{"doi":"10.1016/j.conb.2025.103138","title":"Recent advances in model systems for interrogating diseases of brain aging and associated dementia: Toward human-relevant endophenotypes","abstract":"Neurodegenerative diseases are characterized by key pathological hallmarks, progressive loss of neuronal structure and function, and synaptic loss. Often, mild behavioral changes including subjective cognitive decline and neuropsychiatric symptoms precede the diagnosis and may be a harbinger of disease inception and progression. Despite the success of new treatments that attenuate pathological burden, the ability to translate clinical benefit for cognitive impairment and dementia-related behavioral syndromes remains challenging. While model systems are essential, the appropriate model must be carefully chosen for the specific research question, with complementary model systems necessary to capture multiple aspects of disease. This review will cover the emergence of model systems that provide more translationally relevant trajectories of the progression of pathological changes throughout brain aging, and the advancement of model systems that are able to better capture the spectrum of behavioral and cognitive changes that signal the early prodromal period prior to diagnosis. • Translational research from model systems to clinical benefit for dementia remains a challenge. • No single model is likely to capture the spectrum of endophenotypes across dementias. • Models to study the early prodromal phases of dementia remain an unmet need. • Complementary model systems that together capture the full spectrum of dementia are necessary. • Incorporating comparative evolutionary genomics and behavior will enable better recapitulation of dementia.","journal":"Current Opinion in Neurobiology","year":2025,"id":581340,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":337865,"name":"Stacey J. Sukoff Rizzo","orcid":"0000-0002-1460-8127","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T02:58:47.357782Z","pmid":"41237745","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}