Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

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Prevalence of abnormal Alzheimer’s disease biomarkers in patients with subjective cognitive decline: cross-sectional comparison of three European memory clinic samples

Alzheimer s Research & Therapy ◽

10.1186/s13195-018-0463-y ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Steffen Wolfsgruber ◽

◽

José Luis Molinuevo ◽

Michael Wagner ◽

Charlotte E. Teunissen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Subjective Cognitive Decline ◽

Memory Clinic ◽

Cross Sectional ◽

Disease Biomarkers

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The Impact of Amyloid-β or Tau on Cognitive Change in the Presence of Severe Cerebrovascular Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200680 ◽

2020 ◽

Vol 78 (2) ◽

pp. 573-585

Author(s):

Hyemin Jang ◽

Hee Jin Kim ◽

Yeong Sim Choe ◽

Soo-Jong Kim ◽

Seongbeom Park ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Interaction Effect ◽

Significant Interaction ◽

Amyloid Β ◽

Cognitive Change ◽

Significant Interaction Effect ◽

The Impact

Background: As Alzheimer’s disease (AD) and cerebral small vessel disease (CSVD) commonly coexist, the interaction between two has been of the considerable interest. Objective: We determined whether the association of Aβ and tau with cognitive decline differs by the presence of significant CSVD. Methods: We included 60 subcortical vascular cognitive impairment (SVCI) from Samsung Medical Center and 82 Alzheimer’s disease-related cognitive impairment (ADCI) from ADNI, who underwent Aβ (florbetaben or florbetapir) and tau (flortaucipir, FTP) PET imaging. They were retrospectively assessed for 5.0±3.9 and 5.6±1.9 years with Clinical Dementia Rating-sum of boxes (CDR-SB)/Mini-Mental State Examination (MMSE). Mixed effects models were used to investigate the interaction between Aβ/tau and group on CDR-SB/MMSE changes. Results: The frequency of Aβ positivity (45% versus 54.9%, p = 0.556) and mean global FTP SUVR (1.17±0.21 versus 1.16±0.17, p = 0.702) were not different between the two groups. We found a significant interaction effect of Aβ positivity and SVCI group on CDR-SB increase/MMSE decrease (p = 0.013/p < 0.001), and a significant interaction effect of global FTP uptake and SVCI group on CDR-SB increase/MMSE decrease (p < 0.001 and p = 0.030). Finally, the interaction effects of regional tau and group were prominent in the Braak III/IV (p = 0.001) and V/VI (p = 0.003) not in Braak I/II region (p = 0.398). Conclusion: The association between Aβ/tau and cognitive decline is stronger in SVCI than in ADCI. Therefore, our findings suggested that Aβ positivity or tau burden (particularly in the Braak III/IV or V/VI regions) and CSVD might synergistically affect cognitive decline.

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Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

10.21203/rs.3.rs-149163/v1 ◽

2021 ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Genome Wide Association Study ◽

Early Stage ◽

Cognitive Change ◽

Preclinical Ad ◽

Genome Wide ◽

A Genome ◽

Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

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Plasma Glutathione Levels Decreased with Cognitive Decline among People with Mild Cognitive Impairment (MCI): A Two-Year Prospective Study

Antioxidants ◽

10.3390/antiox10111839 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1839

Author(s):

Chieh-Hsin Lin ◽

Hsien-Yuan Lane

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Function ◽

Prospective Study ◽

Cognitive Decline ◽

Cognitive Change ◽

Disease Assessment ◽

Healthy Individuals

Glutathione (GSH) is a major endogenous antioxidant. Several studies have shown GSH redox imbalance and altered GSH levels in Alzheimer’s disease (AD) patients. Early detection is crucial for the outcome of AD. However, whether GSH can serve as a biomarker during the very early-phase of AD, such as mild cognitive impairment (MCI), remains unknown. The current prospective study aimed to examine the longitudinal change in plasma GSH concentration and its influence on cognitive decline in MCI. Overall, 49 patients with MCI and 16 healthy individuals were recruited. Plasma GSH levels and cognitive function, measured by the Mini-Mental Status Examination (MMSE) and Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog), were monitored every 6 months. We employed multiple regressions to examine the role of GSH level in cognitive decline in the 2 years period. The MCI patients showed significant decline in plasma GSH levels and cognitive function from baseline to endpoint (month 24). In comparison, the healthy individuals’ GSH concentration and cognitive function did not change significantly. Further, both GSH level at baseline and GSH level change from baseline to endpoint significantly influenced cognitive decline among the MCI patients. To our knowledge, this is the first study to demonstrate that both plasma GSH levels and cognitive function declined 2 years later among the MCI patients in a prospective manner. If replicated by future studies, blood GSH concentration may be regarded as a biomarker for monitoring cognitive change in MCI.

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Quantitative detection and staging of presymptomatic cognitive decline in familial Alzheimer’s disease: a retrospective cohort analysis

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00695-2 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Antoinette O’Connor ◽

Philip S. J. Weston ◽

Ivanna M. Pavisic ◽

Natalie S. Ryan ◽

Jessica D. Collins ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Symptom Onset ◽

Cognitive Change ◽

Data Driven ◽

Quantitative Detection ◽

Familial Alzheimer’S Disease ◽

Cognitive Domains ◽

Familial Alzheimer's Disease

Abstract Background Understanding the earliest manifestations of Alzheimer’s disease (AD) is key to realising disease-modifying treatments. Advances in neuroimaging and fluid biomarkers have improved our ability to identify AD pathology in vivo. The critical next step is improved detection and staging of early cognitive change. We studied an asymptomatic familial Alzheimer’s disease (FAD) cohort to characterise preclinical cognitive change. Methods Data included 35 asymptomatic participants at 50% risk of carrying a pathogenic FAD mutation. Participants completed a multi-domain neuropsychology battery. After accounting for sex, age and education, we used event-based modelling to estimate the sequence of cognitive decline in presymptomatic FAD, and uncertainty in the sequence. We assigned individuals to their most likely model stage of cumulative cognitive decline, given their data. Linear regression of estimated years to symptom onset against model stage was used to estimate the timing of preclinical cognitive decline. Results Cognitive change in mutation carriers was first detected in measures of accelerated long-term forgetting, up to 10 years before estimated symptom onset. Measures of subjective cognitive decline also revealed early abnormalities. Our data-driven model demonstrated subtle cognitive impairment across multiple cognitive domains in clinically normal individuals on the AD continuum. Conclusions Data-driven modelling of neuropsychological test scores has potential to differentiate cognitive decline from cognitive stability and to estimate a fine-grained sequence of decline across cognitive domains and functions, in the preclinical phase of Alzheimer’s disease. This can improve the design of future presymptomatic trials by informing enrichment strategies and guiding the selection of outcome measures.

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