Neuropsychiatric Symptoms Predict Progression to Alzheimer’s Disease Pathology
Overview
This study demonstrates that mild behavioural impairment (MBI), characterized by persistent neuropsychiatric symptoms (NPS) emerging later in life, is strongly associated with underlying Alzheimer’s disease (AD) pathology approximately five years prior to death. MBI significantly increases the risk and rate of progression to AD dementia, particularly among individuals with normal cognition, and is not associated with Lewy body disease (LBD) or TDP-43 pathologies.
Background
Alzheimer’s disease is the leading cause of dementia, with neuropathological confirmation as the diagnostic gold standard. Neuropsychiatric symptoms often precede cognitive decline, but their relationship to AD and other neurodegenerative pathologies remains unclear. The mild behavioural impairment (MBI) construct identifies later-life emergent and persistent NPS as a high-risk state for cognitive decline and dementia. Prior research has linked MBI to AD biomarkers and genetic risk factors, but the role of co-pathologies such as LBD and TDP-43 inclusions in MBI and dementia progression requires further elucidation.
Data Highlights
Measure
MBI+ Odds Ratio (95% CI)
P Value
AD Pathology Presence
1.88 (1.29–2.75)
<0.01
Non-MBI NPS
1.22 (0.90–1.66)
0.20
Progression Rate to AD Dementia (MBI+ vs no NPS)
2.03 (1.60–2.57)
<0.01
Hazard Ratio Normal Cognition with MBI
3.05 (1.37–6.80)
<0.01
Hazard Ratio MCI with MBI
1.93 (1.51–2.47)
<0.01
Hazard Ratio Limbic LBD+ with MBI
4.64 (2.05–10.50)
<0.001
Hazard Ratio Limbic LBD− with MBI
1.87 (1.46–2.40)
<0.001
Key Findings
Individuals with AD pathology were 88.4% more likely to exhibit MBI approximately five years before death compared to those without AD pathology.
Non-MBI neuropsychiatric symptoms did not significantly associate with AD pathology.
Lewy body disease and TDP-43 pathologies showed no significant association with MBI status.
Among MBI individuals progressing to dementia, AD pathology was the most common, often co-occurring with LBD and TDP-43 pathologies.
MBI presence doubled the rate of progression to AD dementia, with a stronger effect observed in cognitively normal individuals than those with mild cognitive impairment.
Limbic LBD pathology amplified the risk of progression to AD dementia in MBI individuals.
Clinical Implications
Assessment of persistent neuropsychiatric symptoms meeting MBI criteria in older adults may serve as an early clinical indicator of underlying AD pathology and heightened risk for progression to dementia. Incorporating MBI evaluation into routine cognitive assessments could improve early identification of patients who may benefit from AD-modifying therapies. The lack of association with LBD and TDP-43 suggests MBI is more specific to AD-related neurodegeneration.
Conclusion
Mild behavioural impairment is a robust clinical marker linked to Alzheimer’s disease neuropathology and increased risk of progression to AD dementia. Integrating MBI into diagnostic frameworks may enhance early detection and intervention strategies for Alzheimer’s disease.
References
Original Article 2024 -- Association of Neuropsychiatric Symptoms with Progression to Pathologically Diagnosed Alzheimer’s Disease
