From function to structure: Cortical thickness correlates of olfactory dysfunction across cognitively normal, mild cognitive impairment and Parkinson's disease.

Linking cognitive variability and Alzheimer's disease biomarkers by neurocognitive status

Abstract INTRODUCTION This study aimed to assess intra‐individual cognitive variability (IICV) in relation to Alzheimer's disease (AD) biomarkers. METHODS The National Alzheimer's Coordinating Center sample (n = 879), aged 50+ with a complete neuropsychological evaluation and AD biomarker data available (64% cognitively intact; 36% cognitively impaired). Moderated regression models using AD biomarkers, neurocognitive status, and interaction effects predicted IICV. AD biomarkers included cerebrospinal fluid (CSF) measures of Aβ1‐42, phosphorylated tau 181 (p‐Tau181), total tau (t‐Tau), and amyloid positron emission tomography. RESULTS Increased AD biomarker burden was associated with increased IICV among cognitively impaired individuals (correlational strength ranging from 0.149 to 0.460) but not among the cognitively intact group. DISCUSSION Increases in measures of amyloid, soluble tau, and neurodegeneration are associated with increased IICV among cognitively impaired older adults. The findings underscore the potential of IICV as a sensitive outcome measure. Future studies should replicate findings longitudinally and in more diverse samples.

Stages of objective memory impairment (SOMI) as a predictor of clinical progression in the A4 study

Background About one third of amyloid positive, cognitively normal individuals develop mild cognitive impairment or clinical Alzheimer dementia (AD) over 5 years of follow-up. Sensitive cognitive measures, in addition to biomarkers of amyloid pathology, add to the efficiency of secondary prevention trials by identifying cognitively normal individuals at greatest risk of clinical progression. The Stages of Objective Memory Impairment (SOMI) system, based on the picture version of the Free and Cued Selective Reminding Test with immediate recall (pFCSRT+IR), predicted clinical progression in two observational studies. Objective Our objective was to extend SOMI’s findings to clinical trials using participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s(A4) study. Methods Eligible participants were cognitively normal, had a Clinical Dementia Rating (CDR) =0, an elevated amyloid level, the pFCSRT+IR, pTau217, and longitudinal data on the CDR. Cox proportional hazards model was used to assess the association of baseline SOMI stage for clinical progression defined by time to the first of 2 consecutive CDRs > 0 or CDR>0 at last assessment. The sample was censored at 4.5 years of follow-up. Results Of the 911 eligible participants, mean age was 72 years, 59% were female, 62% were APOE ε4 carriers, and 37% progressed over 4.5 years. Hazard ratios (HR) for progression were estimated with follow-up time as the timescale and the SOMI 0 group as the reference. The HRs for progression across SOMI stage increased from 1.48(1.15–1.92 p=.003) for SOMI-1, to 1.83 (1.32–2.54, p ≤ 0.001) for SOMI-2, and to 3.04 (1.97–4.68, p ≤ 0.001) for SOMI 3/4. SOMI remained an independent and significant predictor when pTau217 was added to the model. Conclusion SOMI’s risk profile in A4 was similar to prior findings in observational cohorts. SOMI provides a low-cost, non-invasive enrichment tool for identifying individuals at risk for early cognitive decline in secondary prevention trials.

Target-level convergence of directional prefrontal connectivity across Alzheimer’s disease stages: an fNIRS study

Background Alzheimer’s disease (AD) is increasingly recognized as involving network-level dysfunction rather than isolated regional impairment. Although functional and effective connectivity have been studied in dementia, the reorganization of directional information flow within prefrontal networks remains incompletely characterized, particularly with functional near-infrared spectroscopy (fNIRS). Objective This study investigated whether target-level convergence of directional effective connectivity within the prefrontal cortex differs across clinically defined cognitive groups, with emphasis on the mild cognitive impairment (MCI) vs. AD contrast. Methods fNIRS signals were recorded from 60 participants (healthy controls (HC), MCI, and AD) during resting state and cognitive paradigms, including working memory (2-back), semantic verbal fluency (SVFT), and Stroop tasks. Signals from 48 prefrontal channels were aggregated into eight anatomically defined regions. Directional interactions were quantified using transfer entropy (TE) with adaptive hyperparameter tuning. Group differences were assessed using linear mixed-effects models with covariate adjustment and target-wise false discovery rate correction. Robustness was evaluated through parameter sensitivity, covariate, and surrogate-normalization analyses. Results The analysis revealed structured target-level convergence patterns of directional connectivity across clinically defined cognitive groups, with the most prominent alterations observed in the MCI vs. AD comparison. Compared with MCI, AD showed reduced directed information flow to the right frontopolar cortex (FPC-R) during the 2-back and SVFT tasks (β = −0.71 to −1.18, q < 0.05), indicating diminished convergence of inputs from distributed prefrontal regions. Conversely, convergence toward the left dorsolateral prefrontal cortex (DLPFC-L) increased across multiple paradigms (β = 0.56–0.85, q < 0.05). Additional task-specific alterations were observed during the Stroop paradigm, although some effects demonstrated reduced stability in sensitivity analyses. Exploratory ROC analysis suggested contrast-specific discriminative utility of selected convergence features, with moderate performance in MCI vs. AD (AUC ≈ 0.77). Conclusion These findings suggest that MCI and AD are associated with distinct patterns of directional information flow within prefrontal networks, characterized by reduced convergence toward FPC-R and increased directional influence toward DLPFC-L. Collectively, the results indicate that TE applied to task-based fNIRS can capture directional alterations in network connectivity, highlighting the potential of directional connectivity metrics for studying network-level changes associated with cognitive decline.

