Dramatic Ivacaftor medial and superior temporal drebrin loss plateaus early with mild cognitive impairment by MMSE 26 [12], so loss has already occurred in trial subjects. While DHA reduced both A?? and tau pathology in 3xTg AD mice [13], that intervention was early (pre-pathology). In contrast, with late post-pathology intervention in human tau transgenic mice with significant neuron loss, we find DHA treatment is insufficient to produce significant cognitive and synaptic improvements (GMC and SAF, Society for Neuroscience presentations, 2010). Finally, epidemiological risk factors may be relevant to prevention, but not necessarily to treatment. Animal model data with DHA support early intervention for primary prevention or mild cognitive impairment and suggest a failure to impact tangle and neuron loss driven deficits at later stages.

Although the data demonstrate that DHA has no general benefit for AD, a concern remains as to whether the key negative effect may be driven by the failure of ApoE4 subjects to respond. Since non-ApoE4 carriers comprise a large segment of the US (approximately 75%) and AD (approximately 50%) populations, whether DHA may slow progression in non-ApoE4 carriers is important. Figure 3 in [2] indicates that 40% of non-ApoE4 carriers showed significant (P = 0.03) stabilization of both ADAS-Cog and MMSE, but not with correction for multiple comparisons. The authors point out that three epidemiological studies showed reduced risk with fish consumption only in the ApoE4 non-carriers, but add that pharmacogenomic interaction was not seen with CDR, ADL or NPI.

For example, NPI showed a trend independent of genotype, worsening less (2.93 points) in the DHA group than in the placebo group (5.09 points, P = 0.11). Are pathogenic mechanisms impacting NPI, ADL, CDR and MMSE/ADAS-Cog the same? Thus, any pharmacogenomic potential of DHA requires clarification. For prevention or treatment, one might Batimastat expect ApoE genotype-DHA interactions. Because ApoE4 accelerates pathogenesis, age-matched ApoE4 patients may have more intractable AD pathology. Further, one important target of DHA is insulin resistance [14], but drugs targeting insulin resistance (insulin or peroxisome proliferator-activated receptor (PPAR)?? agonists) appears more effective at reducing cognitive deficits in ApoE3 carriers than ApoE4 carriers [15]. ApoE is a major central nervous system lipid transport protein with isoform-dependent tracking likely to impact DHA compartmentalization in the brain. Finally, ApoE4 increases oxidative stress, and with six double bonds, DHA is readily oxidized. This raises other critical issues that need to be addressed before pursuing a future selleck products trial: dose and oxidation.