF, SH, GC, AW, FB, HZ, KB, VV, JG No competing interests declared, JM is currently a full-time employee of H. Lundbeck A/S and previously has 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, AS Employee of Takeda Pharmaceutical Company Ltd, IS Is a full-time employee and shareholder of Roche Diagnostics International Ltd, GK Is a full-time employee of Roche Diagnostics GmbH, AB Is a full-time employee and shareholder of Roche Diagnostics GmbH, MS 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 Diagnósticos, Sociedade Unipessoal, Lda, (© 2023, Cumplido-Mayoral et al.)

Introduction: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort., Methods: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice., Results: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms., Discussion: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose: To determine whether the APOE-ε4 allele modulates the relationship between regional β-amyloid (Aβ) accumulation and cognitive change in middle-aged cognitively unimpaired (CU) participants., Methods: The 352 CU participants (mean aged 61.1 [4.7] years) included completed two cognitive assessments (average interval 3.34 years), underwent [ 18 F]flutemetamol Aβ positron emission tomography (PET), T1w magnetic resonance imaging (MRI), as well as APOE genotyping. Global and regional Aβ PET positivity was assessed across five regions-of-interest by visual reading (VR) and regional Centiloids. Linear regression models were developed to examine the interaction between regional and global Aβ PET positivity and APOE-ε4 status on longitudinal cognitive change assessed with the Preclinical Alzheimer's Cognitive Composite (PACC), episodic memory, and executive function, after controlling for age, sex, education, cognitive baseline scores, and hippocampal volume., Results: In total, 57 participants (16.2%) were VR+ of whom 41 (71.9%) were APOE-ε4 carriers. No significant APOE-ε4*global Aβ PET interactions were associated with cognitive change for any cognitive test. However, APOE-ε4 carriers who were VR+ in temporal areas (n = 19 [9.81%], p = 0.04) and in the striatum (n = 8 [4.14%], p = 0.01) exhibited a higher decline in the PACC. The temporal areas findings were replicated when regional PET positivity was determined with Centiloid values. Regionally, VR+ in the striatum was associated with higher memory decline. As for executive function, interactions between APOE-ε4 and regional VR+ were found in temporal and parietal regions, and in the striatum., Conclusion: CU APOE-ε4 carriers with a positive Aβ PET VR in regions known to accumulate amyloid at later stages of the Alzheimer's disease (AD) continuum exhibited a steeper cognitive decline. This work supports the contention that regional VR of Aβ PET might convey prognostic information about future cognitive decline in individuals at higher risk of developing AD., Clinicaltrials: gov Identifier: NCT02485730. Registered 20 June 2015 https://clinicaltrials.gov/ct2/show/NCT02485730 and ClinicalTrials.gov Identifier:NCT02685969. Registered 19 February 2016 https://clinicaltrials.gov/ct2/show/NCT02685969 ., (© 2023. The Author(s).)

Background: Conventional neuropsychological norms likely include cognitively unimpaired (CU) individuals with preclinical Alzheimer's disease (AD) pathology (amyloid-β, tau, and neurodegeneration) since they are based on cohorts without AD biomarkers data. Due to this limitation, population-based norms would lack sensitivity for detecting subtle cognitive decline due to AD, the transitional stage between healthy cognition and mild cognitive impairment. We have recently published norms for memory tests in individuals with normal cerebrospinal fluid (CSF) AD biomarker levels., Objective: The aim of the present study was to provide further AD biomarker-based cognitive references covering attentional, executive function, linguistic, and visual processing tests., Methods: We analyzed 248 CU individuals aged between 50-70 years old with normal CSF Aβ, p-tau, and neurodegeneration (t-tau) biomarker levels. The tests included were the Trail Making Test (TMT), Semantic Fluency Test, Digit and Symbol Span, Coding, Matrix Reasoning, Judgement of Line Orientation and Visual Puzzles. Normative data were developed based on regression models adjusted for age, education, and sex when needed. We present equations to calculate z-scores, the corresponding normative percentile tables, and online calculators., Results: Age, education, and sex were associated with performance in all tests, except education for the TMT-A, and sex for the TMT-B, Coding, and Semantic Fluency. Cut-offs derived from the current biomarker-based reference data were higher and more sensitive than standard norms., Conclusion: We developed reference data obtained from individuals with evidence of non-pathologic AD biomarker levels that may improve the objective characterization of subtle cognitive decline in preclinical AD.

