The COVID-19 pandemic presented a huge challenge for the world because of the disease COVID-19 itself, as well as the psychosocial consequences of the pandemic. To explore the long-term effects of COVID-19, we used data from an ongoing prospective study, including comprehensive pre-pandemic baseline measures, to study the biological and psychiatric effects of both receiving a medical COVID-19 diagnosis at any point during the pandemic (labeled “COVID diagnosis”) and the perceived stress in the subjectively worst month of the pandemic (labeled “pandemic stress”). We included 129 Swiss young adults (regardless of COVID-19 status) who participated before (T1) and after the onset of the COVID-19 pandemic (T2). We measured depression, anxiety, and stress symptoms using clinical interviews and psychological questionnaires and further included heart rate variability, blood-based hormone, and gut microbiome measurements as physical health outcomes. Individuals reporting a medical COVID-19 diagnosis (N = 59) exhibited more expert-rated depression symptoms and a marginally worse expert-rated depression trajectory throughout the pandemic than those without a diagnosis (N = 70). In addition, they exhibited a significant restructuring of the gut microbiome and dehydroepiandrosterone changes throughout the pandemic. Pandemic stress was positively related with T2 observer-rated depression symptoms and sleep problems. These findings show the lasting differential effects of COVID-19 illness and pandemic stress on depression-related psychological and physiological outcomes.

Intravoxel incoherent motion (IVIM) is a diffusion-weighted magnetic resonance imaging (MRI) method that models slow (D, tissue diffusivity) and fast (D*, microvascular perfusion) signal components (f, signal fraction). This observational study explores the relationship between IVIM metrics and sleep macrostructure and physical activity levels in nineteen healthy elderly individuals (mean age 72.2 ± 5.0). Participants underwent two MRI sessions during wakefulness, four weeks apart, on a GE 3T Premier scanner. IVIM parameters (D, D*, f and their product fD*) were calculated using non-linear least-squares and a deep learning transformer-based estimator and analysed across seven regions of interest. Sleep was recorded at home on 10-14 consecutive nights, following each MRI scan, using a portable electroencephalography (EEG) system. Physical activity was recorded in parallel with actigraphy. Associations were tested using linear mixed effects models, with activity included in sensitivity analyses. Better EEG-derived sleep quality and higher physical activity were predominantly linked to lower estimated values for IVIM fD*. These findings may reflect differences in microvascular perfusion and/or the cerebrospinal fluid compartment associated with sleep and warrant further investigation of the mechanisms linking IVIM metrics to sleep quality. Clinicaltrials.gov: NCT05539378, trial registry name: Exploring the Link Between Sleep and Brain Clearance (BBCDS).

INTRODUCTION:Major depressive disorder (MDD) is one of the most frequent psychiatric diseases worldwide. Growing evidence suggests that cortical gyrification measures may present an early risk marker for depression. Medial views of cortical surface reconstructions provide the basis for a simple, expert-rated measure of cortical gyrification. In this study, we examined left anterior cingulate cortex (ACC) gyrification as a potential marker of MDD. We selected this region of interest based on the limbic-cortical dysregulation model of depression and prior research results. METHODS:In a sample of 386 healthy and depressed young adults (147 with MDD), experts rated ACC gyrification using structural MRI reconstructions. Gyrification patterns were compared on clinical (e.g., MDD status), MRI (e.g., automatically derived region-wise curvature and volumetric variables), and psychological outcomes (e.g., personality questionnaire scores). RESULTS:One-third of subjects exhibited two anteroposterior gyri in the left hemisphere, whereas the other subjects exhibited one longitudinal gyrus or longitudinal gyrification was interrupted. Subjects with the fewer-gyri left ACC variant more often experienced MDD at some point in their lifetime (p = 0.048). Moreover, among all subjects with MDD, disorder onset happened earlier in subjects with the fewer gyri variant (d = -0.30), hinting at early developmental contributions to the phenotypic marker. In addition, subjects with fewer longitudinal gyri scored higher on neuroticism (η2 = 0.02), but not on extraversion. Automatically derived measures of gyrification and cortical surface area were largely consistent with the differences observed using the expert rater-based gyrification measure. CONCLUSION:Future studies should investigate left ACC gyrification and, to what extent, it exists in at-risk subjects, further elucidating it with ACC structural and functional connectivity measures.

