Alzheimer Disease (AD) protein aggregate lesions accumulate and begin to plateau prior to the cognitive decline that accompanies the onset of regionally selective synapse and neuron loss. These lesions include amyloid beta (A�42) accumulation in plaques and intraneuronal neurofibrillary tangle aggregates comprised of the microtubule-associated protein tau. Prevention approaches that target plaque and tangle lesion accumulation should begin in the decades prior to cognitive deficits and therefore require outstanding safety and side-effect profiles. However, most prevention and treatment approaches have not been tested post-lesion accumulation in animal models or have side-effect concerns and most have failed in the clinic.  Our research has focused on testing dietary interventions with outstanding safety profiles including the omega-3 fatty acid, DHA, and curcumin, a polyphenolic antioxidant/ non-steroidal anti-inflammatory component of the curry spice, turmeric. DHA reduces A�42  production, while curcumin limits aggregation and promotes clearance of pre-existing A� deposits. Both agents have neuroprotective and anti-inflammatory activities that promote insulin/ neurotrophic pathways and both show efficacy in reducing A�42 accumulation in a late intervention (post pathology) paradigm in amyloid plaque forming transgenic mice. We have recently tested late intervention with DHA and curcumin in a pure tau pathology model and find evidence of efficacy even with an intervention beginning after tangles, synapse loss and cognitive deficits are well-established. We find synergistic pleiotropic mechanisms for anti-inflammatory control of arachidonic acid metabolism, tau kinase activation and downstream loss of tau function and insulin/neurotrophic factor resistance relevant to synaptic and cognitive protection with these interventions.  Omega 3 fatty acids already show promise with early intervention in the clinic, but testing curcumin efficacy in humans has been limited by bioavailability issues that can be resolved.  Because of their low cost and outstanding safety profiles, DHA and curcumin show great promise for cost-effective prevention of AD and likely other age-related pathologies.

Prevention approaches to Alzheimer disease: Omega-3 fatty acids and curcumin

240th National Meeting (2010)

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