Clinical Manifestations

Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) frequently coexists with Alzheimer's disease (AD), Lewy body disease (LBD), and vascular pathology. While neuropsychiatric symptoms in AD/LATE-NC are beginning to be explored, the impact of LATE-NC in mixed AD/LBD and LBD is still underexamined. This study investigated neuropsychiatric symptom profiles in individuals with AD, LBD, and mixed AD/LBD with and without LATE-NC.

In this retrospective cohort study, individuals from the UBC Hospital Clinic for Alzheimer's and Related Disorders (UBCH-CARD) autopsy database with AD, LBD or both plus LATE-NC pathology (LATE+, n = 42) were matched by age and neuropathology to controls without LATE-NC (LATE-, n = 38). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q) at initial, intermediate, and final visits before death. Outcomes included symptom severity scores at the final visit, odds ratios of symptoms at the final visit and trajectories of symptom progression. Parametric and non-parametric tests were used to compare symptom severity scores, while linear mixed-effects models analyzed longitudinal symptom data, adjusting for age, sex, education, and Clinical Dementia Rating Scale (CDR).

Mean age at death was 80.5 years (LATE+) and 77.9 years (LATE-), and participants were followed on average 5.8 years. Both groups had a high burden of moderate-to-severe AD pathology (LATE+ 97.6% vs. LATE- 94.4%) and moderate numbers had neocortical LBD (31.7% vs. 41.7%, p = 0.50). At the final visit, total NPI-Q severity scores were similar between groups (5.65 vs. 6.12, p = 0.71). Symptom severity scores for apathy (0.73 vs. 1.29, p = 0.01), hallucinations (0.24 vs. 0.82, p = 0.01), and appetite changes (0.08 vs. 0.41, p = 0.04) were lower in LATE+. Odds ratios for symptom presence at the final visit, adjusted for coexisting pathology, remained significant for hallucinations only (0.013, 95% CI 0.001-0.218, p = 0.002). Longitudinal modeling showed no significant differences in total burden of neuropsychiatric symptoms.

LATE-NC did not appear to increase overall neuropsychiatric symptom burden in this autopsy cohort study of individuals with AD and/or LBD. Hallucinations were less frequent in the LATE+ group, but this may be due to incomplete adjustment for coexisting Lewy Body pathology. Further modelling of longitudinal symptom progression will be presented at the conference.