Accounting for common co-pathologies such as white matter hyperintensities (WMH) may improve the prognostic performance of imaging and blood-based biomarkers for cognitive decline in Alzheimer’s disease (AD). Plasma biomarkers including p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) as well as imaging biomarkers including hippocampus volume, amyloid-β (Aβ) PET, and WMH have been reported to be associated with decline across multiple cognitive domains. However, a comprehensive comparison of these biomarkers in predicting domain-specific cognitive decline and their potential additive or interactive effects with WMH volume, is lacking. We analyzed data from 216 (median age [range]: 67.2 years [51–90]) community-dwelling older adults who underwent MRI, Aβ PET, and blood-based biomarker assessments. Participants were followed for a median of 5.3 years with annual clinical and neuropsychological evaluations. We created cognitive composite scores for episodic memory, executive functions, processing speed/attention, language, visuospatial abilities, and global cognition. Linear mixed-effects models were used to compare the predictive value of imaging and blood-based biomarkers individually and in interaction with WMH volume for decline across cognitive domains and clinical dementia rating-sum of boxes (CDR-SOB) progression. Multigroup path analysis was used to investigate multiple biomarker interactions simultaneously. Individual biomarkers significantly predict decline across multiple cognitive domains. WMHs independently predicted decline in processing speed/attention (β = -0.024, 95

BACKGROUND:Socio-cognitive assessment in neurocognitive disorders (NCDs) is rare in clinical practice and no consensus exists as to a uniform operationalization of socio-cognitive measures for NCDs in memory clinics. The SIGNATURE initiative aims to optimize the use of socio-cognitive measures in memory clinics, defining expert recommendations. We report consortium guidelines for the use of socio-cognitive measures in NCDs based on available evidence from the literature and the current state of practices in memory clinics. METHODS:Using a Delphi consensus method supported by a literature review and the results of an international survey, 22 specialists defined recommendations for the context of use, relevance in NCD diagnosis, priorities for future research and facilitators/obstacles of socio-cognitive assessment in major and mild NCDs. RESULTS:Overall, panelists recommended social cognition testing in routine diagnostic assessment to evaluate both socio-cognitive and socio-behavioral alterations. A set of clinical, methodological, implementation and external factors facilitating or hampering the use of socio-cognitive tasks was identified. CONCLUSIONS:This is the first focused endeavor to favor the implementation of socio-cognitive assessment, which is required by DSM-5 but seldom performed despite clear evidence of its clinical relevance for diagnosis and care. Our results provide an initial set of recommendations, refinable through the future actions of the SIGNATURE initiative. Future collaborative clinical research projects should overcome current limitations and foster the use of ecological and cross-culturally validated measures in clinics.

Introduction: Accounting for common co-pathologies such as white matter hyperintensities (WMH) of presumed vascular origin may improve the prognostic performance of imaging and blood-based biomarkers for cognitive decline in Alzheimers disease (AD). Methods: We analyzed longitudinal cognitive data from 216 (median age: 67.2 years; median follow up: 5.3 years) community-dwelling older adults who underwent MRI, amyloid PET, and plasma p-tau217, neurofilament light chain, and glial fibrillary acidic protein assessment. Results: WMHs predicted declines in executive function, processing speed, and global cognition, and amplified the effects of imaging and plasma biomarkers, especially on episodic memory. The interaction between amyloid-PET and WMH volume was the primary interaction associated with faster memory decline. Discussion: Coexisting AD pathology and WMHs shorten the preclinical stage of AD. Consideration of amyloid-PET and blood-based biomarkers in the context of an individual s WMH burden may improve the prognostic value of these biomarkers. ### Competing Interest Statement K.B. has served as a consultant and at advisory boards for Abbvie, AC Immune, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Neurimmune, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers. He has served at data monitoring committees for Julius Clinical and Novartis. He has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics. He 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; H.Z. 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, Enigma, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, 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); R.M.N. and C.H. are employees and shareholders of Neurimmune AG, Switzerland. All other authors report no competing interests. ### Funding Statement This work was supported by institutional funding from the University of Zurich, funding from the Maxi Foundation (to C.H.). D.B.s salary was funded through a grant from the Swiss National Science Foundation (SNSF) (project number: 10000763). K.B. is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270, and #AF-994551), Hjarnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimers Association 2021 Zenith Award (ZEN-21-848495), the Alzheimers Association 2022-2025 Grant (SG-23-1038904 QC), La Fondation Recherche Alzheimer (FRA), Paris, France, the Kirsten and Freddy Johansen Foundation, Copenhagen, Denmark, and Familjen Ronstroms Stiftelse, Stockholm, Sweden. H.Z. is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356, #2022-01018 and #2019-02397), the European Unions Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the European Partnership on Metrology, co-financed from the European Unions Horizon Europe Research and Innovation Programme and by the Participating States (NEuroBioStand, #22HLT07), the Bluefield Project, Cure Alzheimers Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Ronstroms Stiftelse, Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden (#FO2022-0270), the European Unions Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL (UKDRI-1003), and an anonymous donor. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the local ethics committee (Kantonale Ethikkommission, Zurich, Switzerland) and conducted in accordance with their guidelines and the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

