Impaired MAPT/tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients.

MAPT/tau proteins propagate between brain regions in a prion-like manner, driving the onset and progression of dementia in Alzheimer disease (AD). However, the basis for variability in dementia progression among AD patients remains poorly understood. Here, we demonstrate that cognitively resilient AD patients, characterized by reduced MAPT/tau pathology, maintain lysosomal integrity, whereas cognitively vulnerable patients, exhibiting greater MAPT/tau burden, display lysosomal dysfunction. Lysosomes in cognitively vulnerable AD brains contain partially digested, seed-competent MAPT/tau species composed mainly of the amyloidogenic core with degraded peripheral regions. These pathogenic MAPT/tau forms are secreted via lysosomal exocytosis, facilitating MAPT/tau propagation and contributing to cognitive decline. Cognitively vulnerable female AD patients show increased lysosome-mediated MAPT/tau secretion relative to their male counterparts. Our findings suggest that lysosomal dysfunction, marked by altered protein expression, pH dysregulation, and MAPT/tau accumulation, underlies the heterogeneity in dementia severity. Targeting lysosomal exocytosis and the amyloidogenic core of MAPT/tau fibrils offer a promising therapeutic avenue to mitigate MAPT/tau pathology and promote cognitive resilience in AD and related dementias.Abbreviation: AD: Alzheimer disease, LAMP1; lysosomal associated membrane protein 1, NFT: neurofibrillary tangles; MAPT: microtubule associated protein tau; PHF: paired helical filaments; TIRF: total internal reflection fluorescence; TARDBP/TDP-43:TAR DNA binding protein.