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Article ; Online: Resistance and Resilience to Alzheimer's Disease.

Latimer, Caitlin S / Prater, Katherine E / Postupna, Nadia / Dirk Keene, C

Cold Spring Harbor perspectives in medicine

2023

Abstract: Dementia is a significant public health crisis; the most common underlying cause of age-related cognitive decline and dementia is Alzheimer's disease neuropathologic change (ADNC). As such, there is an urgent need to identify novel therapeutic targets ... ...

Abstract	Dementia is a significant public health crisis; the most common underlying cause of age-related cognitive decline and dementia is Alzheimer's disease neuropathologic change (ADNC). As such, there is an urgent need to identify novel therapeutic targets for the treatment and prevention of the underlying pathologic processes that contribute to the development of AD dementia. Although age is the top risk factor for dementia in general and AD specifically, these are not inevitable consequences of advanced age. Some individuals are able to live to advanced age without accumulating significant pathology (resistance to ADNC), whereas others are able to maintain cognitive function despite the presence of significant pathology (resilience to ADNC). Understanding mechanisms of resistance and resilience will inform therapeutic strategies to promote these processes to prevent or delay AD dementia. This article will highlight what is currently known about resistance and resilience to AD, including our current understanding of possible underlying mechanisms that may lead to candidate preventive and treatment interventions for this devastating neurodegenerative disease.
Language	English
Publishing date	2023-12-27
Publishing country	United States
Document type	Journal Article
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a041201
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Article ; Online: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Pillai, Jagan A / Bena, James / Tousi, Babak / Rothenberg, Kasia / Keene, C Dirk / Leverenz, James B

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024 Volume 20, Issue 4, Page(s) 2564–2574

Abstract: Introduction: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage.: Methods: We conducted a retrospective neuropathology- ... ...

Abstract	Introduction: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. Methods: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. Results: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). Discussion: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Highlights: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.
MeSH term(s)	Male ; Humans ; Alzheimer Disease/pathology ; Apolipoprotein E4/genetics ; Lewy Bodies/pathology ; Retrospective Studies ; Cerebral Amyloid Angiopathy/epidemiology ; Cerebral Amyloid Angiopathy/pathology ; Amyloid ; Risk Factors ; Hemorrhage ; Plaque, Amyloid/pathology
Chemical Substances	Apolipoprotein E4 ; Amyloid
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13704
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Article: Co-registration of MALDI-MSI and histology demonstrates gangliosides co-localize with amyloid beta plaques in Alzheimer's disease.

Ollen-Bittle, Nikita / Pejhan, Shervin / Pasternak, Stephen H / Keene, C Dirk / Zhang, Qi / Whitehead, Shawn N

Research square

2024

Abstract: Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioural alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have ... ...

Abstract	Alzheimer's disease (AD) is a progressive neurological condition characterized by impaired cognitive function and behavioural alterations. While AD research historically centered around mis-folded proteins, advances in mass spectrometry techniques have triggered increased exploration of the AD lipidome with lipid dysregulation emerging as a critical player in AD pathogenesis. Gangliosides are a class of glycosphingolipids enriched within the central nervous system. Previous work has suggested a shift in a-series gangliosides from complex (GM1) to simple (GM2 and GM3) species may be related to the development of neurodegenerative disease. Additionally, complex gangliosides with 20 carbon sphingosine chains have been shown to increase in the aging brain. In this study, we utilized matrix assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) to interrogate the
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3985371/v1
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Article ; Online: Leveraging neuropathological data in pharmacoepidemiology: A promising approach for dementia prevention?

Marcum, Zachary A / Keene, C Dirk / Larson, Eric B

Pharmacoepidemiology and drug safety

2020 Volume 30, Issue 1, Page(s) 1–3

MeSH term(s)	Alzheimer Disease ; Dementia/epidemiology ; Dementia/prevention & control ; Humans ; Nervous System Diseases ; Pharmacoepidemiology
Language	English
Publishing date	2020-06-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1099748-9
ISSN	1099-1557 ; 1053-8569
ISSN (online)	1099-1557
ISSN	1053-8569
DOI	10.1002/pds.5068
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Article ; Online: Mapping the individual human cortex using multidimensional MRI and unsupervised learning.

