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

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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Neuroinflammation characterizes the earliest changes in Alzheimer’s disease pathology and associated subjective cognitive impairment in adult hydrocephalus biopsies

10.1101/2020.10.01.322511 ◽

2020 ◽

Author(s):

Wenrui Huang ◽

Anne Marie Bartosch ◽

Harrison Xiao ◽

Xena Flowers ◽

Sandra Leskinen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Status ◽

Subjective Cognitive Decline ◽

Cognitive Symptoms ◽

Microglial Phenotype ◽

Neuronal Genes ◽

Early Alzheimer’S Disease ◽

Disease Associated Genes ◽

Microglial Response

AbstractIn an effort to better characterize the transcriptomic changes that accompany early Alzheimer’s disease (AD) pathology in living patients and correlate with contemporaneous cognitive data, we performed RNA-seq on 106 cortical biopsies that were taken during shunt placement for adult onset hydrocephalus with varying degrees of comorbid AD pathology. 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 β-amyloid and tau pathology in comparison to patients who report no cognitive symptoms. Interestingly, downregulation of homeostatic genes and upregulation of disease-associated genes also correlate with microglial plaque invasion and an activated microglial morphology, and this change is not sensitive to cognitive status, suggesting that an initial microglial response to AD pathology is eventually maladaptive. Taken together, these findings highlight a restricted set of microglial and non-microglial genes and suggest that early AD pathology is largely characterized by a loss of homeostatic genes and an activated microglial phenotype that continues to evolve in conjunction with accumulating AD pathology in the setting of subjective cognitive decline.

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Neuropsychiatric and cognitive symptoms across the Alzheimer’s disease clinical spectrum: Cross-sectional and longitudinal associations

10.1101/2021.02.18.21251064 ◽

2021 ◽

Author(s):

Willem S. Eikelboom ◽

Esther van den Berg ◽

Ellen Singleton ◽

Sara J. Baart ◽

Michiel Coesmans ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Functioning ◽

Neuropsychiatric Symptoms ◽

Clinical Stage ◽

Clinical Spectrum ◽

Subjective Cognitive Decline ◽

Cognitive Symptoms ◽

Cross Sectional ◽

Over Time

ABSTRACTObjectiveTo investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of amyloid-β positive individuals across the Alzheimer’s disease (AD) clinical spectrum.MethodsWe included 1,524 amyloid-β positive individuals from the Amsterdam Dementia Cohort with subjective cognitive decline (SCD, n=113), mild cognitive impairment (MCI, n=321), or dementia (n=1,090). We measured NPS with the neuropsychiatric inventory (NPI), examining total scores and the presence of specific NPI-items. Cognition was assessed across five cognitive domains and with the MMSE. We examined trajectories including model based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time-points (subsample n=520, Mean=1.8 [SD=0.7] years follow-up).ResultsNPS were prevalent across all clinical AD stages (NPI total score ≥1 81.4% in SCD, 81.2% in MCI, 88.7% in dementia). Cognitive functioning showed an uniform gradual decline; while in contrast, large intra-individual heterogeneity of NPS was observed over time across all groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β:-0.18–0.11, FDR-adjusted p<0.05), while there were no cross-sectional relationships in SCD and MCI (β:-0.32– 0.36, FDR-adjusted p>0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (β:-0.13–0.44, FDR-adjusted p>0.05).ConclusionNPS and cognitive symptoms are both prevalent across the AD continuum, but show a different evolution during the course of the disease.

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

Communications Biology ◽

10.1038/s42003-020-1079-x ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 4

Author(s):

Tyler C. Hammond ◽

Xin Xing ◽

Chris Wang ◽

David Ma ◽

Kwangsik Nho ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Stage ◽

Machine Learning Method ◽

Early Dementia ◽

Optimal Target ◽

Amyloid Aβ ◽

Β Amyloid ◽

Early Alzheimer’S Disease ◽

Glucose Hypometabolism

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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Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine

Neurobiology of Disease ◽

10.1016/j.nbd.2019.104570 ◽

2019 ◽

Vol 132 ◽

pp. 104570 ◽

Cited By ~ 11

Author(s):

Francisco Q. Gonçalves ◽

João P. Lopes ◽

Henrique B. Silva ◽

Cristina Lemos ◽

António C. Silva ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Dysfunction ◽

Extracellular Adenosine ◽

Β Amyloid ◽

Early Alzheimer’S Disease

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

Alzheimer s & Dementia ◽

10.1002/alz.040523 ◽

2020 ◽

Vol 16 (S5) ◽

Author(s):

Tyler C Hammond ◽

Xin Xing ◽

David W Ma ◽

Kwangsik Nho ◽

Paul K Crane ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Β Amyloid ◽

Early Alzheimer’S Disease ◽

Glucose Hypometabolism

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Alzheimer’s Disease: Pharmacotherapy of subjective cognitive decline

NeuroPharmac Journal ◽

10.37881/1.321 ◽

2018 ◽

pp. 57-62

Author(s):

Aslam Pathan ◽

Abdulrahman Alshahrani

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Executive Function ◽

Cognitive Decline ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Subjective Cognitive Decline ◽

Cognitive Symptoms ◽

Behavioral Impairment ◽

Accurate Treatment

Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive and behavioral impairment that significantly interferes with social and occupational functioning. AD is progressive and fatal dementia of unknown cause characterized by loss of cognitive and physical functioning, commonly with behavior or cognitive symptoms. Cognitive decline is gradual and includes memory loss, aphasia, apraxia, agnosia, disorientation, and impaired executive function. physicians will often play a major role in diagnosing and treating dementia and related disorders in the community. Accurate treatment of cognitive symptoms is important. Accordingly, we reviewed the available pharmacotherapy in the clinical management of cognitive symptoms of dementia.

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