S2 Fig -

β-diversities of the fecal microbiome between Aβ− CN participants and Aβ+ CN participants based on (A) Bray-Curtis (B) unweighted UniFrac (C) weighted UniFrac and (D) Aitchison values. Abbreviations. Aβ+ CN: cognitively normal participants with amyloid retention; Aβ− CN: cognitively normal participants without amyloid retention. (TIF)</p

Participant characteristics.

Participant characteristics.</p

Table_1.docx

<p>Background: Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer’s disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Aβ) pathology and AD-related neurodegeneration in non-demented older adults.</p><p>Methods: Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral Aβ deposition and Aβ positivity were measured using ¹¹C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using ¹⁸F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire.</p><p>Results: Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CA_early) was associated with significantly increased AD-CMglu (B = 0.035, SE = 0.013, P = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43–0.98, P = 0.04) but was not associated with Aβ deposition or positivity. We observed no association between midlife CA (CA_mid) and any AD-related brain changes. Late-life CA (CA_late) showed an association with both global Aβ deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results.</p><p>Conclusion: Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral Aβ pathology.</p

Comparison of relative abundances of predicted KEGG functional pathway analysis between Aβ+ CN participants and Aβ− CN participants.

(PDF)</p

Relative differences in predicted gene contents in microbiome between Aβ− CN participants and Aβ+ CN participants.

Abbreviations. Aβ+ CN: cognitively normal participants with amyloid retention Aβ− CN: cognitively normal participants without amyloid retention.</p

S1 Fig -

Comparison of α-diversities of the fecal microbiome between Aβ− CN participants and Aβ+ CN participants according to (A) evenness (B) observed species (C) Shannon index and (D) phylogenic diversity (PD). Abbreviations. Aβ+ CN: Cognitively normal participants with amyloid retention; Aβ− CN: Cognitively normal participants without amyloid retention; PD: phylogenetic diversity. (TIF)</p

GLM analysis results of taxonomic differences in microbiome between Aβ+ CN participants and Aβ− CN participants.

GLM analysis results of taxonomic differences in microbiome between Aβ+ CN participants and Aβ− CN participants.</p

Receiver operating characteristic (ROC) curve analysis of the multivariate logistic model to detect preclinical AD using microbiome.

The blue line represents the model with the presence or absence of nine genera revealed from the GLM analysis and covariates (i.e., age, sex, APOE4 positivity and BMI), while a green line represents the reference model including only the covariates. Abbreviation. AD: Alzheimer’s disease; APOE4: apolipoprotein E ε4; BMI: body mass index.</p

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Log predicted counts of the genera associated with Aβ positivity.

Prediction was made using GLM analysis adjusted for age, gender, BMI, APOE4 positivity. Only genera with q <0.05 are shown. Abbreviation. Aβ: amyloid beta; GLM: generalized linear model; Aβ+ CN: cognitively normal participants with amyloid retention Aβ− CN: cognitively normal participants without amyloid retention; APOE4: apolipoprotein E ε4; BMI: body mass index.</p