The genetics of dementia, dyslipidemia, and diabetes may hold the key to preventive therapy.
The genetics of Alzheimer-type cognitive decline, dyslipidemia, and diabetes may be the long-sought key that unlocks the door to prevention for a significant portion of the population at risk.1,2 Dietary modification and/or use of statins may play a major role.
Research shows particular vulnerability in persons who are homozygous for the apolipoprotein E4 (E4) allele.1,2 Indeed, E4 carriage and type 2 diabetes, as well as drivers of diabetes such as obesity, are known major risk factors for cognitive decline and late-onset Alzheimer disease (AD). A study by researchers affiliated with the Oregon Health & Sciences University in Portland found that cognitive deficits were more extensive and pronounced in E4 murine models fed a high-fat diet compared with E3 models, but that dietary modification ameliorated symptoms.1
Another multicenter study-supported by the National Institutes of Health, National Institute on Aging, and the University of Southern California-showed that, despite heretofore equivocal data, statins have a therapeutic role in AD prevention, particularly in persons who are homozygous for E4.2
The researchers involved in the murine study pointed out that E4 phenotypes and insulin resistance (ie, type 2 diabetes) seem to interact as drivers of cognitive dysfunction. In seeking a common denominator, they looked at the role of caloric excess. They hypothesized that E4 mice would be more susceptible than E3 mice to the harmful cognitive effects of insulin resistance consequential to a high-fat diet.
Although both E3 and E4 mice fed a high-fat diet for 5 months demonstrated peripheral metabolic and cognitive impairments, E4 mice displayed “exaggerated” deficits in hippocampal-dependent spatial learning and memory. However, the metabolic and cognitive deficiencies sustained in the E4 mice were completely reversed as were hippocampal changes when the mice were switched to a low-fat diet for 1 month.
The researchers concluded that E4 carriers are particularly susceptible to metabolic and cognitive impairments instigated by insulin resistance. They added that effects potentially can be ameliorated through diet and that the knowledge gleaned from this murine study may be useful in guiding development of novel therapies for cognitive decline and dementia.
Researchers in the second study pointed out that the value of statins in AD prevention has been equivocal despite knowledge of the role of hypercholesterolemia in AD risk.2 In assessing data from integrated clinical trials (n = 4574) and observational studies, they concluded that continual long-term use of various statins was associated with better cognitive performance, as measured on the Alzheimer’s Disease Assessment Scale-cognitive subscale, compared with non-use of statins (P < .01). When individual statins were examined, the greatest effect was seen with atorvastatin (P = .026) and the least with lovastatin (NS).
Furthermore, data gleaned from Rush University’s Religious Order Study and Memory Aging Project databases showed a lower prevalence of AD among statin users versus non-statin users (25% vs 31%; P < .0005). No statistically significant differences in cognitive function were seen over time between statin and non-statin users; however, E4 homozygous patients with AD who received statins had significantly better cognitive function over the course of 10-year follow-up compared with statin-naive comparators (P < .01).
These researchers concluded that statins may benefit all patients with AD and may be most beneficial for those who are homozygous for E4. They called for further research into which genotypes and phenotypes would be most appropriate for preventive or disease-modifying statin therapy, with the goal of prevention or delay of AD.
1. Johnson LA, Torres ER, Impey S, et al. Apolipoprotein E4 and insulin resistance interact to impair cognition and alter the epigenome and metabolome. Sci Rep. 2017;7:43701.
2. Geifman N, Brinton RD, Kennedy RE, et al. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimers Res Ther. 2017;9:10.