{"doi":"10.1002/alz.70848","title":"Neuropsychiatric symptoms preceding cognitive impairment: diagnostic value and clinical relevance","abstract":"We appreciate the opportunity to respond to the letter by Tang et al. regarding our recent article “Late-life emergence of neuropsychiatric symptoms and risk of cognitive impairment in cognitively unimpaired individuals.”1 We thank Tang et al. for their thoughtful, clinician-focused interpretation of our findings and for highlighting practical avenues for extension. We share the authors’ interest in the clinical implications of neuropsychiatric symptoms (NPSs) and their potential role in early detection algorithms for dementia. Rapid advances in amyloid/tau imaging and biofluid assays, along with the development of targeted treatments such as anti-amyloid and anti-tau therapies,2-4 signal that we are entering an era in which Alzheimer's disease (AD) can be more precisely diagnosed through biomarkers that capture underlying neuropathology prior to the onset of cognitive impairment, creating opportunities for prevention through early intervention with targeted therapies. However, for these technologies to be effectively integrated into everyday clinical practice and to deliver meaningful benefits to patients, several key challenges must first be addressed. How can we reliably identify individuals at high risk for dementia before the onset of cognitive decline, in a way that is feasible and widely applicable? And who should be considered eligible for specialized diagnostic procedures, which are costly and available only in limited centers, in the absence of measurable cognitive impairment? Accordingly, increasing attention has turned to non-cognitive early symptoms of dementia, including NPSs, motor decline, sensory changes, and disturbances in sleep and appetite.5-7 Among these, NPSs appear particularly promising given their strong and consistent association with emerging dementia. Although NPSs show promise as early clinical indicators of potential cognitive decline, their presentation may overlap with chronic psychiatric conditions or stress-related symptoms, making diagnosis particularly challenging in older adults without cognitive impairment. In this context, our study supports the concept that older adults with newly emergent, persistent, clinically significant NPSs represent a high-risk group for future cognitive decline.1 As highlighted by Tang et al., focusing on such NPSs may help promote awareness of NPSs as pre-dementia symptoms. Moreover, our study suggests that combining NPS assessment with cerebrospinal fluid (CSF)/genetic biomarkers may further improve the accuracy of risk prediction.1 In their letter, Tang et al. suggested incorporating blood-based biomarkers into the screening process alongside NPSs. CSF and plasma biomarkers may serve different roles in diagnostic processes. While CSF biomarkers provide high sensitivity and specificity for AD diagnosis at the cost of invasiveness, plasma biomarkers are much less invasive and more readily accessible.8, 9 In line with this suggestion, we underscore that including a plasma AD biomarker assay in the evaluation of an older adult without cognitive difficulties should consider the clinical context and whether the result would meaningfully inform clinical care for the individual. While we strongly support incorporating NPS screening into routine clinical evaluations, replication in diverse population-based and clinic-based cohorts is needed before specific diagnostic or management algorithms can be recommended. As Tang et al. also noted, further studies with larger samples should investigate factors such as symptom persistence, domain-specific effects of NPSs, interactions between NPSs and biomarkers, and the potential impact of psychotropic medications – most of which were beyond the scope of our study due to sample size limitations. In addition, other elements such as subjective cognitive decline, additional non-cognitive early symptoms of dementia, and known risk/protective factors could also be integrated into diagnostic or management algorithms to improve the ear","journal":"Alzheimer s & Dementia","year":2025,"id":579302,"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":0.9605,"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":286072,"name":"David L. Sultzer","orcid":"0009-0006-5264-5611","position":1,"is_corresponding":false},{"id":1389644,"name":"Therese H. Kim","orcid":null,"position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:58:30.282164Z","pmid":"41147429","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":[]}