Progression to Dementia in Very Late‐Onset Schizophrenia‐Like Psychosis Stratified by Alzheimer's Disease and Lewy Body Disease Biomarkers: A Retrospective Cohort Study
Aug 2026· Psychogeriatrics· Vol 26· 0 citations· 41 references
Medicine
TL;DR
AD and/or LBD biomarker‐positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design.
Abstract
ABSTRACT Background Very late‐onset schizophrenia‐like psychosis (VLOSLP) is clinically heterogeneous, and its relationship with dementia‐related neurodegenerative disease remains unresolved. We examined whether Alzheimer's disease (AD) and Lewy body disease (LBD) biomarker status were associated with dementia progression in VLOSLP. Methods We retrospectively identified patients who visited the University of Osaka Hospital between January 2018 and December 2023 and met criteria for VLOSLP. Twenty‐two participants with AD and/or LBD biomarker data and at least one follow‐up assessment within 775 days were classified as biomarker‐negative (BMs‐neg; n = 7) or biomarker‐positive (BMs‐pos; n = 15). Group comparisons were performed using Mann–Whitney U tests and Fisher's exact tests. Results The BMs‐pos group showed older onset age and lower memory scores than the BMs‐neg group. Dementia progression was more frequent in the BMs‐pos group than in the BMs‐neg group, although the difference was not statistically significant (8/15 [53.3%] vs. 1/7 [14.3%]; p = 0.165; odds ratio 6.31; 95% CI 0.55–353.18). Five of eight participants with AD biomarker positivity progressed to AD dementia. Three of seven participants with LBD biomarker positivity progressed to dementia, including two diagnosed with dementia with Lewy bodies. Follow‐up MMSE, CDR, and CDR‐SB scores differed significantly between groups. Conclusions AD and/or LBD biomarker‐positive VLOSLP may be associated with greater dementia progression and cognitive decline, although findings should be interpreted cautiously given the small sample size and retrospective design. These results support the clinical value of considering neurodegenerative biomarkers when evaluating the prognosis and underlying pathology of VLOSLP.
INTRODUCTION
Early-Onset (EOAD) and Late-Onset Alzheimer's Disease (LOAD) are often described as presenting distinct cognitive phenotypes. However, reported differences are inconsistent and may reflect demographic and severity-related confounding rather than stable etiological distinctions.
MATERIALS AND METHODS
A retrospective analysis was conducted in 776 patients with clinically diagnosed Alzheimer's disease (EOAD, n = 175; LOAD, n = 601). Cognitive performance was assessed using the Addenbrooke's Cognitive Examination III (ACE-III) and the Mini-Mental State Examination (MMSE). Dementia severity was staged using the Functional Assessment Staging Tool (FAST). Cognitive outcomes were analysed using age- and severity-adjusted ANCOVA models including a diagnosis × age interaction. Severity-stratified and domain-level analyses were also performed.
RESULTS
Unadjusted analyses revealed limited EOAD-LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic variables and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive performance showed similar cross-sectional patterns across groups and was primarily determined by dementia severity.
DISCUSSION
Small, stage-dependent differences observed at mild and moderate stages did not persist in more advanced dementia and did not indicate stable cognitive dissociation between EOAD and LOAD.
CONCLUSIONS
After adjustment for demographic factors and dementia severity, EOAD and LOAD do not exhibit distinct cognitive profiles on ACE-III. Cognitive performance reflects disease stage rather than age at onset, supporting the use of ACE-III for staging cognitive impairment rather than for differentiating EOAD from LOAD in typical amnestic presentations.
Anna Barczak, Anna Krempa-Kowalewska, M. Golan· Current Alzheimer Research· 0 citations
ABSTRACT Background Gait speed (GS) has been suggested as a predictor of incident dementia in old age. However, the mechanisms underlying this body–mind connection remain unclear, and it is still unknown whether trajectories of GS decline differ according to levels of blood biomarkers related to Alzheimer's disease (ad). This study aims to investigate the association between levels of seven blood biomarkers related to AD and long‐term GS changes in dementia‐free older adults living in the community. Methods The present study included 1665 community‐dwelling adults ≥ 60 years, followed for 15 years, drawn from the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). GS (m·s−1) was assessed at baseline and at five subsequent follow‐up time points. Blood biomarkers, including serum amyloid‐β42 to amyloid‐β40 ratio (Aβ42/40), phosphorylated Tau181 (p‐Tau181) and Tau217 (p‐Tau217), total Tau (t‐Tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), were collected from peripheral venous blood samples at baseline. Linear mixed‐effects models were implemented to investigate the association between blood biomarkers and GS changes over time. Results After adjusting for potential confounders, participants in the highest quartile of p‐Tau181 (Model I; 4th quartile β: −0.008, 95% CI: −0.013; −0.003), p‐Tau217 (Model I; 4th quartile β: −0.010, 95% CI: −0.015; −0.005), NfL (Model I; 4th quartile β: −0.013, 95% CI: −0.019; −0.006) and GFAP (Model I; 4th quartile β: −0.007, 95% CI: −0.013; −0.002) exhibited a steeper decline in GS over time, as compared with those in the lowest quartile. Notably, participants in these highest quartiles developed mobility limitations (GS < 0.8 m·s−1), on average, 2.3 to 6.0 years earlier. Of note, only the association between NfL and GS changes over time persisted after further adjusting for time‐varying global cognition. Conclusions Higher blood biomarker levels of AD are associated with accelerated trajectories of GS decline and earlier onset of mobility limitations. Consequently, a faster decline in GS may reflect underlying neurodegeneration and indicate changes in brain health.
