Alzheimer´s disease is a fat problem

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer´s disease (AD). How APOE4 increases the risk of AD is despite ample research still not fully understood.

Apolipoprotein E (apoE), the protein product of APOE, is a major lipid carrier and accumulating evidence points to a prominent role of lipid metabolism in the etiology of AD.

In the proposed studies we will investigate a potential AD-causal relationship between elevated peripheral triglycerides and pathological processes leading to neurodegeneration of the brain.

Triglycerides, opposite to cholesterol, are known to cross the blood-brain-barrier where they have been shown to promote pathological conditions when present in higher concentrations.

We will use fluid samples from three different clinical cohorts including sporadic and familial AD patients to establish a relationship between the APOE4 AD risk-allele, the lipases that regulate triglyceride levels in the periphery, and triglyceride levels per se in plasma, disease status and progression.

We will further use primary human hepatocytes, cultured iPSC-derived human neurons and a mouse model with humanized livers to study a direct relationship between APOE genotype, peripheral lipases, triglyceride levels and pathological processes leading to synaptic deficits and neurodegeneration in the brain.

Timely and appropriate management of peripheral triglyceride levels we believe may be a viable target for disease modification and prevention of AD.