Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Nelson, Peter T.; Brayne, Carol; Flanagan, Margaret E.; Abner, Erin L.; Agrawal, Shweta; Attems, Johannes; Castellani, Rudolph J.; Corrada, María M.; Cykowski, Matthew D.; Di, Jing; Dickson, Dennis W.; Dugger, Brittany N.; Ervin, John F.; Fleming, Jane; Graff‐Radford, Jonathan; Grinberg, Lea T.; Hokkanen, Suvi R. K.; Hunter, Sally; Kapasi, Alifiya; Kawas, Claudia H.; Keage, Hannah A.D.; Keene, C. Dirk; Kero, Mia; Knopman, David S.; Kouri, Naomi; Kovács, Gábor G.; Labuzan, Sydney A.; Larson, Eric B.; Latimer, Caitlin S.; Leite, Renata; Matchett, Billie J.; Matthews, Fiona; Merrick, Richard; Montine, Thomas J.; Murray, Melissa E.; Myllykangas, Liisa; Nag, Sukriti; Nelson, Ruth S.; Neltner, Janna H.; Nguyen, Aivi T.; Petersen, Ronald C.; Polvikoski, Tuomo; Reichard, R. Ross; Rodriguez, Roberta Diehl; Suemoto, Cláudia Kimie; Wang, Shih‐Hsiu J.; Wharton, Stephen B.; White, Lon R.; Schneider, Julie A.

doi:10.1007/s00401-022-02444-1

Cited by 96 publications

(90 citation statements)

References 122 publications

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“…When available, understanding the microstructure of the brain and the individual neurons can provide vital information about the mechanisms of cognitive decline in dementia [ 65 , 66 , 67 ]. This includes standard histology and immunopathology [ 68 , 69 ]. However, electron microscopy provides crucial information regarding the state of subcellular organelles and structures [ 70 , 71 ].…”

Section: Specific Challengesmentioning

confidence: 99%

A Perspective: Challenges in Dementia Research

Stecker

2022

Medicina

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Although dementia is a common and devastating disease that has been studied intensely for more than 100 years, no effective disease modifying treatment has been found. At this impasse, new approaches are important. The purpose of this paper is to provide, in the context of current research, one clinician’s perspective regarding important challenges in the field in the form of specific challenges. These challenges not only illustrate the scope of the problems inherent in finding treatments for dementia, but can also be specific targets to foster discussion, criticism and new research. One common theme is the need to transform research activities from small projects in individual laboratories/clinics to larger multinational projects, in which each clinician and researcher works as an integral part. This transformation will require collaboration between researchers, large corporations, regulatory/governmental authorities and the general population, as well as significant financial investments. However, the costs of transforming the approach are small in comparison with the cost of dementia.

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Section: Specific Challengesmentioning

confidence: 99%

A Perspective: Challenges in Dementia Research

Stecker

2022

Medicina

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“…We have shown previously insignificant interval change in diagnosis of not dementia over 2 years between last research evaluation and death for individuals who had neuropsychological test results in the upper quartile for the cohort [42]; all NC and RAD participants had < 2 years between last evaluation and death with an average interval of 352 days. Criteria for including only none/low levels of the four prevalent comorbidities that do not significantly contribute to the risk of dementia were: (i) for VBI: no territorial or lacunar infarcts, no hemorrhages, <2 microinfarcts/microhemorrhages [43], (ii) for LB: none or amygdala only [44], (iii) for LATE-NC: none or amygdala only [45], and (iv) no hippocampal sclerosis in the unilateral hippocampus available for histopathologic analysis.…”

Section: Clinico-pathologic Groupsmentioning

confidence: 99%

Proteomics of resilience to Alzheimer’s disease identifies brain regional soluble Aβ levels, actin filament processes, and response to injury

Huang

Merrihew

Larson

et al. 2022

Preprint

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Resilience to Alzheimer's disease (RAD) is an uncommon combination of high disease burden without dementia that may provide critical insights into limiting the clinical impact of this incurable disease. In this study, we used mass spectrometry-based proteomics to quantify regional protein differences that characterize RAD. Starting with over 700 brain donations, we identified 43 extensively annotated research participants who met stringent inclusion exclusion criteria and analyzed matched isocortical regions, hippocampus, and caudate nucleus. Differential expression analysis of 7,115 soluble proteins identified lower isocortical and hippocampal soluble Aβ; peptide levels as a significant feature of RAD. Protein co-expression analysis revealed a group of 181 densely-interacting proteins significantly associated with RAD that were enriched for actin filament-based process, cellular detoxification, and wound healing in isocortex and hippocampus. We further support our findings using data from 689 human isocortical samples from four independent external cohorts that were the closest approximations of our clinico-pathologic groups. The molecular basis of RAD, a widely replicated state in older adults for which there is no experimental model, likely holds important insights into therapeutic interventions for Alzheimer's disease.

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“…Aggregated toxic variants of TDP-43 have been correlated with several neurodegenerative diseases including AD, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) [ 13 ]. TDP-43 inclusions are present in a subset of AD cases, primarily in limbic regions [ 14 , 15 ] where they can overlap with tau pathology [ 16 ] as well as in a significant fraction of all elderly patients [ 17 ]. TDP-43 is prone to form aggregate species, where TDP-43 mutations linked to an increased risk of sporadic ALS aggregate more readily [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer’s Disease

Cho

Schulz

Venkataraman

et al. 2022

IJMS

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Blood-based biomarkers are needed for the early diagnosis of Alzheimer’s disease (AD). We analyzed longitudinal human plasma samples from AD and control cases to identify biomarkers for the early diagnosis of AD. Plasma samples were grouped based on clinical diagnosis at the time of collection: AD, mild cognitive impairment (MCI), and pre-symptomatic (preMCI). Samples were analyzed by ELISA using a panel of reagents against nine different AD-related amyloid-β (Aβ), tau, or TDP-43 variants. Receiver operating characteristic (ROC) curves of different biomarker panels for different diagnostic sample groups were determined. Analysis of all of the samples gave a sensitivity of 92% and specificity of 76% for the diagnosis of AD. Early-stage diagnosis of AD, utilizing only the preMCI and MCI samples, identified 88% of AD cases. Using sex-biased biomarker panels, early diagnosis of AD cases improved to 96%. Using the sex-biased panels, we also identified 6 of the 25 control group cases as being at high risk of AD, which is consistent with what is expected given the advanced age of the control cases. Specific AD-associated protein variants are effective blood-based biomarkers for the early diagnosis of AD. Notably, significant differences were observed in biomarker profiles for the early detection of male and female AD cases.

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Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Abstract: Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Cited by 96 publications

References 122 publications

A Perspective: Challenges in Dementia Research

A Perspective: Challenges in Dementia Research

Proteomics of resilience to Alzheimer’s disease identifies brain regional soluble Aβ levels, actin filament processes, and response to injury

Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer’s Disease

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