Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study

Dugan, Adam; Nelson, Peter T.; Katsumata, Yuriko; Shade, Lincoln MP; Boehme, Kevin L.; Teylan, Merilee; Cykowski, Matthew D.; Mukherjee, Shubhabrata; Kauwe, John S. K.; Hohman, Timothy J.; Schneider, Julie A.; Fardo, David W.

doi:10.1186/s40478-021-01250-2

Cited by 30 publications

(31 citation statements)

References 67 publications

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“…In a recent study of autopsy cohort data combined with genetic information, associations were confirmed between HS risk and TMEM106B , ABCC9 , GRN , and APOE gene variants. 46 Unlike the other HS risk genes, ABCC9 genetic variation was not associated with LATE-NC but was associated only with the risk for HS pathology among individuals with LATE-NC. 46 The ABCC9 genetic variation may contribute pathogenetically by causing differential vulnerability for vascular pathologies that are upstream of HS in a mechanistic sense.…”

Section: Discussionmentioning

confidence: 89%

Limbic-Predominant Age-Related TDP-43 Encephalopathy

et al. 2022

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Background and Objectives:Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is present in ∼25% of older persons’ brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathological correlates of HS in LATE-NC are not well understood.Methods:In this retrospective autopsy cohort study, data derived from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, which included neurological status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p<0.05 in this exploratory study.Results:A total of 408 participants were included (n=221 were LATE+/HS-; n=145 were LATE+/HS+, and n=42 were LATE-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% demented). Compared to HS- participants, LATE-NC+ participants with HS trended towards having worse cognitive status and scored lower on the “Personal Care” and “Orientation” domains (both p=0.03). Among LATE-NC+ participants with Braak NFT Stages 0-IV (n=88), HS+ participants were more impaired in the “Memory” and “Orientation” domains (both p=0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n=42) were relatively likely to have had strokes (p=0.03). Comparing LATE-NC+ participants with or without HS, there were no differences in Alzheimer’s disease neuropathologies (Thal Aβ phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC Stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC Stage 3); p<0.001. LATE-NC+ brains with HS also tended to have more severe Circle of Willis atherosclerosis and arteriolosclerosis pathologies.Discussion:In this cohort skewed toward severely demented participants, LATE-NC+HS pathology was not associated with seizures or with Alzheimer’s-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy, and with more severe non-Aβ vessel wall pathologies.

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Section: Discussionmentioning

confidence: 89%

Limbic-Predominant Age-Related TDP-43 Encephalopathy

et al. 2022

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“…AD; and ALCDEM could not work well for LATE vs. Control. The APOE e4 genetic variation was related to LATE and AD [17, 31], so we further examined the relationships of LATE and AD with ALCDEM/ALCDEMIF and APOE e4 carrier. First, by using the chi-square test, we analyzed the relationship between alcohol and APOE e4 carrier status (see Table 7).…”

Section: Resultsmentioning

confidence: 99%

“…Another related work [40] studied the old-aged male cohort for cognitive functions and clinical dementia diagnosis, without considering APOE or pathological or etiological distinction between AD and LATE. In addition, recent work [31] tested 4 genetic variants for their links with LATE and AD adjusted for APOE e4, with no environmental or lifestyle factors considered.…”

Section: Discussionmentioning

confidence: 99%

Alcohol Intake Differentiates AD and LATE: A Telltale Lifestyle from Two Large-Scale Datasets

Peng

Nelson

et al. 2022

Preprint

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Alzheimer’s disease (AD), as a progressive brain disease, affects cognition, memory, and behavior. Similarly, limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently defined common neurodegenerative disease that mimics the clinical symptoms of AD. At present, the risk factors implicated in LATE and those distinguishing LATE from AD are largely unknown. We leveraged an integrated feature selection-based algorithmic approach, to identify important factors differentiating subjects with LATE and/or AD from Control on significantly imbalanced data. We analyzed two datasets ROSMAP and NACC and discovered that alcohol consumption was a top lifestyle and environmental factor linked with LATE and AD and their associations were differential. In particular, we identified a specific subpopulation consisting of APOE e4 carriers. We found that, for this subpopulation, light-to-moderate alcohol intake was a protective factor against both AD and LATE, but its protective role against AD appeared stronger than LATE. The codes for our algorithms are available at https://github.com/xinxingwu-uk/PFV.

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“…SUR1-TRPM4 is blocked by some sulfonylureas, such as glibenclamide [ 58 ]. Moreover, polymorphism of the ABCC9 gene, which encodes SUR2, is associated with hippocampal sclerosis [ 59 , 60 ]. Unfortunately, to date, no BBB-permeable and clinically used sulfonylureas have been reported.…”

Section: Association Of Pharmacological and Pharmacokinetic Propertie...mentioning

confidence: 99%

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

Ogura

Yamaguchi

2022

IJMS

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Dementia dramatically affects the activities of daily living and quality of life; thus, many therapeutic approaches for overcoming dementia have been developed. However, an effective treatment regimen is yet to be developed. As diabetes is a well-known risk factor for dementia, drug repositioning and repurposing of antidiabetic drugs are expected to be effective dementia treatments. Several observational studies have been useful for understanding the effectiveness of antidiabetic drugs in treating dementia, but it is difficult to conclusively analyze the association between antidiabetic drug treatment and the risk of developing dementia after correcting for potential confounding factors. Mechanism-based approaches may provide a better understanding of the effectiveness of antidiabetic drugs for treating dementia. Since the peripheral circulation and the central nerve system are separated by the blood–brain barrier, it is important to understand the regulation of the central glucose metabolism. In this review, we discuss the pharmacological and pharmacokinetic properties of antidiabetic drugs in relation to treating dementia.

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Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study

Cited by 30 publications

References 67 publications

Limbic-Predominant Age-Related TDP-43 Encephalopathy

Limbic-Predominant Age-Related TDP-43 Encephalopathy

Alcohol Intake Differentiates AD and LATE: A Telltale Lifestyle from Two Large-Scale Datasets

The Effectiveness of Antidiabetic Drugs in Treating Dementia: A Peek into Pharmacological and Pharmacokinetic Properties

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