Does aging weaken brain proteostasis and clearance, promoting amyloid and tau accumulation?

Age-related failure of protein quality control and brain solute clearance is a credible contributor to Alzheimer-type pathology, but the human causal evidence differs substantially by pathway and by protein.

Clinical and translational evidence

• Aging-associated decline in neuronal proteostasis is moderately supported: reduced autophagic and lysosomal efficiency can impair clearance of damaged proteins. Alzheimer brain tissue shows autophagic vacuoles and dystrophic neurites consistent with defective cargo processing.
• The strongest clearance-related human signal concerns glymphatic function and amyloid. In 423 older adults, lower DTI-ALPS—an indirect diffusion-MRI marker of glymphatic/perivascular function—was associated with greater amyloid burden among APOE ε4 carriers. DTI-ALPS was not significantly associated with tau.
• Amyloid positivity has also been associated with faster enlargement of centrum-semiovale perivascular spaces in older adults. This supports a relationship between amyloid pathology and altered perivascular physiology, but does not establish direction of causation.

Mechanistic interpretation

• Autophagic-lysosomal pathways normally contribute to degradation of amyloid-beta and tau. Their age-related impairment could therefore permit intracellular accumulation, although amyloid and pathological tau may also secondarily worsen lysosomal function.
• Loss of perivascular AQP4 polarization offers a biologically coherent route to impaired glymphatic transport. Preclinical evidence supports AQP4/glymphatic involvement in amyloid and tau removal, while direct human evidence is more persuasive for amyloid than tau.
• Arterial stiffening and altered pulsatility with age could reduce vascular/perivascular solute efflux, but available human vascular imaging markers show mixed, indirect associations with amyloid and tau.

Bottom line

• The claim is directionally well founded: aging-related proteostatic impairment is supported, and weakened glymphatic, lysosomal, and vascular clearance are plausible contributors to cerebral amyloid and tau accumulation. The most substantiated translational link is impaired glymphatic/perivascular function with amyloid; causal human evidence for tau, lysosomal, and vascular pathways remains less direct.