The Central Premise: Endosomes are cellular sorting stations directing proteins to degradation or recycling. When Rab5 overactivation enlarges these stations, they become amyloid assembly lines instead.

The Mechanism:

Rab5 Hyperactivity: In AD neurons, Rab5 (master regulator of early endocytosis) becomes overactivated. This expands early endosomes 2-3x normal size visible pathologically.

APP Misdirection: APP normally cycles through endosomes briefly. Enlarged, prolonged endosomal retention exposes APP to β-secretase (BACE1) which works optimally at acidic endosomal pH.

Amyloid Factory: Trapped in enlarged endosomes, APP encounters more BACE1 for longer periods. Aβ generation increases dramatically endosomes become amyloid production factories.

Signaling Failure: Enlarged endosomes cannot recycle receptors (TrkB, insulin receptor) properly. Neurons lose trophic support and metabolic signaling.

Propagation: Endosomal abnormalities appear in mild cognitive impairment preceding plaques. APOE4 accelerates Rab5 overactivation via lipid raft disruption.

Therapeutic Implications:

Rab5 inhibitors normalizing endosomal size

BACE1 trafficking blockers preventing amyloidogenic encounter

Endosomal pH modulators reducing BACE1 activity

Recycling enhancers restoring receptor return to surface

This reframes AD as endosomopathy sorting stations become production lines.