Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.

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A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.