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Mixed Pathologies and Cognitive Outcomes in Persons Considered for Anti-Amyloid Treatment Eligibility Assessment: A
Alifiya Kapasi1,2, Bryan David James1,3, Lei Yu1,4
1Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
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.
Insights
Mixed brain pathologies are common in individuals eligible for anti-amyloid therapies. These co-occurring conditions, including tangles and LATE-NC, significantly drive cognitive decline, particularly in episodic memory.
Area of Science:
- Neuropathology
- Neurodegenerative Diseases
- Cognitive Aging
Background:
- Anti-amyloid monoclonal antibodies show limited clinical efficacy despite lowering brain β-amyloid (Aβ).
- Other brain pathologies may impede the effectiveness of anti-amyloid treatments in individuals with mild cognitive impairment (MCI) or mild dementia.
- This study investigated the prevalence and cognitive impact of mixed pathologies in individuals considered for anti-amyloid therapy eligibility.
Purpose of the Study:
- To examine the burden of mixed brain pathologies in individuals eligible for anti-amyloid treatment.
- To determine the association between various neuropathologies and cognitive decline rates.
- To understand how coexisting pathologies influence cognitive outcomes in the context of potential anti-amyloid therapy.
Main Methods:
- Analysis of autopsy data from 428 older individuals meeting eligibility criteria for anti-amyloid therapy (MMSE ≥20, MCI or mild Alzheimer dementia, moderate Aβ pathology).
- Examination of the number and types of copathologies, including Alzheimer disease neuropathologic changes (ADNC), LATE-NC, Lewy bodies (LBs), and infarcts.
- Application of mixed-effects models to assess the relationship between Aβ, tangles, LATE-NC, infarcts, LBs, and vessel diseases with cognitive decline rates.
Main Results:
- Of 428 individuals, 94% had ADNC, but only 26% had ADNC alone; 68% had ADNC with at least one copathology.
- Tangles and arteriolosclerosis were associated with faster global cognitive decline.
- Tangles and LATE-NC were linked to faster episodic memory decline; ADNC to semantic memory decline; Aβ to working memory decline; atherosclerosis to perceptual speed decline.
Conclusions:
- Mixed pathologies are highly prevalent in individuals considered for anti-amyloid therapy.
- Beyond Aβ, tangles, LATE-NC, and vascular pathologies significantly contribute to cognitive decline, especially in episodic memory.
- The presence of coexisting pathologies may limit the clinical efficacy of anti-amyloid therapies even in eligible patients.
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