INTRODUCTION:The present paper identified key components of anxiety and fear based on a large community sample of 387 psychiatrically healthy or depressed participants. METHODS:Subfactors were defined based on a principal component analysis with promax rotation and characterized via correlations with other psychiatric as well as physiological and volumetric indicators collected in this large study. RESULTS:The key components were labeled "discomfort," "fright," "nervousness," "lack of self-confidence," and "worry." We discuss the components according to their organizational complexity, but also in terms of their affective and motivational content. CONCLUSION:The components may be useful for future research, as they are based on three of the most-used psychiatric questionnaires assessing anxiety and fear symptoms.

OBJECTIVE: Our objective was to study health state appraisals in healthy older Swiss with a focus on health deficits typically associated with dementia. We also aimed to elucidate the congruency of self-ratings of health states with proxy-ratings by possible future surrogate decision-makers. METHODS: This is a single-center, cross-sectional survey among a convenience sample of pairs of healthy older adults and their possible future surrogate decision-makers. Following a States Worse Than Death (SWD) approach, participants were asked to appraise health deficit states in relation to death both for themselves and for their dyadic partners. RESULTS: The final sample consisted of 248 participants, i.e. 124 pairs of healthy older adults (62.1% male; mean age: 71.6ys (SD: 10.5ys)) and their possible future surrogate decisionmakers (mostly spouses or children). Of the 17 health states included in the survey, eleven were rated as equal or worse than death by more than half of healthy older adults. Similarly, ten health states were rated as equal or worse than death by more than half of possible future surrogate decision-makers. Overall, there was good - and higher than random - congruency between ratings of dyadic partners. DISCUSSION: Participants of our study preferred death over living with various types of health impairments to a striking extent, particularly those associated with dementia. There was a good consistency of health state appraisals between dyadic partners which could translate into consistent decision-making - in case proxy decision-making were to become necessary. The use of patient-centered health measures such as SWD approaches may aid goals-of-care discussions, facilitate end-of-life communications and thus improve healthcare decision-making. Future research should investigate how SWD appraisals change over time and with deterioration of health and how they depend on societal acceptance of health impairments.

OBJECTIVE:Socioeconomic status (SES) and lifestyle activities (LA) are strongly related, and both are associated with dementia risk. We investigated the influence of SES and LA on brain atrophy and cognitive decline considering amyloid-beta (Aβ) positron emission tomography and white matter hyperintensity (WMH) load. METHODS:We investigated 221 older adults (mean age, 67.1 ± 8.2 years) who underwent cognitive testing annually over a median follow-up period of 3.4 years. Longitudinal T1-weighted magnetic resonance imaging was available for 181 participants. Measures of SES and LA were collected using questionnaires and combined to SES and LA scores using a latent variable approach. We used linear mixed-effects models to investigate if SES and LA are independently or interactively with Aβ and WMH load associated with decline in domains language, processing speed/attention, executive function, and episodic memory. Mediation models assessed whether these associations were explained by gray matter atrophy. RESULTS:SES and LA were associated with better cognitive performance at baseline, but were not associated with cognitive decline over time. In interaction with brain pathologies, higher LA reduced the detrimental effects of Aβ and WMH load on language decline, whereas higher SES reduced the detrimental effects of Aβ pathology on episodic memory decline. Individuals with low SES showed faster Aβ-related gray matter atrophy, which mediated the association between Aβ and episodic memory decline but not language decline. INTERPRETATION:These results suggest that multiple resilience mechanisms underlie the protective effects of SES and LA on cognitive decline. Interventions targeting SES-related risk factors may be most effective when implemented early, before neurodegenerative changes begin. ANN NEUROL 2025;98:1222-1236.

