Neuropsychiatric Symptoms in Patients With Pathologically Confirmed Comorbid Alzheimer Disease and Frontotemporal...

Little is known about the clinical presentation in patients with comorbid Alzheimer disease neuropathologic change (ADNC) and frontotemporal lobar degeneration (FTLD) neuropathology, despite frequent comorbidity of neurodegenerative diseases on autopsy. In other neurodegenerative conditions, multiple pathologies alter the presentation of neuropsychiatric symptoms, complicating clinical care. We examined whether neuropsychiatric symptoms differ in patients with comorbid ADNC/FTLD compared with patients with each pathology alone.

This was a retrospective examination of data from 29 US Alzheimer's Disease Research Centers, obtained through the National Alzheimer's Coordinating Center September 2024 data freeze. Patients with intermediate-to-high ADNC and/or FTLD neuropathology on autopsy were included. Neuropsychiatric symptoms were apathy, depressed mood, visual/auditory hallucinations, delusions, disinhibition, irritability, agitation, personality change, REM sleep behavior disorder, and anxiety, identified by clinicians at patients' final visit. Logistic regression models examined the odds of the comorbid vs single pathology groups expressing each neuropsychiatric symptom, controlling for age, sex, race, ethnicity, education, and interval between first visit and death.

Data from 919 patients (mean age 81 years [SD 12 years], 49% female) were analyzed. Ninety-four patients (mean age 84 years [SD 10 years], 46% female) had comorbid ADNC/FTLD pathology, 590 had ADNC only, and 235 had FTLD only. Compared with the FTLD-only group, patients in the comorbid ADNC/FTLD group were more likely to present with anxiety (odds ratio [OR] 3.11, 95% CI 1.38-6.98, p = 0.007), delusions (OR 2.59, 95% CI 1.15-5.79, p = 0.02), and irritability (OR 1.87, 95% CI 1.07-3.25, p = 0.03). Conversely, compared with the ADNC-only group, patients in the comorbid ADNC and FTLD group were more likely to present with personality change (OR 3.17, 95% CI 1.70-5.90, p < 0.001) and disinhibition (OR 2.00, 95% CI 1.14-3.53, p = 0.02).

Comorbid presence of ADNC and FTLD neuropathology, compared with each pathology alone, was associated with a greater likelihood of presenting with known neuropsychiatric symptoms of the other disease, irrespective of patients' clinical syndrome. Findings highlight the potential clinical diagnostic value of antemortem behavioral symptoms in identifying patients with comorbid pathology, although conclusions are limited by the cross-sectional nature of the neuropsychiatric data.