To Örebro University

INTRODUCTION: Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology in CSF. We refitted and validated the ABIDE model, predicting progression from mild cognitive impairment (MCI) to dementia, with CSF measurements from the automated Elecsys platform.

METHODS: We included 2413 MCI participants (998 [41%] amyloid-positive) from seven observational cohorts. Elecsys was used in 958 (40%) participants. The parameters of the previous ABIDE Cox model were re-estimated. Model discrimination and calibration were evaluated with leave-one-cohort-out cross-validation.

RESULTS: During follow-up, 1034 (42%; 585 [58%] amyloid-positive) participants developed dementia. Discrimination was good with Harrell's C of 0.70 (95% confidence interval [CI]: 0.66-0.73). Calibration was good in the total population and amyloid-positive subgroup, with substantial predicted progression risks for all amyloid-positive participants.

DISCUSSION: We refitted the ABIDE model, predicting MCI to dementia progression, with automated CSF measurements. The model was well calibrated in amyloid-positive patients and may support clinical discussions regarding ATTs.

Background: The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood.

Objective: The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology.

Methods: For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology.

Results: We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66-0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73-0.99, p = 0.029; OR = 0.62, 95%CI 0.45-0.86, p = 0.004).

Conclusions: In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

BACKGROUND: Depressive symptoms are common in cognitive decline and Alzheimer's disease (AD), but their underlying pathology remains poorly understood. We aimed to investigate the pathophysiology of depressive symptoms in the context of AD.

METHODS: Individuals with normal cognition (NC), mild cognitive impairment (MCI), or mild AD dementia from two independent, large cohorts were included. Untargeted mass spectrometry-based cerebrospinal fluid (CSF) proteomics, regression analyses, and pathway-enrichment analyses were applied.

RESULTS: A total of 688 individuals (223 NC, 190 MCI, and 275 AD dementia) were included. The levels of 57 out of 946 robustly quantified CSF proteins were associated with depressive symptoms consistently across both cohorts. These proteins were enriched for cell adhesion/inflammation, synaptic signaling, and neurogenesis. In amyloid-positive subjects, cholesterol metabolism and transport were additionally associated with depressive symptoms.

CONCLUSION: The identified proteome alterations may reflect shared biological mechanisms involved in both AD and depression in older people. HIGHLIGHTS: This is the first study to investigate cerebrospinal fluid proteome alterations associated with depressive symptoms in the context of cognitive decline and Alzheimer's disease (AD). Dysregulated proteins in patients with higher depression scores were related to pathways linked to cell adhesion/inflammation, synaptic signaling, and neurogenesis, as well as cholesterol metabolism in amyloid-positive individuals. The identified proteome alterations may represent shared biological mechanisms involved in both AD and depression in older people.

BACKGROUND: The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome.

METHODS: Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A-T-), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways. RESULTS: Five hundred forty-nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood-brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism.

DISCUSSION: Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity.

HIGHLIGHTS: Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Combining cohorts enabled analysis of rare APOE ε2-associated protection in AD. The rare ε2 genotype may confer protection through improved neuronal plasticity. APOE ε4 carriers show increased blood-brain barrier dysfunction and glucose metabolism. These findings offer new insights into genotype-specific mechanisms in early AD.

Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing individuals with abnormal tau and/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid beta 1-42 and phosphorylated tau 181, as amyloid-negative/tau-negative (controls), amyloid-negative/tau-positive (SNAP), amyloid-positive/tau-negative and amyloid-positive/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (n = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive/tau-positive individuals, while distinct from amyloid-positive/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid beta 1-40 and amyloid beta 1-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive/tau-negative, and amyloid-positive/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by APOE. Individuals with NC and SNAP or amyloid-positive/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies. Suspected non-Alzheimer's disease pathophysiology (SNAP) refers to individuals with abnormal tau but normal amyloid. Delvenne et al. investigated the pathophysiology of SNAP in cognitively unimpaired individuals using cerebrospinal fluid proteomics and found that SNAP individuals exhibit increased neuroplasticity proteins, similar to those in Alzheimer's disease, suggesting that tau drives these changes.

IMPORTANCE: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology.

OBJECTIVE: To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia.

DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024.

MAIN OUTCOMES AND MEASURES: Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms.

RESULTS: In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI.

