β‐amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline

AbstractClinical trials focusing on therapeutic candidates that modify β-amyloid (Aβ) have repeatedly failed to treat Alzheimer’s disease (AD), suggesting that Aβ may not be the optimal target for treating AD. The evaluation of Aβ, tau, and neurodegenerative (A/T/N) biomarkers has been proposed for classifying AD. However, it remains unclear whether disturbances in each arm of the A/T/N framework contribute equally throughout the progression of AD. Here, using the random forest machine learning method to analyze participants in the Alzheimer’s Disease Neuroimaging Initiative dataset, we show that A/T/N biomarkers show varying importance in predicting AD development, with elevated biomarkers of Aβ and tau better predicting early dementia status, and biomarkers of neurodegeneration, especially glucose hypometabolism, better predicting later dementia status. Our results suggest that AD treatments may also need to be disease stage-oriented with Aβ and tau as targets in early AD and glucose metabolism as a target in later AD.

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β-Amyloid is Associated with Aberrant Metabolic Connectivity in Subjects with Mild Cognitive Impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.66 ◽

2014 ◽

Vol 34 (7) ◽

pp. 1169-1179 ◽

Cited By ~ 17

Author(s):

Felix Carbonell ◽

Arnaud Charil ◽

Alex P Zijdenbos ◽

Alan C Evans ◽

Barry J Bedell ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Disease Process ◽

Brain Regions ◽

Apoe Ε4 ◽

Positron Emission ◽

Β Amyloid ◽

Glucose Hypometabolism

Positron emission tomography (PET) studies using [18F]2-fluoro-2-deoxyglucose (FDG) have identified a well-defined pattern of glucose hypometabolism in Alzheimer's disease (AD). The assessment of the metabolic relationship among brain regions has the potential to provide unique information regarding the disease process. Previous studies of metabolic correlation patterns have demonstrated alterations in AD subjects relative to age-matched, healthy control subjects. The objective of this study was to examine the associations between β-amyloid, apolipoprotein ε4 (APOE ε4) genotype, and metabolic correlations patterns in subjects diagnosed with mild cognitive impairment (MCI). Mild cognitive impairment subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were categorized into β-amyloid-low and β-amyloid-high groups, based on quantitative analysis of [18F]florbetapir PET scans, and APOE ε4 non-carriers and carriers based on genotyping. We generated voxel-wise metabolic correlation strength maps across the entire cerebral cortex for each group, and, subsequently, performed a seed-based analysis. We found that the APOE ε4 genotype was closely related to regional glucose hypometabolism, while elevated, fibrillar β-amyloid burden was associated with specific derangements of the metabolic correlation patterns.

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Modulation of glucose metabolism and metabolic connectivity by β-amyloid

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16654492 ◽

2016 ◽

Vol 36 (12) ◽

pp. 2058-2071 ◽

Cited By ~ 9

Author(s):

Felix Carbonell ◽

Alex P Zijdenbos ◽

Donald G McLaren ◽

Yasser Iturria-Medina ◽

Barry J Bedell ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Disease Process ◽

Continuous Variable ◽

Amyloid Burden ◽

Early Stages ◽

Metabolic Connectivity ◽

Β Amyloid ◽

Glucose Hypometabolism

Glucose hypometabolism in the pre-clinical stage of Alzheimer’s disease (AD) has been primarily associated with the APOE ɛ4 genotype, rather than fibrillar β-amyloid. In contrast, aberrant patterns of metabolic connectivity are more strongly related to β-amyloid burden than APOE ɛ4 status. A major limitation of previous studies has been the dichotomous classification of subjects as amyloid-positive or amyloid-negative. Dichotomous treatment of a continuous variable, such as β-amyloid, potentially obscures the true relationship with metabolism and reduces the power to detect significant changes in connectivity. In the present work, we assessed alterations of glucose metabolism and metabolic connectivity as continuous function of β-amyloid burden using positron emission tomography scans from the Alzheimer’s Disease Neuroimaging Initiative study. Modeling β-amyloid as a continuous variable resulted in better model fits and improved power compared to the dichotomous model. Using this continuous model, we found that both APOE ɛ4 genotype and β-amyloid burden are strongly associated with glucose hypometabolism at early stages of Alzheimer’s disease. We also determined that the cumulative effects of β-amyloid deposition result in a particular pattern of altered metabolic connectivity, which is characterized by global, synchronized hypometabolism at early stages of the disease process, followed by regionally heterogeneous, progressive hypometabolism.

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An immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies

Nature Communications ◽

10.1038/s41467-021-25902-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Wenrui Huang ◽

Anne Marie Bartosch ◽

Harrison Xiao ◽

Suvrajit Maji ◽

Elliot H. H. Youth ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Pressure ◽

Subjective Cognitive Decline ◽

Cognitive Symptoms ◽

Rna Seq ◽

Microglial Phenotype ◽

Neuronal Genes ◽

Β Amyloid ◽

Early Alzheimer’S Disease

AbstractEarly Alzheimer’s disease (AD) pathology can be found in cortical biopsies taken during shunt placement for Normal Pressure Hydrocephalus. This represents an opportunity to study early AD pathology in living patients. Here we report RNA-seq data on 106 cortical biopsies from this patient population. A restricted set of genes correlate with AD pathology in these biopsies, and co-expression network analysis demonstrates an evolution from microglial homeostasis to a disease-associated microglial phenotype in conjunction with increasing AD pathologic burden, along with a subset of additional astrocytic and neuronal genes that accompany these changes. Further analysis demonstrates that these correlations are driven by patients that report mild cognitive symptoms, despite similar levels of biopsy β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Taken together, these findings highlight a restricted set of microglial and non-microglial genes that correlate with early AD pathology in the setting of subjective cognitive decline.

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