Introduction: The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep., Methods and Analysis: We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers., Ethics and Dissemination: The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals., Trial Registration Number: NCT04932473., Competing Interests: Competing interests: JM is currently a full-time employee of Lundbeck and priorly has served as a consultant or at 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. MS-C has given lectures in symposia sponsored by Roche Diagnostics, S.L.U. HZ 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 cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB 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 cofounder of Brain BBS, which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. The rest of the authors have no conflict of interest to declare in regarding the current project., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-ɛ4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF Aβ and higher levels of CSF NfL only in APOE-ɛ4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations., (© 2022. The Author(s).)

Purpose: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([ 18 F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants., Methods: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [ 18 F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages)., Results: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [ 18 F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism., Conclusions: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes., (© 2022. The Author(s).)

Background and Objectives: Increased anxious-depressive symptomatology is observed in the preclinical stage of Alzheimer disease (AD), which may accelerate disease progression. We investigated whether β-amyloid, cortical thickness in medial temporal lobe structures, neuroinflammation, and sociodemographic factors were associated with greater anxious-depressive symptoms during the COVID-19 confinement., Methods: This retrospective observational study included cognitively unimpaired older adults from the Alzheimer's and Families cohort, the majority with a family history of sporadic AD. Participants performed the Hospital Anxiety and Depression Scale (HADS) during the COVID-19 confinement. A subset had available retrospective (on average: 2.4 years before) HADS assessment, amyloid [ 18 F] flutemetamol PET and structural MRI scans, and CSF markers of neuroinflammation (interleukin-6 [IL-6], triggering receptor expressed on myeloid cells 2, and glial fibrillary acidic protein levels). We performed multivariable linear regression models to investigate the associations of prepandemic AD-related biomarkers and sociodemographic factors with HADS scores during the confinement. We further performed an analysis of covariance to adjust by participants' prepandemic anxiety-depression levels. Finally, we explored the role of stress and lifestyle changes (sleep patterns, eating, drinking, smoking habits, and medication use) on the tested associations and performed sex-stratified analyses., Results: We included 921 (254 with AD biomarkers) participants. β-amyloid positivity (B = 3.73; 95% CI = 1.1 to 6.36; p = 0.006), caregiving (B = 1.37; 95% CI 0.24-2.5; p = 0.018), sex (women: B = 1.95; 95% CI 1.1-2.79; p < 0.001), younger age (B = -0.12; 95% CI -0.18 to -0.052; p < 0.001), and lower education (B = -0.16; 95% CI -0.28 to -0.042; p = 0.008) were associated with greater anxious-depressive symptoms during the confinement. Considering prepandemic anxiety-depression levels, we further observed an association between lower levels of CSF IL-6 (B = -5.11; 95% CI -10.1 to -0.13; p = 0.044) and greater HADS scores. The results were independent of stress-related variables and lifestyle changes. Stratified analysis revealed that the associations were mainly driven by women., Discussion: Our results link AD-related pathophysiology and neuroinflammation with greater anxious-depressive symptomatology during the COVID-19-related confinement, notably in women. AD pathophysiology may increase neuropsychiatric symptomatology in response to stressors. This association may imply a worse clinical prognosis in people at risk for AD after the pandemic and thus deserves to be considered by clinicians., Trial Registration Information: ClinicalTrials.gov Identifier NCT02485730., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The COVID-19 pandemic may worsen the mental health of people reporting subjective cognitive decline (SCD) and therefore their clinical prognosis. We aimed to investigate the association between the intensity of SCD and anxious/depressive symptoms during confinement and the underlying mechanisms., Methods: Two hundred fifty cognitively unimpaired participants completed the Hospital Anxiety and Depression Scale (HADS) and SCD-Questionnaire (SCD-Q) and underwent amyloid-β positron emission tomography imaging with [ 18 F] flutemetamol (N = 205) on average 2.4 (± 0.8) years before the COVID-19 confinement. During the confinement, participants completed the HADS, Perceived Stress Scale (PSS), Brief Resilience Scale (BRS), and an ad hoc questionnaire on worries (access to primary products, self-protection materials, economic situation) and lifestyle changes (sleep duration, sleep quality, eating habits). We investigated stress-related measurements, worries, and lifestyle changes in relation to SCD. We then conducted an analysis of covariance to investigate the association of SCD-Q with HADS scores during the confinement while controlling for pre-confinement anxiety/depression scores and demographics. Furthermore, we introduced amyloid-β positivity, PSS, and BRS in the models and performed mediation analyses to explore the mechanisms explaining the association between SCD and anxiety/depression., Results: In the whole sample, the average SCD-Q score was 4.1 (± 4.4); 70 (28%) participants were classified as SCD, and 26 (12.7%) were amyloid-β-positive. During the confinement, participants reporting SCD showed higher PSS (p = 0.035) but not BRS scores (p = 0.65) than those that did not report SCD. No differences in worries or lifestyle changes were observed. Higher SCD-Q scores showed an association with greater anxiety/depression scores irrespective of pre-confinement anxiety/depression levels (p = 0.002). This association was not significant after introducing amyloid-β positivity and stress-related variables in the model (p = 0.069). Amyloid-β positivity and PSS were associated with greater HADS irrespective of pre-confinement anxiety/depression scores (p = 0.023; p < 0.001). The association of SCD-Q with HADS was mediated by PSS (p = 0.01)., Conclusions: Higher intensity of SCD, amyloid-β positivity, and stress perception showed independent associations with anxious/depressive symptoms during the COVID-19 confinement irrespective of pre-confinement anxiety/depression levels. The association of SCD intensity with anxiety/depression was mediated by stress perception, suggesting stress regulation as a potential intervention to reduce affective symptomatology in the SCD population in the face of stressors., (© 2022. The Author(s).)

