Amyloid and Tau Pathology in Cognitively Unimpaired Individuals With a Parental History of Alzheimer Disease

Background and ObjectivesFemale 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) beta-amyloid (A beta) and tau burden/accumulation, (2) the association between A beta and tau burden, and (3) brain and cognitive resilience to A beta and tau burden.MethodsThe 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 A beta and tau burden/accumulation; (2) 2-way interactions between sex, or affected AD parent's sex, and A beta on tau burden; and (3) 3-way interactions between time, sex or affected AD parent's sex, and A beta or tau deposition on hippocampal volume (brain resilience) and cognition (cognitive resilience) over time.ResultsParticipants (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 beta = 0.13 +/- 0.3) and showed a stronger association between global A beta and tau deposition than men (standardized beta = 0.79 +/- 0.1). Individuals with an affected AD father showed stronger association between global A beta and tau deposition than those with an affected AD mother (standardized beta = 0.65 +/- 0.1). Women showed less A beta-associated hippocampal atrophy over time (standardized beta = 0.24 +/- 0.1).DiscussionWomen and, surprisingly, individuals with a paternal history of AD seemed more vulnerable to the A beta-related spread of tau, whereas women showed greater brain resilience to A beta. 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.