Neuropsychiatric symptoms and progression to pathologically confirmed Alzheimer’s disease

Brain. 2025 Apr 25:awaf156. doi: 10.1093/brain/awaf156. Online ahead of print.

ABSTRACT

Whether or not neuropsychiatric symptoms (NPS) in advance of dementia are associated with Alzheimer 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 postmortem AD and other neurodegenerative pathologies were associated with MBI in the five years before death. National Alzheimer’s Coordinating Center study autopsy participants (n=1016, 82.6 years, 48.7% female, 60% normal cognition) were included in the analyses. Using the Neuropsychiatric Inventory-Questionnaire, MBI+ status was operationalized as NPS persistence at >2/3 of pre-dementia study visits; otherwise, status was non-MBI NPS. The presence of AD, Lewy body disease (LBD), and TDP-43 neuropathological changes were determined using published guidelines. Adjusted multinomial logistic regressions modeled pathology-NPS status associations. Adjusted Cox proportional hazards regressions modeled 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 (OR):1.88, 95% confidence interval (CI):1.29-2.75, p<0.01); however, the likelihood of having non-MBI NPS was not different (OR: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 TDP-43 in those with MBI compared to no MBI. Among MBI progressors to dementia (n=106), 33.0% were solely AD+, 18.9% were mixed AD+/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 noNPS (CI: 1.60-2.57, p<0.01). Progression rate was higher in MCI, but the effect of MBI on progression was greater in NC (HR:3.05, CI:1.37-6.80, p<0.01) vs. MCI (HR:1.93, CI:1.51-2.47, p<0.01). Limbic LBD appeared to also moderate the association between MBI and incident AD (Limbic LBD+ HR: 4.64, CI: 2.05-10.50, p<0.001; Limbic LBD- HR: 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 may aid in identification of early stages of neurodegenerative disease, which may be helpful for selecting patients for treatment with AD disease-modifying drugs.

PMID:40279515 | DOI:10.1093/brain/awaf156