Association of deposition of tau and amyloid-β proteins with structural connectivity changes in cognitively normal older adults and Alzheimer’s disease spectrum patients

Abstract Tau is associated with hypometabolism in patients with Alzheimer’s disease. In normal aging, the association between tau and glucose metabolism is not fully characterized. We used [18F] AV-1451, [18F] Fluorodeoxyglucose, and [11C] Pittsburgh Compound-B (PiB) PET to measure associations between tau and glucose metabolism in cognitively normal older adults (N = 49). Participants were divided into amyloid-negative (PiB–, n = 28) and amyloid-positive (PiB+, n = 21) groups to determine effects of amyloid-β. We assessed both local and across-brain regional tau–glucose metabolism associations separately in PiB–/PiB+ groups using correlation matrices and sparse canonical correlations. Relationships between tau and glucose metabolism differed by amyloid status, and were primarily spatially distinct. In PiB– subjects, tau was associated with broad regions of increased glucose metabolism. In PiB+ subjects, medial temporal lobe tau was associated with widespread hypometabolism, while tau outside of the medial temporal lobe was associated with decreased and increased glucose metabolism. We further found that regions with earlier tau spread were associated with stronger negative correlations with glucose metabolism. Our findings indicate that in normal aging, low levels of tau are associated with a phase of increased metabolism, while high levels of tau in the presence of amyloid-β are associated with hypometabolism at downstream sites.

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Faculty Opinions recommendation of Exercise and Alzheimer's disease biomarkers in cognitively normal older adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5414956.5527067 ◽

2010 ◽

Author(s):

Elio Scarpini ◽

Daniela Galimberti

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitively Normal ◽

Disease Biomarkers

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Faculty Opinions recommendation of Relationships between tau and glucose metabolism reflect alzheimer's disease pathology in cognitively normal older adults.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733457144.793547250 ◽

2018 ◽

Author(s):

Daniela Perani

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Cognitively Normal

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Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-201122 ◽

2020 ◽

pp. 1-10

Author(s):

Christopher Gonzalez ◽

Nicole S. Tommasi ◽

Danielle Briggs ◽

Michael J. Properzi ◽

Rebecca E. Amariglio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Early Stage ◽

Cognitively Normal ◽

Financial Capacity ◽

Posterior Cingulate ◽

Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p < 0.001; inferior temporal: p < 0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p < 0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p < 0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

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Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-200759 ◽

2021 ◽

pp. 1-13

Author(s):

Jonathan D. Drake ◽

Alison B. Chambers ◽

Brian R. Ott ◽

Lori A. Daiello ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Functional Impairment ◽

Amyloid Β ◽

Intercellular Adhesion Molecule ◽

Csf Biomarkers ◽

Linear Regression Models ◽

Cognitively Normal

Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ 42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ 42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

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Influence of White Matter Hyperintensities on Baseline and Longitudinal Amyloid-β in Cognitively Normal Individuals

Journal of Alzheimer s Disease ◽

10.3233/jad-210333 ◽

2021 ◽

pp. 1-11

Author(s):

Fennie Choy Chin Wong ◽

Seyed Ehsan Saffari ◽

Chathuri Yatawara ◽

Kok Pin Ng ◽

Nagaendran Kandiah ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

White Matter ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Amyloid Β ◽

Intracranial Volume ◽

Linear Regression Models ◽

Cognitively Normal

Background: The associations between small vessel disease (SVD) and cerebrospinal amyloid-β1-42 (Aβ1-42) pathology have not been well-elucidated. Objective: Baseline (BL) white matter hyperintensities (WMH) were examined for associations with month-24 (M24) and longitudinal Aβ1-42 change in cognitively normal (CN) subjects. The interaction of WMH and Aβ1-42 on memory and executive function were also examined. Methods: This study included 72 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Multivariable linear regression models evaluated associations between baseline WMH/intracranial volume ratio, M24 and change in Aβ1-42 over two years. Linear mixed effects models evaluated interactions between BL WMH/ICV and Aβ1-42 on memory and executive function. Results: Mean age of the subjects (Nmales = 36) = 73.80 years, SD = 6.73; mean education years = 17.1, SD = 2.4. BL WMH was significantly associated with M24 Aβ1-42 (p = 0.008) and two-year change in Aβ1-42 (p = 0.006). Interaction between higher WMH and lower Aβ1-42 at baseline was significantly associated with worse memory at baseline and M24 (p = 0.003). Conclusion: BL WMH was associated with M24 and longitudinal Aβ1-42 change in CN. The interaction between higher WMH and lower Aβ1-42 was associated with poorer memory. Since SVD is associated with longitudinal Aβ1-42 pathology, and the interaction of both factors is linked to poorer cognitive outcomes, the mitigation of SVD may be correlated with reduced amyloid pathology and milder cognitive deterioration in Alzheimer’s disease.

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