INTRODUCTION:Identifying at-risk individuals and selecting sensitive cognitive outcome measures are critical for designing efficient clinical trials targeting early Alzheimer's disease (AD) stages. METHODS:We compared amyloid beta (Aβ)-positron emission tomography (PET), plasma tau phosphorylated at threonine 217 (p-tau217), Aβ42/40, and p-tau217/Aβ42-related decline across neuropsychological and functional measures in 225 individuals (176 cognitively unimpaired (CU), 49 with mild cognitive impairment (MCI). Johnson-Neyman analysis identified the biomarkers, which were used as trial inclusion criteria to estimate sample sizes needed to detect a 30% slowing across cognitive outcomes. RESULTS:In the CU, using combined plasma Aβ42/40 and p-tau217 cut-offs for eligibility yielded the lowest sample size estimates for a comprehensive multidomain cognitive composite score, whereas sample sizes were higher for all other inclusion criteria based on single biomarkers. In MCI, estimates were substantially lower and less variable across most inclusion criteria and outcome measures. DISCUSSION:These findings highlight the need for careful consideration of outcome measures, baseline diagnosis, and inclusion criteria, given their substantial effect on sample size estimation in trials. HIGHLIGHTS:Aβ SUVR, plasma p-tau217, and the p-tau217/Aβ42 ratio predicted decline across multiple cognitive domains. Using cohort-specific biomarker cutoffs, sample size estimates were similar for p-tau217 combined with Aβ42/40 or Aβ SUVR. A multidomain composite best detected AD-related decline. Outcome measures and eligibility criteria strongly impact sample size estimates, especially in CU.

INTRODUCTION:We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). METHODS:We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n = 138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n = 78; ADNI: n = 89). RESULTS:The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. DISCUSSION:Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. HIGHLIGHTS:Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

INTRODUCTION:Female sex is associated with increased [18F]-flortaucipir signal, which may be affected by amyloid pathology, age, and off-target binding in skull and meninges. METHODS:In this cross-sectional study comprising 52 females and 52 matched males, we examined sex-related differences in regional tau-positron emission tomography (PET) with and without considering off-target binding. We assessed the respective contributions of sex, age, amyloid-PET burden, and off-target binding to tau-PET signal. We explored associations between age at menopause and hormone replacement therapy (HRT) use with regional tau-PET signals. RESULTS:Female sex was associated with increased regional tau both independently and interactively with amyloid, but amyloid-independent associations were largely reduced when controlling for off-target binding. Age but not age*sex interactions explained a small but significant amount of tau-PET signal in temporoparietal regions. Considering the sample size and limited range of amyloid-PET burden, no clear associations between regional tau-PET signals and age at menopause or HRT use could be found. DISCUSSION:Female sex is associated with increased [18F]-flortaucipir signal mainly through its interaction with amyloid.

Background White matter hyperintensities (WMHs) are often measured globally, but spatial patterns of WMHs could underlie different risk factors and neuropathological and clinical correlates. We investigated the spatial heterogeneity of WMHs and their association with comorbidities, Alzheimer's disease (AD) risk factors, and cognition.Methods In this cross-sectional study, we studied 171 cognitively unimpaired (CU; median age: 65 years, range: 50 to 89) and 51 mildly cognitively impaired (MCI; median age: 72, range: 53 to 89) individuals with available amyloid (18F-flutementamol) PET and FLAIR-weighted images. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each participant's white matter was segmented into 38 parcels, and WMH volume was calculated in each parcel. Correlated principal component analysis was applied to the parceled WMH data to determine patterns of WMH covariation. Adjusted and unadjusted linear regression models were used to investigate associations of component scores with comorbidities and AD-related factors. Using multiple linear regression, we tested whether WMH component scores predicted cognitive performance.Results Principal component analysis identified four WMH components that broadly describe FLAIR signal hyperintensities in posterior, periventricular, and deep white matter regions, as well as basal ganglia and thalamic structures. In CU individuals, hypertension was associated with all patterns except the periventricular component. MCI individuals showed more diverse associations. The posterior and deep components were associated with renal disorders, the periventricular component was associated with increased amyloid, and the subcortical gray matter structures was associated with sleep disorders, endocrine/metabolic disorders, and increased amyloid. In the combined sample (CU + MCI), the main effects of WMH components were not associated with cognition but predicted poorer episodic memory performance in the presence of increased amyloid. No interaction between hypertension and the number of comorbidities on component scores was observed.Conclusion Our study underscores the significance of understanding the regional distribution patterns of WMHs and the valuable insights that risk factors can offer regarding their underlying causes. Moreover, patterns of hyperintensities in periventricular regions and deep gray matter structures may have more pronounced cognitive implications, especially when amyloid pathology is also present.