Blood biomarkers indicating elevated amyloid-β (Aβ) pathology in preclinical Alzheimer's disease are needed to facilitate the initial screening process of participants in disease-modifying trials. Previous biofluid data suggest that phosphorylated tau231 (p-tau231) could indicate incipient Aβ pathology, but a comprehensive comparison with other putative blood biomarkers is lacking. In the ALFA+ cohort, all tested plasma biomarkers (p-tau181, p-tau217, p-tau231, GFAP, NfL and Aβ42/40) were significantly changed in preclinical Alzheimer's disease. However, plasma p-tau231 reached abnormal levels with the lowest Aβ burden. Plasma p-tau231 and p-tau217 had the strongest association with Aβ positron emission tomography (PET) retention in early accumulating regions and associated with longitudinal increases in Aβ PET uptake in individuals without overt Aβ pathology at baseline. In summary, plasma p-tau231 and p-tau217 better capture the earliest cerebral Aβ changes, before overt Aβ plaque pathology is present, and are promising blood biomarkers to enrich a preclinical population for Alzheimer's disease clinical trials., (© 2022. The Author(s).)

Higher grey matter volumes/cortical thickness and fluorodeoxyglucose uptake have been consistently found in cognitively unimpaired individuals with abnormal Alzheimer's disease biomarkers compared with those with normal biomarkers. It has been hypothesized that such transient increases may be associated with neuroinflammatory mechanisms triggered in response to early Alzheimer's pathology. Here, we evaluated, in the earliest stages of the Alzheimer's continuum , associations between grey matter volume and fluorodeoxyglucose uptake with CSF biomarkers of several pathophysiological mechanisms known to be altered in preclinical Alzheimer's disease stages. We included 319 cognitively unimpaired participants from the ALFA+ cohort with available structural MRI, fluorodeoxyglucose PET and CSF biomarkers of amyloid-β and tau pathology (phosphorylated tau and total tau), synaptic dysfunction (neurogranin), neuronal and axonal injury (neurofilament light), glial activation (soluble triggering receptor on myeloid cells 2, YKL40, GFAP, interleukin-6 and S100b) and α-synuclein using the Roche NeuroToolKit. We first used the amyloid-β/tau framework to investigate differences in the neuroimaging biomarkers between preclinical Alzheimer's disease stages. Then, we looked for associations between the neuroimaging markers and all the CSF markers. Given the non-negative nature of the concentrations of CSF biomarkers and their high collinearity, we clustered them using non-negative matrix factorization approach (components) and sought associations with the imaging markers. By groups, higher grey matter volumes were found in the amyloid-β-positive tau-negative participants with respect to the reference amyloid-β-negative tau-negative group. Both amyloid-β and tau-positive participants showed higher fluorodeoxyglucose uptake than tau-negative individuals. Using the obtained components, we observed that tau pathology accompanied by YKL-40 (astrocytic marker) was associated with higher grey matter volumes and fluorodeoxyglucose uptake in extensive brain areas. Higher grey matter volumes in key Alzheimer-related regions were also found in association with two other components characterized by a higher expression of amyloid-β in combination with different glial markers: one with higher GFAP and S100b levels (astrocytic markers) and the other one with interleukin-6 (pro-inflammatory). Notably, these components' expression had different behaviours across amyloid-β/tau stages. Taken together, our results show that CSF amyloid-β and phosphorylated tau, in combination with different aspects of glial response, have distinctive associations with higher grey matter volumes and increased glucose metabolism in key Alzheimer-related regions. These mechanisms combine to produce transient higher grey matter volumes and fluorodeoxyglucose uptake at the earliest stages of the Alzheimer's continuum , which may revert later on the course of the disease when neurodegeneration drives structural and metabolic cerebral changes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP., Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP., Design, Setting, and Participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD., Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD., Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology., Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.

