Neuropsychiatric symptoms and progression to pathologically confirmed Alzheimer’s disease

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.