Amyloid beta (Aβ) follows a sigmoidal time function with varying accumulation rates. We studied how the position on this function, reflected by different Aβ accumulation phases, influences APOE ɛ4’s association with Aβ and cognitive decline in 503 participants without dementia using Aβ-PET imaging over 5.3-years. First, Aβ load and accumulation were analyzed irrespective of phases using linear mixed regression. Generally, ɛ4 carriers displayed a higher Aβ load. Moreover, Aβ normal (Aβ-) ɛ4 carriers demonstrated higher accumulation. Next, we categorized accumulation phases as “decrease”, “stable”, or “increase” based on trajectory shapes. After excluding the Aβ-/decrease participants from the initial regression, the difference in accumulation attributable to genotype among Aβ- individuals was no longer significant. Further analysis revealed that in increase phases, Aβ accumulation was higher among noncarriers, indicating a genotype-related timeline shift. Finally, cognitive decline was analyzed across phases and was already evident in the Aβ-/increase phase. Our results encourage early interventions for ɛ4 carriers and imply that monitoring accumulating Aβ- individuals might help identify those at risk for cognitive decline.

Glutathione (GSH) is a brain marker for oxidative stress and has previously been associated with cerebral amyloid deposition and memory decline. However, to date, no study has examined the links among GSH, sex, age, amyloid, and Apolipoprotein E (ApoE) genotype in a large non-clinical cohort of older adults. We performed ApoE genotyping, magnetic resonance spectroscopy (MRS) as well as simultaneous positron emission tomography with the radiotracer Flutemetamol (Amyloid-PET), in a group of older adults. The final analysis set comprised 140 healthy older adults (mean age: 64.7 years) and 49 participants with mild cognitive impairment (mean age: 71.4 years). We recorded metabolites in the posterior cingulate cortex (PCC) by a GSH-edited MEGAPRESS sequence. Structural equation modeling revealed that higher GSH levels were associated with female sex, but neither ApoE- epsilon 4 carrier status nor age showed significant associations with GSH. Conversely, older age and the presence of an ApoE4 allele, but not sex, are linked to higher global amyloid load. Our results suggest that the PCC shows sex-specific GSH alterations in older adults.

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50–89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.

OBJECTIVE:Evidence on associations of lifestyle factors with Alzheimer's pathology and cognition are ambiguous, potentially because they rarely addressed inter-relationships of factors and sex effects. While considering these aspects, we examined the relationships of lifestyle factors with brain amyloid burden and cognition. METHODS:We studied 178 cognitively normal individuals (women, 49%; 65.0 [7.6] years) and 54 individuals with mild cognitive impairment (women, 35%; 71.3 [8.3] years) enrolled in a prospective study of volunteers who completed 18 F-Flutemetamol amyloid positron emission tomography. Using structural equation modeling, we examined associations between latent constructs representing metabolic/vascular risk, physical activity, and cognitive activity with global amyloid burden and cognitive performance. Furthermore, we investigated the influence of sex in this model. RESULTS:Overall, higher cognitive activity was associated with better cognitive performance and higher physical activity was associated with lower amyloid burden. The latter association was weakened to a nonsignificant level after excluding multivariate outliers. Examination of the moderating effect of sex in the model revealed an inverse association of metabolic/vascular risk with cognition in men, whereas in women metabolic/vascular risk trended toward increased amyloid burden. Furthermore, a significant inverse association between physical activity and amyloid burden was found only in men. Inheritance of an APOE4 allele was associated with higher amyloid burden only in women. INTERPRETATION:Sex modifies effects of certain lifestyle-related factors on amyloid burden and cognition. Notably, our results suggest that the negative impact of metabolic/vascular risk influences the risk of cognitive decline and Alzheimer's disease through distinct paths in women and men. ANN NEUROL 2022;92:451-463.