Altered Olfactory Adaptation of Primary Olfactory Cortex-Hippocampus-Parietal Lobe in Alzheimer's Disease Continuum: An Olfactory Task fMRI Study.

Olfactory adaptation, the progressive reduction of neural responses to repeated odor stimulation, is closely linked to cognitive function and is altered in Alzheimer's disease (AD). However, its evolution across biomarker-defined stages and relationship with plasma p-tau217 remain unclear. We studied 168 participants classified by plasma p-tau217: cognitively normal (p-tau217-NC, n = 37; p-tau217+NC, n = 8), subjective cognitive decline (p-tau217-SCD, n = 57; p-tau217+SCD, n = 16), and mild cognitive impairment (p-tau217-MCI, n = 40; p-tau217+MCI, n = 10). Odor-induced fMRI with four concentrations (0.032%, 0.1%, 0.32%, 1.0%) presented in a fixed ascending order, although concentration effects could not be fully separated from time-related factors and other confounders, to assess activation in the primary olfactory cortex (POC), hippocampus (HP), and parietal lobe (PL). Receiver operating characteristic (ROC) analyses were performed using logistic regression models. In NC groups, adaptation emerged at 0.1% and 0.32% odor conditions. In p-tau217-SCD, POC adaptation was delayed to 1.0% odor condition, HP was largely preserved, and PL was dysregulated. p-tau217+SCD and MCI groups showed delayed and dysregulated adaptation across all regions. Odor adptations were associated with plasma p-tau217 levels and olfactory memory (p_unc < 0.05, p_FDR > 0.05). Furthermore, plasma p-tau217 partially mediated the relationship between adaptation-related alterations and olfactory memory. ROC analyses indicated that olfactory adaptation may distinguished individuals across disease stages, require further confirmation in independent cohorts. These findings reveal that impaired olfactory adaptation may represent an early signature associated with AD continuum, particularly in SCD and p-tau217-positive stages.

Alzheimer's Co-Pathology Burden on Basal Forebrain Atrophy and Cognitive Impairment in Dementia with Lewy Bodies: A Cross-Sectional Pilot Study.

OBJECTIVE Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer's disease (AD), with significant pathological overlap between the two conditions. However, the impact of Alzheimer's co-pathology on basal forebrain (BF) atrophy and its relationship with neurodegeneration and cognitive decline in patients with DLB remains underexplored. METHODS Forty patients with DLB and 14 healthy controls (HCs) were included from the Centre for Neurodegenerative Diseases, University of Bari. Participants underwent neuropsychological evaluations, 3T magnetic resonance imaging (MRI) scans, and Alzheimer's biomarkers assessment. Patients with DLB were grouped by AD co-pathology using in vivo biomarkers. BF and hippocampal volumes and mean cortical thickness values were analyzed using analysis of covariance (ANCOVA), adjusted for age, sex, and total intracranial volume. Mediation analyses were conducted to examine the indirect effects of Alzheimer's pathology and BF atrophy on neurodegeneration (hippocampal volume and cortical thickness) and cognitive function (Mini-Mental State Examination [MMSE]). RESULTS Patients with DLB exhibited significant BF atrophy compared with HCs (p < 0.001). AD co-pathology was associated with greater BF atrophy (p = 0.046) and reduced mean cortical thickness (p = 0.025). Significant correlations were found between BF volume and the pTAU181/Aβ1-42 ratio (p = 0.009) and between BF volume and MMSE scores (p = 0.016). Mediation analysis revealed that BF atrophy mediated the relationship between the pTau/Aβ42 ratio and neurodegeneration, and that the BF has a direct association with cognitive impairment. INTERPRETATION AD co-pathology in DLB exacerbates BF atrophy, correlating with cognitive decline. These results emphasize the need to consider AD co-pathology in evaluating neurodegeneration in DLB, suggesting future studies should explore targeted interventions to address this pathological overlap. ANN NEUROL 2026.

Functional and Effective EEG Connectivity Patterns in Alzheimer’s Functional and Effective EEG Connectivity Patterns in Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review Disease and Mild Cognitive Impairment: A Systematic Review