Scientists identify hidden Alzheimer's trigger: IDOL enzyme
Researchers have identified a new potential target in the fight against Alzheimer's disease: an enzyme called IDOL. The findings of the new study showed that removing IDOL from neurons sharply reduced amyloid plaques and improved key brain processes.
IDOL (Inducible Degrader Of LDL receptor) had previously been associated with cholesterol metabolism; it marks the LDL receptor for degradation. The new work has shown that IDOL is also highly expressed in brain neurons and plays a pathological role in Alzheimer's disease.
The research, conducted at the UCLA David Geffen School of Medicine in Los Angeles, was performed in mouse models in which the IDOL gene had been knocked out. The brains of those mice showed 60 percent fewer amyloid plaques than control-group mice. Markers of inflammation and synaptic loss were also markedly reduced.
The lead author of the study, Dr Stephen Young, said: 'IDOL occupies a central position in Alzheimer's pathology. The enzyme is three-way effective: it regulates cholesterol metabolism, affects processing of amyloid precursor protein (APP), and plays a role in neuronal synaptic plasticity.'
In mechanistic terms, IDOL accelerates the APP processing pathway that contributes to amyloid plaque formation, and it also affects the role of APOE on the cell surface. APOE is known as the strongest single genetic risk factor for Alzheimer's; the IDOL-APOE interaction is a connection that was not previously understood.
The study suggests that inhibition of IDOL before the onset of disease could be protective. In the animal models, the IDOL-knockout mice not only showed reduced amyloid plaques but also improved on measures of learning and memory. In water maze tests, the knockout mice arrived at the solution 30 percent faster than the control group.
The research team has launched a two-year preliminary drug-discovery programme to target IDOL with small molecules. Fifty small-molecule candidates are currently being screened, and the first human trials are planned for the end of 2027. That implies at least a five- to eight-year road map to clinical use.
Current Alzheimer's drugs largely target amyloid plaques directly (Aducanumab, Lecanemab, Donanemab). These drugs slow disease progression by 25 to 30 percent but do not reverse it. An upstream-target approach such as IDOL could create a preventative treatment option that blocks plaque formation.
International experts responded with cautious optimism. Cambridge University's Professor Bart de Strooper said: 'This is a mechanistically very interesting study. But the differences between mouse models and human Alzheimer's are well documented. More mechanistic understanding is needed before human clinical trials.'
Globally there are currently around 55 million people living with dementia, 60 to 70 percent of whom have Alzheimer's. The figure is projected to rise to 152 million by 2050. New treatments targeting IDOL could change the course of the disease; however, for daily medical decisions readers should always consult a neurology specialist and should not stop existing treatments on their own.