Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease

Abstract

Clarifying the relationships between neuropsychiatric symptoms and Alzheimer's disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes.

Keywords: Alzheimer’s disease; amyloid plaques; anxiety; appetite behavior; depression; neurofibrillary tangles; neuropathology; neuropsychiatry; sleep; tau protein.

Fig. 1.

Increased odds for neuropsychiatric symptoms across Alzheimer’s disease neurofibrillary tangle progression. There are significantly higher odds of developing agitation, anxiety, appetite dysfunction, depression, and sleep disturbances during Braak stages I/II, when pathology is restricted to subcortical regions and the transentorhinal cortex, after correcting for age, sex, years of education, Braak stage, and CDR-SOB. After Braak stages I/II, the odds of anxiety, appetite dysfunction, depression, and sleep disturbances are not significant when correcting for CDR-SOB. Agitation remains at significantly increased odds during Braak stages III/IV. Increased odds of delusions are associated with Braak stages V/VI. This illustrates that neuropsychiatric symptoms could possibly be used as a clinical marker in stages preceding the onset cognitive decline. The trajectory for cognitive decline represents median CDR-SOB score (Table 1).