Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later‐life emergent and persistent NPS that may mark early‐stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non‐MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non‐MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta‐region of interest (ROI) mean cortical thickness were acquired from T1‐weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non‐MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later‐life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non‐MBI NPS.

Whether or not neuropsychiatric symptoms (NPS) in advance of dementia are associated with Alzheimer’s disease (AD) and/or other neurodegenerative dementias remains to be determined. The mild behavioural impairment (MBI) construct selects persons with NPS that are later-life emergent and persistent to identify a high-risk group for cognitive decline and incident dementia. Here, in older adults without dementia at baseline, we examined whether post-mortem AD and other neurodegenerative pathologies were associated with MBI in the 5 years before death. National Alzheimer’s Coordinating Center study autopsy participants (n = 1016, 82.6 years of age, 48.7% female, 60% normal cognition) were included in the analyses. Using the Neuropsychiatric Inventory-Questionnaire, MBI+ status was operationalized as NPS persistence at more than two-thirds of pre-dementia study visits; otherwise, status was non-MBI NPS. The presence of AD, Lewy body disease (LBD) and transactive response DNA-binding protein 43 neuropathological changes was determined using published guidelines. Adjusted multinomial logistic regressions modelled pathology–NPS status associations. Adjusted Cox proportional hazards regressions modelled hazard for AD dementia at each NPS status level, including interaction terms with cognitive status and each co-pathology. AD+ individuals (51.4%) were 88.4% more likely to be MBI+ ∼5 years prior than AD− individuals [odds ratio: 1.88, 95% confidence interval (CI): 1.29–2.75, P < 0.01]; however, the likelihood of having non-MBI NPS was not different (odds ratio: 1.22, CI: 0.90–1.66, P = 0.20). No significant associations were seen for LBD pathology, even among AD+ participants. There were no significant differences in the levels of LBD or transactive response DNA-binding protein 43 in those with MBI in comparison to no MBI. Among MBI progressors to dementia (n = 106), 33.0% were solely AD+, 18.9% were mixed AD+ and LBD+, and 11.3% had all three pathologies. For all those with MBI (including dementia non-progressors), of persons with LBD, 83.4% were comorbid with AD. In the survival analysis, MBI+ individuals had a 2.03-fold greater progression rate to AD dementia than those without NPS (CI: 1.60–2.57, P < 0.01). The progression rate was higher in mild cognitive impairment , but the effect of MBI on progression was greater in normal cognition (hazard ratio: 3.05, CI: 1.37–6.80, P < 0.01) versus mild cognitive impairment (hazard ratio: 1.93, CI: 1.51–2.47, P < 0.01). Limbic LBD appeared also to moderate the association between MBI and incident AD (limbic LBD+ hazard ratio: 4.64, CI: 2.05–10.50, P < 0.001; limbic LBD− hazard ratio: 1.87, CI: 1.46–2.40, P < 0.001). Antecedent MBI was strongly associated with AD pathology but not with other neurodegenerative dementias. Inclusion of MBI in research and clinical frameworks for dementia might aid in identification of early stages of neurodegenerative disease, which might be helpful for selecting patients for treatment with AD-modifying drugs.

Background: Recent evidence suggests the experience of menopausal symptoms (i.e., perimenopausal symptoms) may be associated with cognitive and behavioural changes. We investigated these two relationships in a sample of postmenopausal females. Design: Cross-sectional observational study. Setting: Participant data was collected from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT) study. Participants: 896 postmenopausal female participants. Methods: Menopausal symptom burden was operationalized by summing the total number of recalled perimenopausal symptoms experienced. Cognitive function was measured using the Everyday Cognition (ECog-II) Scale, with higher scores reflecting greater severity. Mild Behavioral Impairment (MBI) was measured using the Mild Behavioral Impairment Checklist (MBI-C), with higher scores reflecting greater severity. A negative-binomial regression model examined the relationship between menopausal symptom burden and cognitive function, while a zero-inflated negative binomial regression model examined the relationship between menopausal symptom burden and MBI symptoms. Models adjusted for age, years of education, age of menopausal onset, type of menopause, and hormone therapy (HT). Age of menopausal onset and use of HT in the two associations were investigated with moderation analyses. Results: Greater menopausal symptom burden was associated with higher ECog-II total scores (b [95% confidence interval (CI)] = 5.37 [2.85, 7.97]) and higher MBI-C total scores (b [95% CI] = 6.09 [2.50, 9.80]). Use of HT did not significantly associate with ECog-II total scores (b [95% CI] = -10.98 [-25.33, 6.35]), however, HT was significantly associated with lower MBI-C total scores (b [95% CI] = -26.90 [-43.35, -5.67]). Conclusions: Menopausal symptom burden is associated with poorer cognitive function and more MBI symptoms in mid- to late life. HT may help mitigate symptoms of MBI. These findings suggest that the experience of menopause may indicate susceptibility to cognitive and behavioural changes, both markers of dementia.

Objectives:We explored the influence of study partner (SP) characteristics on SP-reported neuropsychiatric symptoms (NPS) presence across the neurocognitive spectrum and on the prognostic utility of mild behavioral impairment (MBI).Design, setting, and participants:We performed cross-sectional (n = 26,748) and longitudinal (n = 12,794) analyses using participant-SP dyad data from the National Alzheimer’s Coordinating Center. Participants were cognitively normal (CN; n = 11,951) or had mild cognitive impairment (MCI; n = 5686) or dementia (n = 9111).Measurements:SPs rated NPS using the Neuropsychiatric Inventory Questionnaire. We used multivariable logistic regression to model the association between SP characteristics (age, sex, and relationship to participant [spouse, child, and other]) and NPS status (outcome). Cox regressions assessed SP characteristics as moderators of MBI associations with incident dementia or as predictors of incident dementia in MBI + participants only.Results:Among CN persons, younger, female, and spouse SPs reported NPS more frequently. In MCI, younger SPs and those who were spouses or children of participants reported higher NPS odds. For dementia participants, NPS odds were higher in female and spouse SPs. MBI associations with incident dementia were slightly weaker when SPs were older but did not depend on SP sex or relationship to participant. Among MBI + participants with spouse or child SPs, hazard for dementia was higher when compared to MBI + participants with other SPs.Conclusions:SP age, sex, and relationship to participant influence NPS reporting across the neurocognitive spectrum, with potential implications for MBI prognosis. Considering SP characteristics may enhance the accuracy of NPS assessments, which may facilitate therapy planning and prognosis.