Kundu, Shinjini / Barsoum, Stephanie / Ariza, Jeanelle / Nolan, Amber L / Latimer, Caitlin S / Keene, C Dirk / Basser, Peter J / Benjamini, Dan

Brain communications

2023 Volume 5, Issue 6, Page(s) fcad258

Abstract: Human evolution has seen the development of higher-order cognitive and social capabilities in conjunction with the unique laminar cytoarchitecture of the human cortex. Moreover, early-life cortical maldevelopment has been associated with various ... ...

Abstract	Human evolution has seen the development of higher-order cognitive and social capabilities in conjunction with the unique laminar cytoarchitecture of the human cortex. Moreover, early-life cortical maldevelopment has been associated with various neurodevelopmental diseases. Despite these connections, there is currently no noninvasive technique available for imaging the detailed cortical laminar structure. This study aims to address this scientific and clinical gap by introducing an approach for imaging human cortical lamina. This method combines diffusion-relaxation multidimensional MRI with a tailored unsupervised machine learning approach that introduces enhanced microstructural sensitivity. This new imaging method simultaneously encodes the microstructure, the local chemical composition and importantly their correlation within complex and heterogenous tissue. To validate our approach, we compared the intra-cortical layers obtained using our
Language	English
Publishing date	2023-10-06
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcad258
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Article: Advancements in high-resolution 3D microscopy analysis of endosomal morphology in postmortem Alzheimer's disease brains.

Rose, Shannon E / Williams, C Andrew / Hailey, Dale W / Mishra, Swati / Kirkland, Amanda / Keene, C Dirk / Garden, Gwenn A / Jayadev, Suman / Young, Jessica E

Frontiers in neuroscience

2024 Volume 17, Page(s) 1321680

Abstract: Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing ... ...

Abstract	Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing sporadic, late-onset AD (LOAD). Characterization of ELN pathology and the underlying pathophysiology is a promising area of translational AD research and drug development. However, rigorous study of ELN vesicles in AD and aged control brains poses a unique constellation of methodological challenges due in part to the small size of these structures and subsequent requirements for high-resolution imaging. Here we provide a detailed protocol for high-resolution 3D morphological quantification of neuronal endosomes in postmortem AD brain tissue, using immunofluorescent staining, confocal imaging with image deconvolution, and Imaris software analysis pipelines. To demonstrate these methods, we present neuronal endosome morphology data from 23 sporadic LOAD donors and one aged non-AD control donor. The techniques described here were developed across a range of AD neuropathology to best optimize these methods for future studies with large cohorts. Application of these methods in research cohorts will help advance understanding of ELN dysfunction and cytopathology in sporadic AD.
Language	English
Publishing date	2024-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2023.1321680
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Article ; Online: Aberrant splicing of PSEN2, but not PSEN1, in individuals with sporadic Alzheimer's disease.

Course, Meredith M / Gudsnuk, Kathryn / Keene, C Dirk / Bird, Thomas D / Jayadev, Suman / Valdmanis, Paul N

Brain : a journal of neurology

2022 Volume 146, Issue 2, Page(s) 507–518

Abstract: Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and ... ...