Javier Leal-Martín, G. Grande, Caterina Gregorio et al.· Journal of Cachexia, Sarcope...· 0 citations
Abstract INTRODUCTION The Mild Behavioral Impairment Checklist (MBI‐C) captures neuropsychiatric symptoms in individuals at risk of dementia. In this study, we examined MBI‐C scores in autosomal dominant Alzheimer's disease (ADAD). METHODS We included 83 cognitively unimpaired presenilin‐1 E280A mutation carriers and 114 non‐carriers with MBI‐C, obfjective cognition, and subjective cognitive decline (SCD) assessments. Study sub‐samples underwent neuroimaging to assess Alzheimer's disease (AD) pathology and neurodegeneration. RESULTS MBI‐C total scores were greater in carriers than non‐carriers (r rb = 0.19 [95% confidence interval (CI) 0.05, 0.31], P = 0.009), driven by impulse dyscontrol symptoms. Elevated MBI‐C scores were associated with higher study partner–reported SCD scores (β = 0.28 [95% CI 0.07, 0.050], P = 0.008) and with greater neocortical amyloid beta (β = 0.46 [95% CI 0.17, 0.075], P = 0.003) among carriers. DISCUSSION Our study reveals that mild behavioral impairment symptoms may emerge before cognitive decline in ADAD and supports the MBI‐C as a tool for detecting early behavioral changes linked to AD pathology and identifying at‐risk individuals for clinical trials and early intervention.
Catarina Tristão-Pereira, D. Vásquez, Jorge Alcina et al.· Alzheimer's & Dementia· 0 citations
Reliable differentiation of Parkinson’s disease/Lewy body dementia (PD/LBD) from frontotemporal dementia (FTD) affects treatment strategy and clinical trial eligibility, yet confirmatory biomarker testing remains costly and unevenly available. Whether routine cognitive trajectories can support testing prioritization has not been systematically quantified. We performed a progressive inclusion analysis of 1,129 National Alzheimer’s Coordinating Center participants with PD/LBD (
n
= 385) or FTD (
n
= 744) to determine the minimum number of serial Montreal Cognitive Assessment (MoCA) administrations required for diagnostic separation. Random forest classifiers used seven MoCA subdomain slopes from the first k chronological assessments (
k
= 2 through
k
= 8), with five-fold stratified cross-validation and 500-iteration bootstrap confidence intervals. In the primary full-cohort analysis, two assessments yielded AUC = 0.785 (95% CI 0.757–0.814; sensitivity = 0.922; specificity = 0.525). The interval-restricted 6–12 month subset yielded AUC = 0.837 (95% CI 0.787–0.885), near the lower edge of published biomarker-panel ranges in an indirect comparison, although its lower confidence bound remained below 0.85. Discrimination persisted after age matching (AUC = 0.794, 95% CI 0.761–0.826; residual age gap = −0.3 years) and age restriction to 55–75 years (AUC = 0.777, 95% CI 0.741–0.814). Age alone yielded lower discrimination (AUC = 0.721, 95% CI 0.691–0.751) than MoCA slopes, while slopes plus age yielded AUC = 0.867 (95% CI 0.845–0.888). Four-assessment performance was AUC = 0.831 (95% CI 0.791–0.873), consistent with an apparent sample-size-limited plateau as eligible N contracted from 391 at
k
= 4 to 98 at
k
= 6. These findings support serial MoCA trajectory analysis as an exploratory tool for prioritizing confirmatory diagnostic testing, with age sensitivity, subtype sensitivity, and operating-point performance quantified.
Wei Lin, Sanjeet S. Grewal, Richard W. Byrne· Frontiers in Aging Neuroscie...· 0 citations
Socio‐demographic variables, rather than individual non‐motor symptoms, demonstrate the strongest independent associations with diagnostic timing in this cohort, highlighting the need for socio‐demographically tailored screening strategies in the prodromal phase of PD.
Shakawat Hossain, Farjana Islam· Health Science Reports· 0 citations
Abstract INTRODUCTION In clinical practice, patients with Alzheimer's disease (AD) often present with cognitive and functional profiles that diverge from what is expected. We tested whether the Mini‐Mental State Examination Clinical Dementia Rating Sum of Boxes (MMSE–CDR‐SB) residual, defined as observed minus expected CDR‐SB from a published MMSE–CDR‐SB reference equation, reflects clinically meaningful deviation from the expected cognitive–functional relationship. METHODS Using National Alzheimer's Coordinating Center data, we analyzed an autopsy cohort (n = 1981) and a separate clinical diagnosis cohort (n = 3184). Negative residual values indicated less functional impairment than expected for a given cognitive score, and positive values indicated greater functional impairment than expected. Associations were examined using multivariable logistic regression adjusted for MMSE score range, age, sex, and education. RESULTS Lower residual values were associated with lower odds of amyloid and AD‐type tau pathology. Higher residual values showed a directional association with transactive response DNA binding protein 43 kDa; vascular burden was also associated with the residual index but across a broader range. In the clinical cohort, higher residual values were enriched in progressive supranuclear palsy and frontotemporal lobar degeneration (other), whereas AD cases clustered near the reference pattern. DISCUSSION The MMSE–CDR‐SB residual may help flag less AD‐typical presentations for further etiologic evaluation, but cannot be interpreted as a pathology‐specific marker due to substantial overlap across diagnostic groups.
A. Mounié, Kenichiro Sato, Saki Nakashima et al.· Alzheimer's & Dementia· 0 citations
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