PrimeCuts- This Week in the Journals

Onyeka Okonkwo MD

Faculty peer reviewed

Alzheimer’s disease (AD) is the most common cause of dementia affecting over 4.5 million Americans, with cases in the US projected to triple over the next 40 years in the absence of advancements in therapy. With the aging of the American population, the disease has become an increasingly significant source of healthcare spending, with over 80 billion dollars dedicated annually to the care of patients with Alzheimer’s. [1] Consequently, a number of research studies have been initiated to investigate possible preventative and therapeutic measures for the disease, including several published in this week’s journals. One such approach involves the use of so called, ‘brain foods’, believed to have the potential to retard the progression of dementia.

A diet rich in omega-3 fatty acids, contained in oily fish, has been shown in multiple studies to bolster cardiovascular health. This week the New York Times reported on a study that investigated the possibility of similar benefits with regard to the prevention of dementia.[2] The observational study published in the August issue of the Journal of Clinical Nutrition examined the self reported diets of 15,000 people 65 years and older living in Asia and South America. Daily consumption of fish was shown to be associated with a 20% decrease in incidence of dementia compared to consumption only a few times a week. While they observed a dose-dependent relationship between the amount of fish consumed and the risk of dementia, they also described an inverse relationship between the consumption of red meat and risk of dementia. While the study controlled for a number of potential confounders including gender, age, education, income, and smoking, a number of other potential confounders were not examined, including other components of the participants’ diets. In addition, the authors did not distinguish between vascular and other types of dementia; it is reasonable to hypothesize that the effect of omega-3 fatty acids on atherosclerotic disease would result in greater prevention of vascular dementia with less of an effect on other types of dementia including AD. Limitations of the study notwithstanding, it would seem advisable to encourage the incorporation of more oily fish into the American diet if only for its already established cardiovascular benefits.

The latest scientific and technological advancements portend the possible development of novel medications or vaccinations to treat and prevent AD. Given the natural history of the disease it would be important to identify patients with incipient disease before their symptoms reach the point of an official diagnosis. A large multi-center prospective case control study published in JAMA this week evaluated the diagnostic accuracy of a number of CSF markers, including total tau protein (T-tau), CSF beta-amyloid (AB42) and tau phosphorylated at position threonine 181 (P-tau), in predicting the developing AD in patient with mild cognitive impairment (MCI). [3]The levels of these proteins were measured in healthy age- and sex-matched control patients, patients diagnosed with MCI and those who with dementia. Participants with MCI were followed until they were diagnosed with AD or found to have stable cognition for two years. About 33% of the 750 patients with MCI developed AD (incipient AD group) after a median time of 24 months. Participants with incipient AD were noted to have higher mean levels of P and T tau proteins and lower levels of AB42 when compared with normal controls, participants with stable MCI and those with dementia of other etiologies. Combination of all three tests yielded a sensitivity of 83%, and specificity of 88% for the distinction between stable MCI and incipient AD with a RR of 5.2 (95% CI, 3.9-6.9). Although this study suggests that these CSF markers may be used to identify incipient AD, at present there does not appear to be much role for them in the care of patients with MCI, as no therapies can be instituted to protect against progression of disease.

The strongest association between a gene mutation and the development of non-familial late onset AD is positivity for the e4 allele of the APOE gene. This past week in the NEJM a study sought to examine the psychological effects of disclosing carrier status to persons with the APOE-e4 gene.[4] The authors excluded participants with significant levels of anxiety, depression and cognitive impairment. The Impact of Events Scale (IES) was used to evaluate participants for stress associated with taking the test. Participants underwent APOE genotyping and were randomized to a disclosure group who were informed of their status and a non-disclosure group that was not, with the later group being further subdivided into the E4 positive (carriers) and negative groups. Both groups were shown charts detailing the incidence of AD in the general population compared with that of first degree relative of AD suffers. The disclosure group was also shown a chart outlining their genotype-specific risk. The primary outcome measures were the degree of anxiety, depression and test-related stress at 6 weeks, 6 months and 1 year. The study found that of the 162 participant who underwent randomization there was no significant difference between the disclosure and non-disclosure groups in terms of the adjusted group mean endpoint test score, change from baseline score and test related stress. Further, subgroup analysis also showed no significant difference in E4 positive subgroup and the non-disclosure group in terms of the studies primary outcome measures. However, a significantly higher IES score was found in E4 positive participants compared to those who were E4 negative. Like the CSF marker study, the potential utility of the findings in this study can only be fully explored as progress is made with regards to therapies for AD.

Finally, a study involving 1054 participants in the Cardiovascular Health Study published in the Archives of Internal Medicine found 65% less decline in serial MMSE among patients using centrally active ACE inhibitors, (those that cross the blood brain barrier including lisinopril, captopril, fosinopril, ramipril, perindopril and trandolapril), compared with those who were treated with other anti-hypertensives. [5]Notably the use of ACEIs as a class was not found to be associated with a decreased risk of dementia compared with other hypertensives with a hazard ratio of 1.01 (95% CI, 0.88-1.15), while non-centrally acting ACEIs as a subclass were associated with an increased risk of dementia when compared with non ACEIs (adjusted HR 1.20 (95% CI, 1.00-1.43 per year of exposure)). While this cohort study and the physiologic plausibility of its findings, (given increased concentrations of ACE receptors in the cerebral cortex of patients with Alzheimer’s dementia), suggest a possible role for centrally acting ACEI inhibitors in the management of patients with a high risk of developing dementia, further randomized trials will be needed to confirm this before widespread clinical recommendations can be made.

Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations

1. Cummings, JL. Alzheimer’s Disease. New England Journal of Medicine 2004;351:56-67
2. Rabin, RC. Large Study Turns to Brain Benefits of Eating Fish. The New York Times, July 21 2009
3. Mattsson et al. CSF Biomarkers and Incipient Alzheimer Disease in Patients with Mild Cognitive Impairment. JAMA 2009; 302(4):385-393
4. Green et al. Disclosure of APOE Genotype for Risk of Alzheimer’s disease. New England Journal of Medicine 2009;361:245-253
5. Sink et al. Angiotensin-Converting Enzyme Inhibitors and Cognitive Decline in Older Adults with Hypertension Arch Intern Med. 2009;169(13):1195-1202.

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