Objective:Mild cognitive impairment (MCI) is an at-risk state for dementia, however not all individuals with MCI transition to dementia, and some revert to normal cognition. Here, we investigate whether mild behavioral impairment (MBI), the late-life onset of persistent neuropsychiatric symptoms (NPS), improves the prognostic specificity of MCI.Methods:Participants with MCI from the National Alzheimer's Coordinating Center Uniform Data Set were included. Neuropsychiatric symptoms were operationalized with the neuropsychiatric inventory questionnaire (NPI-Q) to identify participants without NPS and those with MBI (persistent, late-onset NPS). Individuals with late-onset NPS not meeting the MBI persistence criterion (NPS_NOT_MBI) were retained for secondary analyses. Progression to dementia, stable MCI, and reversion to NC after 3 years of follow-up were defined as per NIA-AA and Petersen criteria.Results:The primary sample consisted of 739 participants (NPS- n=409 and MBI+ n=330; 75.16±8.6 years old, 40.5% female). After 3 years, 238 participants (33.6%) progressed to dementia and 90 (12.2%) reverted to NC. Compared to participants without NPS, participants with MBI were significantly more likely to progress to dementia (Adjusted Odds Ratio [AOR]=2.13, 95%CI 1.52-2.99), with an annual progression rate of 14.7% (vs 8.3% for MCI participants without NPS). Compared to participants without NPS, MBI participants were less likely to revert to NC (AOR=0.48, 95%CI 0.28-0.83, 2.5% vs 5.3% annual reversion rate). The NPS_NOT_MBI group (n=331, 76.5±8.6 years old 45.9% female), were more likely to progress to dementia (AOR=2.18, 95%CI 1.56-3.03, 14.3% annual progression rate) but not less likely to revert to NC than those without NPS. Accordingly, both NPS_NOT_MBI and MBI+ participants had lower MMSE scores than NPS- participants after 3 years.Discussion:Late-onset NPS improve the specificity of MCI as an at-risk state for progression to dementia. However, only persistent late-onset NPS are associated with a lower likelihood of reversion to NC, with transient NPS (i.e., NPS_NOT_MBI) not differing from the NPS- group. Clinical prognostication can be improved by incorporating late-onset NPS, especially those that persist (i.e., MBI), into risk assessments. Clinical trials may benefit from enrichment with these higher-risk MCI participants.

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Background Mild behavioral impairment (MBI) is a syndrome that uses later‐life emergent and persistent neuropsychiatric symptoms (NPS) to identify a group at high risk for incident dementia. MBI is associated with neurodegenerative disease markers in advance of syndromic dementia. Functional connectivity (FC) correlates of MBI are understudied and could provide further insights into mechanisms early in the disease course. We used resting‐state functional magnetic resonance imaging (rs‐fMRI) to test the hypothesis that FC within the default mode network (DMN) and salience network (SN) of persons with MBI (MBI+) is reduced, relative to those without (MBI–). Methods From two harmonized dementia‐free cohort studies, using a score of ≥6 on the MBI Checklist to define MBI status, 32 MBI+ and 63 MBI– individuals were identified (mean age: 71.7 years; 54.7% female). Seed‐based connectivity analysis was implemented in each MBI group using the CONN fMRI toolbox (v20.b), with the posterior cingulate cortex (PCC) as the seed region within the DMN and anterior cingulate cortex (ACC) as the seed within the SN. The average time series from the PCC and ACC were used to determine FC with other regions within the DMN (medial prefrontal cortex, lateral inferior parietal cortex) and SN (anterior insula, supramarginal gyrus, rostral prefrontal cortex), respectively. Age, sex, years of education, and Montreal Cognitive Assessment scores were included as model covariates. The false discovery rate approach was used to correct for multiple comparisons, with a p ‐value of .05 considered significant. Results For the DMN, MBI+ individuals exhibited reduced FC between the PCC and the medial prefrontal cortex, compared to MBI–. For the SN, MBI+ individuals exhibited reduced FC between the ACC and left anterior insula. Conclusion MBI in dementia‐free older adults is associated with reduced FC in networks known to be disrupted in dementia. Our results complement the evidence linking MBI with Alzheimer's disease biomarkers. Highlights Resting‐state functional magnetic resonance imaging was completed in 95 dementia‐free persons from FAVR and COMPASS‐ND studies. Participants were stratified by informant‐rated Mild Behavioral Impairment Checklist (MBI‐C) score, ≥6 for MBI+. MBI+ participants showed reduced functional connectivity (FC) within the default mode network and salience network. These FC changes are consistent with those seen in early‐stage Alzheimer's disease. MBI may help identify persons with early‐stage neurodegenerative disease.

Background Dementia has an increasing global burden with over 40 million affected individuals. With sub‐optimal advances in drug development, there is an increasing shift to determine risk of dementia in the non‐demented population. Assessment of neuropsychiatric symptoms (NPS) may offer an opportunity to capture the at‐risk group earlier. Mild Behavioural Impairment (MBI) is a validated neurobehavioural syndrome, characterized by the emergence of sustained NPS in older adults as an at‐risk state for dementia. Cognitively, subjective cognitive decline (SCD) is a dementia at‐risk group in which cognitive symptoms are reported in the absence of objective findings. The apolipoprotein epsilon 4 (ApoE ε4) gene is a well‐known risk marker for dementia. We aim to determine the frequency of ApoE homozygosity in SCD, stratified by MBI status cross‐sectionally, and calculate the hazard of incident cognitive decline in this group longitudinally. Method Data from 5005 participants in the National Alzheimer’s Coordinating Center (NACC) were used to capture older adults who were cognitively normal, but had subjective cognitive complaints (SCD). We determined MBI status (+/‐) using a previously published transformation algorithm of NPI‐Q scores. We tabulated ApoE genotype in both groups. We compared proportion of ApoE homozygousity (APOE ε4+/+)in the MBI+ versus the MBI‐ group. Additionally, a Cox proportional hazards regression will be done to capture hazard of incident mild cognitive impairment in MBI+ versus MBI‐. Result A two‐sample test of proportions of MBI+/‐ status stratified by ApoE ε4+/+resulted in significant differences between groups with homozygosity more frequent in MBI+ versus MBI‐ (p<0.001). We will also present the results of the Cox proportional hazards regression analysis. Conclusion In older adults with subjective cognitive decline, ApoE ε4 allele homozygosity was more frequently seen in the MBI+ group. These findings provide additional evidence for the utility in determining MBI status in SCD.