Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease: Role of Sex and Parent's Sex

Abstract

Background and objectives: Female sex and a parental history of Alzheimer disease (AD), especially maternal, confer increased risk of AD. Associations between sex, or affected AD parent's sex, and biomarkers of AD are less clear. We examined whether sex or affected AD parent's sex influences (1) β-amyloid (Aβ) and tau burden/accumulation, (2) the association between Aβ and tau burden, and (3) brain and cognitive resilience to Aβ and tau burden.

Methods: The sample included 243 participants from the Presymptomatic Evaluation of Experimental or Novel Treatments for AD cohort in Canada. All participants with [18F]-NAV4694 and [18F]-AV1451 PET and MRI were included. We examined (1) sex or affected AD parent's sex differences on regional Aβ and tau burden/accumulation; (2) 2-way interactions between sex, or affected AD parent's sex, and Aβ on tau burden; and (3) 3-way interactions between time, sex or affected AD parent's sex, and Aβ or tau deposition on hippocampal volume (brain resilience) and cognition (cognitive resilience) over time.

Results: Participants (69.4% female) were aged 68.3 ± 5.1 years at their first PET scans. All were cognitively unimpaired at baseline. Longitudinal cognitive data were available for 242 participants (follow-up, 6.72 ± 2.38 years), including 238 (6.53 ± 2.48 years of follow-up) with MRI follow-ups and 115 (4.4 ± 0.6 years of follow-up) with PET follow-ups, and 71 developed mild cognitive impairment. Women showed greater tau deposition (standardized β = 0.13 ± 0.3) and showed a stronger association between global Aβ and tau deposition than men (standardized β = 0.79 ± 0.1). Individuals with an affected AD father showed stronger association between global Aβ and tau deposition than those with an affected AD mother (standardized β = 0.65 ± 0.1). Women showed less Aβ-associated hippocampal atrophy over time (standardized β = 0.24 ± 0.1).

Discussion: Women and, surprisingly, individuals with a paternal history of AD seemed more vulnerable to the Aβ-related spread of tau, whereas women showed greater brain resilience to Aβ. Understanding sex-specific risk and resilience could allow more clinical trial precision and personalization. A major limitation included the reduced sample for the affected AD parent's sex analyses.