Background: Air quality contributes to incidence of Alzheimer's disease (AD) although the underlying neurobiological mechanisms are unclear. This study was aimed to examine the association between air pollution and concentrations of cerebrospinal fluid (CSF) AD biomarkers and amyloid-β (Aβ) deposition. Participants and methods The sample included 156 cognitively unimpaired adults aged 57 years (61 at biomarkers assessment) with increased risk of AD from the ALFA + Study. We examined CSF levels of Aβ42, Aβ40, p-Tau, t-Tau, neurofilament light (NfL) and cerebral amyloid load (Centiloid). A Land Use Regression model from 2009 was used to estimate residential exposure to air pollutants including nitrogen dioxide (NO 2 ,) and particulate matter (PM 2.5 , PM 2.5 abs , PM 10 ). This model was considered a surrogate of long-term exposure until time of data collection in 2013-2014. Participants have resided in the same residence for at least the previous 3 years. Multiple linear regression models were used to estimate associations between air pollutants and biomarkers. The effect modification by CSF Aβ status and APOE-ε4 carriership was also assessed., Results: A consistent pattern of results indicated that greater exposure to NO 2 and PM 2.5 absorbance was associated with higher levels of brain Aβ deposition, while greater exposure to PM 10 and PM 2.5 was associated with higher levels of CSF NfL. Most associations were driven by individuals that were Aβ-positive. Although APOE-ε4 status did not significantly modify these associations, the effect of air pollutants exposure on CSF NfL levels was stronger in APOE-ε4 carriers., Conclusion: In a population of cognitively unimpaired adults with increased risk of AD, long-term exposure to air pollution was associated with higher levels in biomarkers of AD pathology. While further research is granted to elucidate the mechanisms involved in such associations, our results reinforce the role of air pollution as an environmental risk factor for AD., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers., Methods: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ) 42/40 , phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers., Results: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ 42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions., Discussion: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4 , and markers of neurodegeneration., Trial Registration Information: ClinicalTrials.gov Identifier NCT02485730., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Growing evidence suggests dementia incidence can be reduced through prevention programs targeting risk factors. To accelerate the implementation of such prevention programs, a new generation of brain health services (BHS) is envisioned, involving risk profiling, risk communication, risk reduction, and cognitive enhancement. The purpose of risk communication is to enable individuals at risk to make informed decisions and take action to protect themselves and is thus a crucial step in tailored prevention strategies of the dementia incidence. However, communicating about dementia risk is complex and challenging.In this paper, we provide an overview of (i) perspectives on communicating dementia risk from an ethical, clinical, and societal viewpoint; (ii) insights gained from memory clinical practice; (iii) available evidence on the impact of disclosing APOE and Alzheimer's disease biomarker test results gathered from clinical trials and observational studies; (iv) the value of established registries in light of BHS; and (v) practical recommendations regarding effective strategies for communicating about dementia risk.In addition, we identify challenges, i.e., the current lack of evidence on what to tell on an individual level-the actual risk-and on how to optimally communicate about dementia risk, especially concerning worried yet cognitively unimpaired individuals. Ideally, dementia risk communication strategies should maximize the desired impact of risk information on individuals' understanding of their health/disease status and risk perception and minimize potential harms. More research is thus warranted on the impact of dementia risk communication, to (1) evaluate the merits of different approaches to risk communication on outcomes in the cognitive, affective and behavioral domains, (2) develop an evidence-based, harmonized dementia risk communication protocol, and (3) develop e-tools to support and promote adherence to this protocol in BHSs.Based on the research reviewed, we recommend that dementia risk communication should be precise; include the use of absolute risks, visual displays, and time frames; based on a process of shared decision-making; and address the inherent uncertainty that comes with any probability., (© 2021. The Author(s).)

