Results of an autopsy-based study of community-dwelling older adults who would have met typical eligibility for amyloid-targeting treatment (ATT) assessment showed that mixed brain pathologies are common and strongly linked to cognitive decline. In addition to the presence of amyloid-beta (Aβ), neurofibrillary tangles, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathologies contributed to cognitive decline. These results, published in Neurology, suggest that cognitive decline may still occur in individuals treated with ATTs due to the presence of copathologies.

The study included 428 autopsied individuals (mean age at death=91 years, 70% women) who met the following eligibility criteria: Mini-Mental State Examination score ≥20, a clinical diagnosis of mild cognitive impairment (MCI) or mild-stage Alzheimer dementia, and autopsy-confirmed Aβ pathology consistent with a positive amyloid PET scan (Consortium to Establish a Registry for Alzheimer’s Disease score ≥moderate). Researchers identified the quantity and types of co-pathologies and used mixed-effects models to relate Aβ, tangles, LATE-NC, infarcts, Lewy bodies (LBs), and vessel disease to rates of decline in global cognition and specific domains (eg, episodic and semantic memory, working memory, perceptual speed).

Among the 428 autopsied individuals:

  • 58% had MCI and 42% had mild-stage Alzheimer dementia.
  • 94% had Alzheimer disease neuropathologic changes (ADNC), but only 26% had ADNC without LATE-NC, LB, or infarcts.
  • 68% had ADNC plus ≥1 copathology.
  • The presence of tangles and LATE-NC were associated with faster decline in episodic memory.
  • ADNC was associated with faster decline in semantic memory.
  • The presence of infarcts and LBs were not associated with decline in global cognition.

These findings underscore the need for comprehensive multimodal assessment and counseling for individuals who are candidates for treatment with ATTs.

Source: Kapasi A, James BD, Yu L, et al. Mixed pathologies and cognitive outcomes in persons considered for anti-amyloid treatment eligibility assessment: a community-based study. Neurology. 2025;105(5):e214004. doi:10.1212/WNL.0000000000214004