Mixed Pathologies and Cognitive Outcomes in Persons Considered for Anti-Amyloid Treatment Eligibility Assessment

BACKGROUND AND OBJECTIVES: Despite the capability of anti-amyloid monoclonal antibodies to lower β-amyloid (Aβ) brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Among individuals with mild cognitive impairment (MCI) or mild-stage dementia, the cognitive impact of other brain pathologies may limit efficacy of anti-amyloid drugs. This study examined the burden and cognitive associations of mixed brain pathologies among autopsied persons who would have been considered as patients to undergo anti-amyloid treatment eligibility assessment. METHODS: Eligibility was defined based on a Mini-Mental State Examination score ≥20, a clinical diagnosis of MCI or mild-stage Alzheimer dementia, and a level of Aβ pathology at autopsy indicative of having a positive amyloid PET scan (Consortium to Establish a Registry for Alzheimer's Disease score ≥moderate). The number and types of copathologies were examined. Mixed-effects models were used to examine the association of Aβ, tangles, limbic predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathologic changes (LATE-NC), infarcts, Lewy bodies (LBs), and vessel diseases, with the rate of cognitive decline. RESULTS: Among 428 older autopsied persons (mean age at death = 91 years, 70% women) considered for anti-amyloid treatment eligibility assessment, 58% had MCI and 42% had mild-stage Alzheimer dementia. Although the majority (94%) had a pathologic diagnosis of Alzheimer disease neuropathologic changes (ADNC), only 26% had ADNC without LATE-NC, LB, or infarcts. The majority (68%) had ADNC with ≥1 copathology with ADNC + infarcts and ADNC + LATE-NC being equally common. In mixed-effects models, tangles and arteriolosclerosis were both associated with a faster rate of global cognitive decline. Separately, tangles and LATE-NC were associated with a faster decline in episodic memory, ADNC was associated with faster decline in semantic memory with Aβ being further associated with decline in working memory, and atherosclerosis was associated with a faster decline in perceptual speed. Infarcts and LBs were not associated with decline in global cognition or any cognitive domain. DISCUSSION: Mixed pathologies are common among community-dwelling older persons considered for anti-amyloid treatment eligibility assessment. Beyond Aβ, tangles, LATE-NC, and vessel pathologies drive cognitive decline in this group of individuals, especially episodic memory decline. These findings suggest that, even among those eligible for anti-amyloid therapies, substantial cognitive decline may occur because of the presence of coexisting pathologies.