Determinants And Mechanisms

Possible risk factors for changes in cognitive functioning and brain structure in patients with type 2 diabetes include diabetes-specific factors (e.g., hyperglycemia, glucose-lowering therapy, microvascular complications), factors that are linked to diabetes but are not specific to the disease (e.g., hypertension, stroke, depression), genetic factors and demographic, socio-economic, and lifestyle factors (Fig. 2). All of these risk factors may affect cognitive functioning at different times during life span, but there are still relatively few studies that have specifically addressed these risk factors in relation to cognition in patients with type 2 diabetes.

Genetic Factors

Genetic predisposition possibly plays a role in the association between type 2 diabetes, cognitive impairment, and dementia, but thus far only the role of the apolipoprotein (APOE) genotype and the Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPARG) genotype has been examined. The presence of the APOE s4 allele is a risk factor for the development of Alzheimer's disease (99). Patients with type 2 diabetes who carry the APOE s4 allele appeared to have a 2-fold increased risk of dementia compared to persons with either of these risk factors in isolation (100, 101). Data on the risk of cognitive impairment in non-demented persons are limited. Some studies reported an interaction with APOE where APOE s4 allele carriers who had diabetes had the highest risk of cognitive decline (14, 102, 103). Results of the Rancho Bernardo Study (32), ra in ni

Genetics

Fig. 2. Relation between type 2 diabetes, related risk factors and cognitive decline. It shows a putative course of development for cognitive dysfunction in type 2 diabetes. In our view, impaired cognitive functioning in patients with type 2 diabetes develops against a background of genetic predisposition and socio-economic and lifestyle factors. In midlife, the presence of vascular risk factors such as hypertension and obesity starts to play an important role, together with insulin resistance, both by increasing the risk of developing diabetes and atherosclerotic vascular disease and by independent associations with cognitive decline and dementia later in life. The development of hyper-glycemia, glucose intolerance, and microvascular and macrovascular complications that are associated with type 2 diabetes then further accelerates diabetes-associated brain dysfunction.

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Genetics

Fig. 2. Relation between type 2 diabetes, related risk factors and cognitive decline. It shows a putative course of development for cognitive dysfunction in type 2 diabetes. In our view, impaired cognitive functioning in patients with type 2 diabetes develops against a background of genetic predisposition and socio-economic and lifestyle factors. In midlife, the presence of vascular risk factors such as hypertension and obesity starts to play an important role, together with insulin resistance, both by increasing the risk of developing diabetes and atherosclerotic vascular disease and by independent associations with cognitive decline and dementia later in life. The development of hyper-glycemia, glucose intolerance, and microvascular and macrovascular complications that are associated with type 2 diabetes then further accelerates diabetes-associated brain dysfunction.

however, failed to show such interaction. A recent study on the role of PPARG Pro12Ala further suggested that risk of cognitive decline is greater in Pro12Ala carriers who develop diabetes (104).

Several demographic factors, such as socio-economic status, age, and sex, are associated with both type 2 diabetes and cognitive dysfunction. For example, women with a lower socio-economic status or a lower educational level have 20-60% increased odds of having type 2 diabetes (105). In addition, the risk of cognitive decline and dementia is increased for persons with lower socio-economic status or educational level (106, 107). Factors such as gender and ethnic background also affect the incidence of vascular disease and vascular risk factors (108-110). These demographic factors may therefore play a role in the association between type 2 diabetes and cognitive decline. The majority of studies that were reviewed in earlier sections of this chapter take the possible confounding effects of sex, ethnicity, and level of education into account, but systematic examination of the potential role

Demographics and Lifestyle of these demographic factors in the association between diabetes and cognitive functioning is lacking. Examination of the results of studies that specifically assessed cognitive functioning in women (111), or men (112), with type 2 diabetes shows essentially the same cognitive impairments across both sexes. The impact of ethnicity is unclear, but the results of studies that adjusted their analyses for ethnic background (25, 49) were similar to those of studies who did not explicitly adjust for this variable. Moreover, the risk of dementia in relation to diabetes was quite consistent across populations from different continents (113).

The effects of age deserve special attention, as type 2 diabetes is particularly common among older individuals. Also, age is an important risk factor for both cognitive decline and type 2 diabetes. As was mentioned in an earlier section of this chapter, the pattern of neuropsychological deficits in younger patients with diabetes, with mild impairments across the cognitive domains, and the largest effects in the domains, verbal memory, information-processing speed, and executive functioning, resembles the pattern of cognitive decline seen in older persons without diabetes (114,115). The effects of age and type 2 diabetes on cognitive functioning may thus interact, which is supported by both studies in patients with type 2 diabetes and in experimentally diabetic rodents (116). Such interaction would also be plausible from a mechanistic point of view as several of the mechanisms that are assumed to mediate the toxic effects of hyperglycemia on the brain, such as oxidative stress, the accumulation of advanced glycation end-products, and microangiopathy are also implicated in brain aging (117).

Lifestyle factors, such as smoking and diet, are associated with both type 2 diabetes (118, 119) and with cognitive decline and dementia (120, 121). Similar to demographic factors, such as sex and socio-economic status, these factors are potentially confounding factors in the association between type 2 diabetes and cognitive decline. More importantly, these factors are potentially modifiable, which may reduce the risk of both type 2 diabetes and cognitive impairment.

