ArticleAnnals of neurology2018
Combined neuropathological pathways account for age-related risk of dementia.
Article in Annals of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers, 2 of them syntheses that pooled it.
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Who cites it
112 citing papers in PubMed, 2 syntheses or guidelines pooled it, 214 citations in OpenAlex.
- The Alzheimer's Association clinical practice guideline for the Diagnostic Evaluation, Testing, Counseling, and Disclosure of Suspected Alzheimer's Disease and Related Disorders (DETeCD-ADRD): Executive summary of recommendations for specialty care.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Guideline
- Exposure to Air Pollution in Relation to Risk of Dementia and Related Outcomes: An Updated Systematic Review of the Epidemiological Literature.Environmental health perspectives · 2021Pooled it
- The Effect of Vitamin D3 Supplementation on the Incidence of Diagnosed Dementia Among Healthy Older Adults-The Finnish Vitamin D Trial.The journals of gerontology. Series A, Biological sciences and medical sciences · 2025Trial
- Morphometric imaging biomarker identifies Alzheimer's disease even among mixed dementia patients.Scientific reports · 2022Trial
- Effect of Age on Clinical Trial Outcome in Participants with Probable Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2021Trial
- Chronic hypertension and social isolation disrupt the blood-brain barrier and memory in a sex-dependent manner.Neurobiology of disease · 2026Article
- Neuropathological diagnoses and age-related differences in Finnish medico-legal autopsies of individuals aged 65 years and older.Forensic science, medicine, and pathology · 2026Article
- Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression.Acta neuropathologica · 2026Article
- Roles of RNA-Binding Nuclear Proteins in Alzheimer's Disease Pathophysiology.ACS pharmacology & translational science · 2026Review
- Four decades of Alzheimer's disease discoveries, data, and research resources: The NIH Alzheimer's Disease Research Center Program.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Microglial reactivity in the hippocampal CA2 is associated with advanced neuronal α-synucleinopathy.bioRxiv : the preprint server for biology · 2026Article
- Vascular cognitive impairment and dementia: Prevention, treatments, mechanisms and management options for the future.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- Neuropathologic Profiles and Associated Cognitive Trajectories in Community-Living Older Adults.JAMA network open · 2026Article
- Radiomics models identifying dementia in patients with normal age-related hippocampal atrophy: a study based on machine learning.BMC geriatrics · 2025Article
- Article
- Beyond Estrogen: Unraveling the Complexities of Hormonal Signaling Pathways in Alzheimer's Disease and Their Implications for Precision Therapy.Molecular neurobiology · 2025Review
- Clinical Implications of an Integrated Clinical and Biological Staging Scheme for Alzheimer's Disease.Journal of clinical neurology (Seoul, Korea) · 2025Article
- The mechanisms underlying TDP-43-associated neurodegeneration in Alzheimer's disease and related dementias.Molecular psychiatry · 2025Review
- Brain and retina in Alzheimer's disease: Pathological intersections and estimates from imaging.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Video Games and Gamification for Assessing Mild Cognitive Impairment: Scoping Review.JMIR mental health · 2025Article
52 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 11 institutions in 2 countries.
Funding
Abstract
objectiveOur objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia.
methodsWe used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively.
resultsAt time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%).
interpretationAge-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.