Abstract	Alzheimer's disease is the most common neurodegenerative disease, characterized by dementia and premature death. Early-onset familial Alzheimer's disease is caused in part by pathogenic variants in presenilin 1 (PSEN1) and presenilin 2 (PSEN2), and alternative splicing of these two genes has been implicated in both familial and sporadic Alzheimer's disease. Here, we leveraged targeted isoform-sequencing to characterize thousands of complete PSEN1 and PSEN2 transcripts in the prefrontal cortex of individuals with sporadic Alzheimer's disease, familial Alzheimer's disease (carrying PSEN1 and PSEN2 variants), and controls. Our results reveal alternative splicing patterns of PSEN2 specific to sporadic Alzheimer's disease, including a human-specific cryptic exon present in intron 9 of PSEN2 as well as a 77 bp intron retention product before exon 6 that are both significantly elevated in sporadic Alzheimer's disease samples, alongside a significantly lower percentage of canonical full-length PSEN2 transcripts versus familial Alzheimer's disease samples and controls. Both alternatively spliced products are predicted to generate a prematurely truncated PSEN2 protein and were corroborated in an independent cerebellum RNA-sequencing dataset. In addition, our data in PSEN variant carriers is consistent with the hypothesis that PSEN1 and PSEN2 variants need to produce full-length but variant proteins to contribute to the onset of Alzheimer's disease, although intriguingly there were far fewer full-length transcripts carrying pathogenic alleles versus wild-type alleles in PSEN2 variant carriers. Finally, we identify frequent RNA editing at Alu elements present in an extended 3' untranslated region in PSEN2. Overall, this work expands the understanding of PSEN1 and PSEN2 variants in Alzheimer's disease, shows that transcript differences in PSEN2 may play a role in sporadic Alzheimer's disease, and suggests novel mechanisms of Alzheimer's disease pathogenesis.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Amyloid beta-Protein Precursor/genetics ; Mutation ; Presenilin-2/genetics ; Presenilin-1/genetics ; Neurodegenerative Diseases
Chemical Substances	Amyloid beta-Protein Precursor ; Presenilin-2 ; Presenilin-1 ; PSEN2 protein, human
Language	English
Publishing date	2022-08-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awac294
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Article ; Online: Neuropathologic Burden and Dementia in Nonagenarians and Centenarians: Comparison of 2 Community-Based Cohorts

Cholerton, Brenna / Latimer, Caitlin S / Crane, Paul K / Corrada, Maria M / Gibbons, Laura E / Larson, Eric B / Kawas, Claudia H / Keene, C Dirk / Montine, Thomas J

Neurology

2024 Volume 102, Issue 3, Page(s) e208060

Abstract: Background and objectives: The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially ... ...

Abstract	Background and objectives: The aim of this study was to compare 2 large clinicopathologic cohorts of participants aged 90+ and to determine whether the association between neuropathologic burden and dementia in these older groups differs substantially from those seen in younger-old adults. Methods: Autopsied participants from The 90+ Study and Adult Changes in Thought (ACT) Study community-based cohort studies were evaluated for dementia-associated neuropathologic changes. Associations between neuropathologic variables and dementia were assessed using logistic or linear regression, and the weighted population attributable fraction (PAF) per type of neuropathologic change was estimated. Results: The 90+ Study participants (n = 414) were older (mean age at death = 97.7 years) and had higher amyloid/tau burden than ACT <90 (n = 418) (mean age at death = 83.5 years) and ACT 90+ (n = 401) (mean age at death = 94.2 years) participants. The ACT 90+ cohort had significantly higher rates of limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), microvascular brain injury (μVBI), and total neuropathologic burden. Independent associations between individual neuropathologic lesions and odds of dementia were similar between all 3 groups, with the exception of μVBI, which was associated with increased dementia risk in the ACT <90 group only (odds ratio 1.5, 95% CI 1.2-1.8, Discussion: Our results suggest that specific neuropathologic features may differ in their effect on dementia among nonagenarians and centenarians from cohorts with different selection criteria and study design. Furthermore, microvascular lesions seem to have a more significant effect on dementia in younger compared with older participants. The results from this study demonstrate that different populations may require distinct dementia interventions, underscoring the need for disease-specific biomarkers.
MeSH term(s)	Aged, 80 and over ; Humans ; Alzheimer Disease/pathology ; Brain/pathology ; Centenarians ; Nonagenarians ; Dementia/epidemiology ; Dementia/pathology ; Nervous System Diseases/pathology
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000208060
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Article ; Online: Brain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer's disease.