Mobile device-assisted dietary ecological momentary assessments (EMAs) have emerged as a new tool allowing the evaluation of dietary intake in real time, in a real-world setting and in a continuous manner. They have the potential to minimize recall bias, participant, and investigator burden, and decrease economic and time investment while maximizing ecological validity. We developed a set of EMAs aimed at evaluating continuous adherence to the MedDiet. Four multiple-choice EMAs are sent daily in a randomized manner from a total of eight questions. The EMAs enquire about the consumption of 11 key food groups of the Mediterranean diet in the last 24-48 h in a semi-quantitative way. EMAs capture the daily frequency of consumption of fruits, vegetables, and extra virgin olive oil on different days of the week. Additionally, EMAs capture the weekly frequency of consumption of whole grain products, sugary drinks, nuts, legumes, sweets, fish and seafood, and red and processed meats. A designed scoring system behind the EMAs extracts the percentage of adherence to the MedDiet recommendations and calculates a quality index of the diet every week. Individualized reports are sent periodically to the volunteers highlighting the strengths and weaknesses of their diet. EMAs are also expected to have a behavioral effect, reinforcing the choice of Mediterranean foods.

Neurofilament light chain (NfL) is an axonal protein that when measured in cerebrospinal fluid (CSF) serves as a biomarker of neurodegeneration. We aimed at investigating the association among CSF NfL, presence of Subjective Cognitive Decline (SCD) and hippocampal volume, and how CSF amyloid-β (Aβ) modifies these associations. We included 278 cognitively unimpaired participants from the Alfa+ cohort (78 SCD and 200 Controls). Linear models accounting for covariates (age, gender, and mood) were used to test the association between CSF NfL and SCD status, and between CSF NfL and bilateral hippocampal volumes. Interactions with Aβ were also explored. Individuals with SCD had higher CSF NfL and lower CSF Aβ42/40 than Controls. There was a significant interaction between SCD and CSF-Aβ42/40 levels. Stratified analyses showed a significant association between SCD and NfL only in Aβ+ individuals. Higher CSF NfL was significantly associated with lower hippocampal volume specifically in Aβ+ individuals with SCD. The presence of SCD in Aβ+ individuals may represent an early symptom in the Alzheimer's continuum related to incipient neurodegeneration., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile., Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [ 18 F]-FDG, and [ 18 F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex., Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2., Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials., Trial Registration: NCT02485730., (© 2021. The Author(s).)

