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Preprint WatchModerateSeptember 22nd, 2026

Centenarians maintain cognition by resisting amyloid-β or decoupling it from tau propagation

Rohde, S. K., Luimes, M. C., Rozemuller, A. J. M., Hulsman, M., van der Lee, S. J., Sikkes, S. A. M. et al.

In 112 centenarians, amyloid-beta pathology was associated with parahippocampal p-tau burden and lower cognition, yet most remained cognitively healthy through two routes: 44% resisted amyloid-beta accumulation and 28% carried substantial amyloid-beta but resisted downstream p-tau propagation, indicating natural uncoupling of amyloid from tau spread.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

Rohde and colleagues (medRxiv, not peer reviewed) examined medial temporal lobe pathology in 112 centenarians and report that amyloid-beta tracked with parahippocampal p-tau and lower cognition, while most individuals stayed cognitively healthy either by resisting amyloid accumulation (44%) or by carrying substantial amyloid without downstream p-tau spread (28%). The matching Claidex record is the Phase 3 failure of valiltramiprosate, an oral anti-oligomer agent, in APOE4 homozygous early Alzheimer's disease (valiltramiprosate-alz801-app-apoe4-alzheimers-phase3-efficacy-failure). The preprint suggests that amyloid-directed therapy is only one of two protective routes and that the amyloid to tau coupling step may be the more tractable point once plaques are established. For programs that, like valiltramiprosate, intervene on amyloid species in already symptomatic carriers, the centenarian data argue for pairing amyloid endpoints with tau propagation readouts. The cohort is post-mortem and observational, so it cannot show that blocking coupling would change outcomes.

Abstract excerpt

Centenarians who maintain cognitive health provide a unique opportunity to investigate naturally occurring mechanisms that protect against Alzheimer's disease. We examined the relationship between subregional amyloid-beta and p-tau distributions in the medial temporal lobe and cognitive performance in 112 centenarians. We show that amyloid-beta pathology was associated with increased parahippocampal, but not hippocampal, p-tau burden and lower cognitive performance. However, the majority of the centenarians maintained high cognitive performance until death, and they appeared to be protected against cognitive decline through two distinct mechanisms: 44% were resistant to amyloid-beta accumulation, while 28% harbored substantial amyloid-beta pathology but resisted downstream p-tau propagation. These findings suggest the existence of natural resilience mechanisms that uncouple amyloid-beta pathology from driving downstream pathogenic tau progression. Both mechanisms warrant further exploration, as they may offer complementary therapeutic entry-points: preventing the accumulation of amyloid-beta pathology altogether, or limiting downstream p-tau propagation once amyloid-beta pathology has already emerged.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.