Huang, Zhi / Merrihew, Gennifer E / Larson, Eric B / Park, Jea / Plubell, Deanna / Fox, Edward J / Montine, Kathleen S / Latimer, Caitlin S / Dirk Keene, C / Zou, James Y / MacCoss, Michael J / Montine, Thomas J

Nature communications

2023 Volume 14, Issue 1, Page(s) 2747

Abstract: Resilience to Alzheimer's disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, ... ...

Abstract	Resilience to Alzheimer's disease is an uncommon combination of high disease burden without dementia that offers valuable insights into limiting clinical impact. Here we assessed 43 research participants meeting stringent criteria, 11 healthy controls, 12 resilience to Alzheimer's disease and 20 Alzheimer's disease with dementia and analyzed matched isocortical regions, hippocampus, and caudate nucleus by mass spectrometry-based proteomics. Of 7115 differentially expressed soluble proteins, lower isocortical and hippocampal soluble Aβ levels is a significant feature of resilience when compared to healthy control and Alzheimer's disease dementia groups. Protein co-expression analysis reveals 181 densely-interacting proteins significantly associated with resilience that were enriched for actin filament-based processes, cellular detoxification, and wound healing in isocortex and hippocampus, further supported by four validation cohorts. Our results suggest that lowering soluble Aβ concentration may suppress severe cognitive impairment along the Alzheimer's disease continuum. The molecular basis of resilience likely holds important therapeutic insights.
MeSH term(s)	Humans ; Alzheimer Disease/metabolism ; Proteomics ; Brain/metabolism ; Cognitive Dysfunction/metabolism ; Hippocampus/metabolism ; Neocortex/metabolism
Language	English
Publishing date	2023-05-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38376-x
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Article ; Online: Traumatic Brain Injury and Risk of Neurodegenerative Disorder.

Brett, Benjamin L / Gardner, Raquel C / Godbout, Jonathan / Dams-O'Connor, Kristen / Keene, C Dirk

Biological psychiatry

2021 Volume 91, Issue 5, Page(s) 498–507

Abstract: Traumatic brain injury (TBI), particularly of greater severity (i.e., moderate to severe), has been identified as a risk factor for all-cause dementia and Parkinson's disease, with risk for specific dementia subtypes being more variable. Among the ... ...

Abstract	Traumatic brain injury (TBI), particularly of greater severity (i.e., moderate to severe), has been identified as a risk factor for all-cause dementia and Parkinson's disease, with risk for specific dementia subtypes being more variable. Among the limited studies involving neuropathological (postmortem) confirmation, the association between TBI and risk for neurodegenerative disease increases in complexity, with polypathology often reported on examination. The heterogeneous clinical and neuropathological outcomes associated with TBI are likely reflective of the multifaceted postinjury acute and chronic processes that may contribute to neurodegeneration. Acutely in TBI, axonal injury and disrupted transport influences molecular mechanisms fundamental to the formation of pathological proteins, such as amyloid-β peptide and hyperphosphorylated tau. These protein deposits may develop into amyloid-β plaques, hyperphosphorylated tau-positive neurofibrillary tangles, and dystrophic neurites. These and other characteristic neurodegenerative disease pathologies may then spread across brain regions. The acute immune and neuroinflammatory response involves alteration of microglia, astrocytes, oligodendrocytes, and endothelial cells; release of downstream pro- and anti-inflammatory cytokines and chemokines; and recruitment of peripheral immune cells. Although thought to be neuroprotective and reparative initially, prolongation of these processes may promote neurodegeneration. We review the evidence for TBI as a risk factor for neurodegenerative disorders, including Alzheimer's dementia and Parkinson's disease, in clinical and neuropathological studies. Further, we describe the dynamic interactions between acute response to injury and chronic processes that may be involved in TBI-related pathogenesis and progression of neurodegeneration.
MeSH term(s)	Alzheimer Disease/metabolism ; Brain/metabolism ; Brain Injuries, Traumatic/complications ; Brain Injuries, Traumatic/metabolism ; Brain Injuries, Traumatic/pathology ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Neurodegenerative Diseases/metabolism ; Parkinson Disease/metabolism
Language	English
Publishing date	2021-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2021.05.025
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