Introduction: Urban environmental exposures might contribute to the incidence of Alzheimer's disease (AD). Our aim was to identify structural brain imaging correlates of urban environmental exposures in cognitively unimpaired individuals at increased risk of AD., Methods: Two hundred twelve participants with brain scans and residing in Barcelona, Spain, were included. Land use regression models were used to estimate residential exposure to air pollutants. The daily average noise level was obtained from noise maps. Residential green exposure indicators were also generated. A cerebral 3D-T1 was acquired to obtain information on brain morphology. Voxel-based morphometry statistical analyses were conducted to determine the areas of the brain in which regional gray matter (GM) and white matter (WM) volumes were associated with environmental exposures., Results: Exposure to nitrogen dioxide was associated with lower GM volume in the precuneus and greater WM volume in the splenium of the corpus callosum and inferior longitudinal fasciculus. In contrast, exposure to fine particulate matter was associated with greater GM in cerebellum and WM in the splenium of corpus callosum, the superior longitudinal fasciculus, and cingulum cingulate gyrus. Noise was positively associated with WM volume in the body of the corpus callosum. Exposure to greenness was associated with greater GM volume in the middle frontal, precentral, and the temporal pole., Discussion: In cognitively unimpaired adults with increased risk of AD, exposure to air pollution, noise, and green areas are associated with GM and WM volumes of specific brain areas known to be affected in AD, thus potentially conferring a higher vulnerability to the disease., Competing Interests: JLM is currently a full‐time employee of Lundbeck and prior to that 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, ProMIS Neurosciences., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: We tested how tube types (ethylenediaminetetraacetic acid [EDTA], serum, lithium heparin [LiHep], and citrate) and freeze-thaw cycles affect levels of blood biomarkers for Alzheimer's disease (AD) pathophysiology, glial activation, and neuronal injury., Methods: Amyloid beta (Aβ)42, Aβ40, phosphorylated tau181 (p-tau181), glial fibrillary acidic protein, total tau (t-tau), neurofilament light, and phosphorylated neurofilament heavy protein were measured using single molecule arrays., Results: LiHep demonstrated the highest mean value for all biomarkers. Tube types were highly correlated for most biomarkers (r > 0.95) but gave significantly different absolute concentrations. Weaker correlations between tube types were found for Aβ42/40 (r = 0.63-0.86) and serum t-tau (r = 0.46-0.64). Freeze-thaw cycles highly influenced levels of serum Aβ and t-tau ( P  < .0001), and minor decreases in EDTA Aβ40 and EDTA p-tau181 were found after freeze-thaw cycle 4 ( P  < .05)., Discussion: The same tube type should be used in research studies on blood biomarkers. Individual concentration cut-offs are needed for each tube type in all tested biomarkers despite being highly correlated. Serum should be avoided for Aβ42, Aβ40, and t-tau. Freeze-thaw cycles > 3 should be avoided for p-tau181., Competing Interests: MSC has served as a consultant and on 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. KB has served as a consultant, on advisory boards, or on data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, 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. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: The number of APOE-ε4 alleles is a major nonmodifiable risk factor for sporadic Alzheimer disease (AD). There is increasing evidence on the benefits of dietary DHA (22:6n-3) before the onset of AD symptoms, particularly in APOE-ε4 carriers. Brain alterations in the preclinical stage can be detected by structural MRI., Objectives: We aimed, in middle-aged cognitively unimpaired individuals at increased risk of AD, to cross-sectionally investigate whether dietary DHA intake relates to cognitive performance and to MRI-based markers of cerebral small vessel disease and AD-related neurodegeneration, exploring the effect modification by APOE-ε4 status., Methods: In 340 participants of the ALFA (ALzheimer and FAmilies) study, which is enriched for APOE-ε4 carriership (n = 122, noncarriers; n = 157, 1 allele; n = 61, 2 alleles), we assessed self-reported DHA intake through an FFQ. We measured cognitive performance by administering episodic memory and executive function tests. We performed high-resolution structural MRI to assess cerebral small vessel disease [white matter hyperintensities (WMHs) and cerebral microbleeds (CMBs)] and AD-related brain atrophy (cortical thickness in an AD signature). We constructed regression models adjusted for potential confounders, exploring the interaction DHA × APOE-ε4., Results: We observed no significant associations between DHA and cognitive performance or WMH burden. We observed a nonsignificant inverse association between DHA and prevalence of lobar CMBs (OR: 0.446; 95% CI: 0.195, 1.018; P = 0.055). DHA was found to be significantly related to greater cortical thickness in the AD signature in homozygotes but not in nonhomozygotes (P-interaction = 0.045). The association strengthened when analyzing homozygotes and nonhomozygotes matched for risk factors., Conclusions: In cognitively unimpaired APOE-ε4 homozygotes, dietary DHA intake related to structural patterns that may result in greater resilience to AD pathology. This is consistent with the current hypothesis that those subjects at highest risk would obtain the largest benefits from DHA supplementation in the preclinical stage.This trial was registered at clinicaltrials.gov as NCT01835717., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages., Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated., Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent., Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials., Methods: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium., Discussion: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions., Competing Interests: The authors declare no conflicts of interest or other relevant disclosures., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Cognitive performance of a given individual should be interpreted in the context of reference standards obtained in cognitively healthy populations. Recent evidence has shown that removing asymptomatic individuals with biomarker evidence of Alzheimer's disease pathology from normative samples increases the sensitivity of norms to detect memory impairments. These kind of norms may be useful for defining subtle cognitive decline, the transitional cognitive decline between normal cognition and mild cognitive impairment., Objective: The present study aims to provide norms for the Free and Cued Selective Reminding Test (FCSRT) and the Logical Memory subtest of the Wechsler Memory Scale-IV in a sample of individuals aged 50-70 years with normal levels of amyloid-β and tau cerebrospinal fluid (CSF) biomarkers., Methods: The sample was composed of 248 individuals from the ALFA+ study with negative amyloid-β and tau CSF biomarker levels. Regression-based norms were developed, including adjustments for age, education, and sex when applicable., Results: We found that education was associated with the performance in all the variables of both tests while age had a marginal effect only in the delayed free recall of the FCSRT. Sex was also related to the performance in the FCSRT, with women outperforming men. Equations to calculate z-scores and normative percentile tables were created. As compared with previously published norms the reference data presented were more sensitive but less specific, as expected., Conclusion: The use of the norms provided in this work, in combination with the already published conventional norms, may contribute to detecting subtle memory impairment.