(Midlife) Vascular Risk Factors

As was described in the previous paragraphs, hypertension, obesity, and dyslipidemia are associated with cognitive decline and may thus be involved in the association between type 2 diabetes and cognitive decline. Thus far, studies on the role of vascular risk factors in the association between diabetes and impaired cognition have focused on hypertension. Several studies have shown cumulative or interactive effects of hypertension and type 2 diabetes (26,122). Other studies, however, do not confirm these results (11, 31, 32, 74). Studies that failed to show interaction or additive associations tend to involve study populations of relatively high age (>70). A recent review on vascular risk factors for dementia has shown that for many vascular risk factors the risk of late-life dementia is generally largest in studies that measured the risk factor in midlife (compared to late-life) and had a long follow-up time (68). These results suggest that midlife hypertension, even in pre-diabetic stages, may indeed be additive to the effects of type 2 diabetes on cognitive functioning later in life.

Data on the effect of (midlife) lipid levels and obesity on cognitive functioning in patients with type 2 diabetes are limited. A recent longitudinal study on predictors of cognitive impairment and dementia in older (>70) patients with diabetes showed that higher baseline total cholesterol level was associated with a 30% decreased risk of cognitive impairment after 7 years (123). Higher baseline waist-to-hip ratio was associated with a 50% decreased risk of cognitive impairment in this study. In addition, a cross-sectional study showed a modest association between the use of lipid-lowering drugs and better cognitive performance (124).

Hyperglycemia and Hypoglycemia

Studies in patients with type 1 diabetes suggest that chronic exposure to hyperglycemia may have a negative impact on cognitive function (125). Several studies in patients with type 2 diabetes reported similar findings. Longer duration of type 2 diabetes was associated with a greater risk of cognitive impairment (9, 11, 26) and elevated HbA1c levels, which reflect chronic hyperglycemia, are found to be associated with impaired cognition in type 2 diabetes (9, 32, 78,126-128), although not invariably (129,130). Figure 3 shows a dose-response relation between quartiles of HbA1c and cognitive performance [adapted from (131)]. A study on acute effects of hyperglycemia further added to these findings that hyperglycemia may be associated with short-term fluctuations in cognitive functioning (132). For these acute fluctuations the relationship with glucose levels is non-linear, and there may be a threshold of glucose levels around 15 mmol/l when cognitive functioning starts to get affected (132).

Hypoglycemia is a well-known complication of glucose-lowering therapy. Although severe hypoglycemic episodes are much less common in type 2 than in type 1 diabetes, such episodes may have detrimental effects on the brain. Data on the impact of hypoglycemic episodes on cognition in type 2 diabetes are limited. A cross-sectional study did not find an association between the prevalence of hypoglycemic episodes and cognition (78). A recent longitudinal study observed an association between the prevalence of severe hypoglycemia and the prevalence of cognitive impairment and dementia at follow-up, but showed no difference in the baseline prevalence

Fig. 3. Relation between HbA1c level and performance on two cognitive domains. (Adapted from Tiehuis et al. (131) with permission from Future Medicine Ltd.)

of hypoglycemic episodes in persons who developed cognitive impairment after 7 years follow-up and those who did not (123). In type 1 diabetes a meta-analysis (125) and results from the Diabetes Control and Complications Trial (DCCT) (133) provided no evidence for an association between the occurrence of hypoglycemic episodes and impaired cognition, despite the fact that small case series suggested that such an association might exist (134).

Microvascular and Macrovascular Complications

In general, longer duration of diabetes and worse glycemic control are associated with an increased prevalence, progression, and severity of microvascular end-organ complications both in type 1 as well as in type 2 diabetes (135, 136). In adults with type 1 diabetes the occurrence of microvascular complications is associated with reduced cognitive performance (137) and accelerated cognitive decline (138). Moreover, type 1 diabetes is associated with decreased white-matter volume of the brain and diminished cognitive performance in particular in patients with retinopa-thy (139). Microvascular complications are also thought to play a role in the development of cognitive decline in patients with type 2 diabetes, but studies that have specifically examined this association are scarce.

Macrovascular disease, including previous vascular events, presence of plaques in the carotid arteries, and presence of peripheral arterial atheroscle rotic disease, is associated with age-related cognitive impairment (140) in the general population. Type 2 diabetes is associated with an increased risk of macrovascular complications. In a recent study in patients with type 2 diabetes macrovascular atherosclerotic disease appeared to be the most consistent determinant of impaired cognition and brain MRI abnormalities (78). In addition, peripheral artery disease was associated with a 2- to 5-fold increased risk of developing cognitive impairment or dementia in a population of older patients with type 2 diabetes (123) and a history of cerebrovas-cular disease was associated with a 3-fold increased risk of a low MMSE score (141).

Depression

A recent meta-analysis reported that patients with type 2 diabetes have a 2-fold increased risk of depression compared to non-diabetic persons (142). The prevalence of major depressive disorder in patients with type 2 diabetes was estimated at 11% and depressive symptoms were observed in 31% of the patients. A recent study in 907 elderly patients with type 2 diabetes showed that higher depression scores were associated with a 10% increased risk of cognitive impairment, measured with MMSE (141). However, the exact nature of the relation between type 2 diabetes and depression is incompletely understood. Depression may result from coping with chronic disease or from metabolic consequences of type 2 diabetes, even at the level of cerebral neurotransmitters. Conversely, depression may even predispose the development of type 2 diabetes (143). Although depressive symptoms probably play a role in the etiology of diabetes-associated cognitive decrements, only a proportion of the patients with diabetes develop clinically relevant depressive symptoms. It is therefore unlikely that depression explains the whole association between diabetes and cognition. Moreover, the majority of studies that assessed cognition in relation to diabetes controlled for the potential confounding effects of depression. Chapter 14 offers a more detailed overview of relation between diabetes and depression.

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