23 August 2013. While people with type 2 diabetes are at greater risk for Alzheimer’s disease, predicting who among them will go on to develop dementia remains difficult. Two new studies offer some clues. In the inaugural Lancet Diabetes & Endocrinology, scientists led by Rachel Whitmer, Kaiser Permanente Division of Research, Oakland, California, reported a system to rate the likelihood of future cognitive decline in diabetes patients. They base their risk score on eight risk factors most associated with dementia, including depression. That factor took the spotlight in an August 14 JAMA Psychiatry paper, as well. First author Mark Sullivan, University of Washington, Seattle, and colleagues reported that higher depression scores corresponded with greater cognitive decline over an observation period of 40 months in a cohort of diabetics. "These papers provide another indication that diabetes is not good for your brain," said Lenore Launer, National Institute on Aging, Bethesda, Maryland, senior author on the Sullivan paper.
A number of scoring methods exist to predict dementia in the general population (see ARF related news story and Jessen et al., 2011). Diabetes patients are different, however, because they have unique co-morbidities such as severe hypoglycemic episodes. Whitmer's group, including first author Lieza Exalto, set out to design a risk score specific to type 2 diabetes (T2D). The researchers scoured the literature for factors that associate T2D with dementia and came up with 45 candidates. They then looked at records of 29,961 T2D patients in the Kaiser Permanente Northern California (KPNC) Diabetes Registry, to see how well those factors predicted dementia. All participants were older than 60 years and free of dementia at baseline.
The strongest predictive factors were age, education, microvascular disease, cerebrovascular disease, cardiovascular disease, acute metabolic events such as hyper- or hypoglycemia, depression, and "diabetic foot," a neuropathic complication of diabetes that encompasses lower limb gangrene, ulcers, and amputations. Exalto and colleagues assigned each factor a point value depending on how strongly it predicted dementia. Age was the strongest risk factor, as it is for sporadic AD. After applying the point system to the KPNC cohort, the researchers found that the highest-scoring patients were 37 times more likely to develop dementia over a decade than people with the lowest scores. Patients with higher scores also developed dementia more quickly than low-scoring individuals. The researchers validated this scoring system in a separate cohort of 2,413 patients.
Though the study offers a new scoring tool, Launer noted that such indices have not yet added much predictive value beyond age. Whitmer countered that the score can detect differences within a given age group, which would escape detection if the entire risk burden came from age.
Whitmer said the next step would be to perform cognitive tests and brain imaging in people with the highest scores. That may help shed light on whether vascular dementia or Alzheimer's disease is responsible for the cognitive decline in diabetes patients, she said. Previous studies have not reached a consensus on that point (see Arvanitakis et al., 2006 and Ahtiluoto et al., 2010).
Whitmer's group previously reported that depression doubled the risk of dementia in diabetes patients (see Katon et al., 2010 and Katon et al., 2012). However, these studies relied on non-standardized diagnoses from medical records that may overlook some cases, wrote Sullivan and colleagues in their paper. To scrutinize the association, the Seattle group prospectively observed 2,977 cognitively normal people enrolled in the Action to Control Cardiovascular Risk in Diabetes–Memory in Diabetes (ACCORD-MIND) study (see Buse et al., 2007). The researchers used the Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, and the modified Stroop test to assess cognition, and the Patient Health Questionnaire to evaluate depression. They also took into account previous cardiovascular disease, age, and diabetes-related treatments.
People who scored highest for depression declined fastest on each of the cognitive tests, regardless of other health factors. For instance, non-depressed patients declined an average of 1.7 points on the digit symbol test, while depressed patients declined 2.7 points. That researchers demonstrated a relationship between cognitive decline and depression before the onset of dementia supports the idea that depression may contribute to decline, rather than just appear as a prodrome, Launer told Alzforum. Depressed patients are less likely to manage their diabetes through diet, exercise, and medication, and both depression and diabetes cause inflammation, insulin resistance, and autonomic dysfunction, the authors pointed out. Any of these factors could contribute to dementia, Launer said.
These results could have implications for prevention of cognitive decline, Whitmer claims. "Depression is a modifiable risk factor. If we treat it, can we lower dementia risk? That's a follow up question," she told Alzforum. Since this was an observational study, the researchers emphasized that they did not control for depression treatment. Further research will have to assess whether treatment can stave off dementia in diabetics.—Gwyneth Dickey Zakaib.
Exalto L, Biessels GJ, Karter AJ, Huang ES, Katon WJ, Minkoff JR, Whitmer RA. Risk score for prediction of 10-year dementia risk in individuals with type 2 diabetes: A cohort study. The Lancet. 2013 August 20. [Epub ahead of print].
Sullivan MD, Katon WJ, Lovato LC, Miller ME, Murray AM, Horowitz KR, Bryan RN, Gerstein HC, Marcovina S, Akpunonu BE, Johnson J, Yale JF, Williamson J, Launer LJ. Association of Depression With Accelerated Cognitive Decline Among Patients With Type 2 Diabetes in the ACCORD-MIND Trial. JAMA Psychiatry. 2013 Aug 14. [Epub ahead of print] Abstract