Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging

Abstract

Objective: To examine the impact of 3 pathologic groups, pure limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE) neuropathologic changes (NC), pure Alzheimer disease neuropathologic change (ADNC), and mixed ADNC with LATE-NC, on late-life cognitive decline.

Methods: Data came from 1,356 community-based older persons who completed detailed annual cognitive testing and systematic neuropathologic examination at autopsy to identify LATE-NC, ADNC, and other age-related pathologies. Persons were categorized into (0) a group without a pathologic diagnosis of LATE or ADNC (n = 378), (1) LATE-NC without ADNC (n = 91), (2) ADNC without LATE-NC (n = 535), and (3) mixed ADNC with LATE-NC (n = 352). We used mixed-effect models to examine the group associations with rate of decline in global cognition and 5 cognitive domains and then examined whether age modified associations.

Results: Compared to those without LATE-NC or ADNC, those with pure LATE-NC had a faster decline in global cognition (p = 0.025) and episodic memory (p = 0.002); however, compared to persons with pure ADNC, those with pure LATE-NC showed a slower decline. Those with mixed ADNC with LATE-NC showed the fastest decline compared to those with either pathology alone. Persons ≥90 years of age with mixed ADNC with LATE-NC had slower cognitive decline compared to those ≤89 years of age.

Conclusion: Persons with pure LATE-NC follow a slower trajectory compared to those with pure ADNC. Those with mixed LATE/ADNC have a steeper decline than individuals with either pathology alone. In addition, age may modify the effect of pathology on cognitive decline. These findings have important implications for the development of biomarkers and prognosis for late-life cognitive decline.

Classification of evidence: This study provides Class I evidence that LATE-NC and Alzheimer disease pathologic changes are associated with different trajectories of late-life cognitive decline.

Figure 1. Sample size

Flowchart shows composition of final sample size. ADNC = Alzheimer disease neuropathologic change; AGA = Anatomical Gift Act; DLB = dementia with Lewy body disease; FTLD = frontotemporal lobar degeneration; HS = hippocampal sclerosis; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.

Figure 2. Cognitive trajectories for those with LATE-NC, AD pathology, and mixed AD with LATE-NC pathology

Derived from mixed-effect models adjusted for age, sex, education, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, any Lewy body pathology, and APOE ε4. AD = Alzheimer disease; LATE-NC = limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.