Due to the aging of the population and to unhealthy lifestyle habits, age-related metabolic and neurodegenerative diseases are a growing and alarming problem around the globe. Sporadic Alzheimer's disease (AD) and type 2 diabetes (T2D), two chronic age-related disorders, have attained epidemic proportions. In 2015, an estimated 46.8 million people worldwide were living with dementia; AD being the most common form of dementia among the elderly. This number will almost double every 20 years, reaching 74.7 million in 2030 and 131.5 million in 2050 . Similarly, in 2010 about 285 million adults were living with diabetes and the number of affected individuals will increase to 439 million by 2030 .
To aggravate this scenario, a growing body of epidemiological and clinical studies has shown that T2D significantly increases the risk of AD . It has been demonstrated that both diseases share several pathophysiological mechanisms such as altered insulin signaling, energy metabolism defects (mainly alterations in glucose metabolism and mitochondria), oxidative stress, inflammation, and amyloidosis, among others [3,4]. Due to the remarkable overlap found between AD and T2D, it has been suggested that AD might be a new form of diabetes or type 3 diabetes [5,6].
Due to the lack of effective treatments for AD, and considering the similarities between AD and T2D, it has been hypothesized that anti-diabetic medication can help treat AD patients . In fact, there are several ongoing clinical trials of antidiabetic drugs in mild cognitive impairment (MCI) and AD subjects.
Promising effects of intranasally administered insulin or insulin analogues such as insulin detemir have been observed in AD and amnestic MCI subjects [8,9]. However, in carriers of the allele ε4 of apolipoprotein E (APOE-ε4) insulin administration seems to exacerbate cognitive deficits .
Regarding the oral antidiabetic agent metformin, a biguanide that stimulates adenosine monophosphate (AMP)-activated protein kinase (AMPK), studies have shown that in diabetic individuals, long-term treatment (>6 years) with metformin seems to reduce the risk of cognitive decline . However, another study showed that individuals with T2D or impaired glucose tolerance had overall worse cognitive performance and, among the participants with T2D, those treated with metformin performed less well on the cognitive tests than those managing diabetes with other approaches .
Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and potent insulin sensitizers. The best characterized PPAR-γ agonists are pioglitazone and rosiglitazone. Rosiglitazone was associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1-year follow up in the symptomatic stages of AD . However, a previous trial involving mild and moderate AD patients showed that patients treated with 8 mg rosiglitazone during 6 months presented a significant improvement in cognitive function in APOE-ε4-negative patients, while individuals with the APOE-ε4 allele showed no benefit . However, a recent systemic review and meta-analysis concluded that there is insufficient evidence to support the use of rosiglitazone in amnestic MCI and AD patients . The same study concluded that pioglitazone may be useful in treating AD patients with comorbid diabetes . A major limitation of TZDs in the prevention of AD is the side effects of edema and congestive heart failure.
Concerning the effects of glucagon-like peptide-1 (GLP-1) receptor agonists that have an insulinotropic action dependent on glucose levels, we are awaiting the results of two clinical trials; a pilot clinic trial of exendin-4 in MCI and early stage AD subjects (NCT01255163) and a phase II clinical trial assessing the safety and efficacy of liraglutide in mild AD (NCT01843075).
The discrepancies found between studies suggest that effects of antidiabetic agents possibly depends on doses and duration of treatment, and target population as deﬁned by the stage and severity of cognitive impairment and dementia as well as APOE gene polymorphism. More studies, particularly large-scale population studies and clinical trials, must be done to evaluate the effect of dose and duration of therapy (monotherapy or combination therapy) using a standardized battery of tests and the participants must be followed over a number of years.
Based on the above, we must ask ourselves: Is antidiabetic medication the right path to achieve sporadic AD cure?
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