CONCLUSIONS AND RELEVANCE: Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

BACKGROUND: Automated cerebrospinal fluid (CSF) biomarker assays have largely replaced manual immunoassays for measuring amyloid pathology. Their relevance is increasing as amyloid-targeting therapies (ATTs) are becoming available for amyloid-positive mild cognitively impaired (MCI) individuals. Therefore, we refitted and validated the ABIDE model, predicting progression from MCI to dementia, with CSF measurements from the automated Elecsys platform. Additionally, we evaluated the performance in an amyloid-positive subpopulation, potentially eligible for ATTs.

METHOD: We combined data from MCI participants of seven single-centre and multicentre observational cohorts: Amsterdam Dementia Cohort (n =648), Alzheimer's Disease Neuroimaging Initiative (n =544), BioFINDER (n =212), European Medical Information Framework for Alzheimer's Disease (n =809), Lleida (n =88), National Alzheimer's Coordinating Centre (n =63), and Wisconsin Alzheimer's Disease Cohort (n =9). Participants were included with MCI at baseline, a baseline Mini-Mental State Examination, either a magnetic resonance imaging hippocampal volume or CSF Aβ1-42 and pTau181 measurements, and at least six months of follow-up. Elecsys was used in 737 (31%) participants. A Cox model was used to predict time to dementia using the variables in the previous ABIDE model (Maurik et al. 2019). Model discrimination and calibration were evaluated with leave-one-cohort-out cross-validation. Calibration was assessed in the pooled cohort (PC) and amyloid-positive (APos) subgroup, stratified by predicted risk: PC/APos1 (<P16), PC/APos2 (P16-P50), PC/APos3 (P50-P86), PC/APos4 (>P86).

RESULT: Of 2372 MCI participants (Table 1; 70±8yrs, 57%F; 41% amyloid-positive) with a median follow-up of 2.1yrs, 997 (42%; 563 [58%] amyloid-positive) developed dementia (IQR:1.3-3.2yrs). The refitted coefficients resemble the prior model, except for a larger effect of the Aβ1-42*pTau interaction (Table 2). Discrimination was similar to the prior ABIDE model, with Harrell's C of 0.70 (95%CI:0.69-0.71), and calibration was good in the pooled cohort, amyloid-positive subgroup (Figure 1), and across CSF assays. In the amyloid-positive subgroup, all four risk groups had a substantial progression risk with a median predicted progression time of 6.3yrs (95%CI:6.1-6.6) in APos1, 3.7yrs (95%CI:3.5-4.0) in APos2, 3.0yrs (95%CI:2.8-3.0) in APos3, and 2.0yrs (95%CI:2.0-2.1) in APos4.

CONCLUSION: We updated the ABIDE model for predicting MCI to dementia progression with automated CSF measurements. The model was well calibrated in amyloid-positive patients and may support clinical discussions regarding the initiation of ATTs.

BACKGROUND: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations.

METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models.

RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups.

CONCLUSIONS: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

INTRODUCTION: It remains unclear whether diabetes mellitus (DM) is associated with Alzheimer's disease (AD) pathology and associated vascular burden.

METHODS: We included cognitively normal (CN), mild cognitive impairment (MCI), and dementia individuals. We assessed associations between DM and AD biomarkers (amyloid beta [Aβ], phosphorylated tau-181 [p-tau181], total tau [t-tau], and medial temporal atrophy [MTA]) and vascular burden (white matter hyperintensities, microbleeds) by logistic regression. Secondary analyses assessed associations between DM and profiles of Aβ combined with p-tau181/t-tau/MTA/white matter hyperintensity/microbleeds.

RESULTS: We included 5550 participants (65.8+-8.7 years, 8.7% DM). DM was associated with lower odds of abnormal AD biomarkers: Aβ in MCI (odds ratio [OR] = 0.70, 95% confidence interval [CI]: 0.51-0.95, p = 0.02) and dementia (OR = 0.44, 0.26-0.78, p = 0.003), and p-tau181 in dementia (OR = 0.64, 0.41-1.00, p = 0.045). Secondary analyses indicated associations of DM with abnormal t-tau (OR = 1.57, 1.00-2.46, p = 0.048) and MTA (OR = 1.96, 1.05-3.68, p = 0.04) only in CN individuals with normal Aβ.

DISCUSSION: In cognitively impaired individuals, DM was associated with lower odds of Aβ pathology, whereas DM was associated with neurodegeneration markers in CN individuals without Aβ pathology.

HIGHLIGHTS: Diabetes mellitus (DM) was associated with lower odds of amyloid beta (Aβ) and phosphorylated tau (p-tau) pathology across clinical populations. DM was associated with total tau and medial temporal atrophy in cognitively normal individuals without Aβ pathology. DM may be associated with dementia through neurodegenerative pathways other than Alzheimer's disease.