Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links

Table 1 Epidemiological studies on the link between Alzheimer’s disease and type 2 diabetes mellitus

Ref.	Methodology	Results
Gudala et al[112]	Meta-analysis with 28 prospective observational studies which evaluated the association between diabetes and the risk of developing AD	A 56% risk of developing AD [RR = 1.56 (95%CI: 1.41-1.73), P < 0.05] was reported in patients with diabetes
Profenno et al[113]	Meta-analysis of 16 cross-sectional studies evaluating the relationship between diabetes and AD	The presence of diabetes significantly and independently increased the risk of AD [OR = 1.54 (95%CI: 1.33-1.79; P < 0.001]
Ohara et al[114]	Prospective study that evaluated the association between glucose tolerance status and the development of neurocognitive disorders in 1017 individuals ≥ 60 yr	AD incidence was significantly higher in subjects with T2DM compared to subjects with normal tolerance to glucose [HR = 2.05 (95%CI: 1.18 to 3.57), P = 0.01]
Xu et al[115]	Prospective study that examined the association between diabetes and the different types of neurocognitive disorders in 1248 older adults. Diagnoses were based on the DSM-III-R criteria	Individuals with non-diagnosed diabetes had a HR of 3.29 (95%CI: 1.20-9.01) P < 0.05 for AD diagnosis
Xu et al[116]	Prospective study that evaluated the association between T2DM and neurocognitive disorders and AD in 1301 older adults	T2DM diagnosis was significantly associated with neurocognitive disorders [HR = 1.5 (95%CI: 1.0-2.1) P = 0.04] and AD [HR = 1.3 (95%CI: 0.9-2.1) P < 0.05]
Peila et al[117]	Prospective study that examines the association between T2DM and neurocognitive disorder incidence in 2574 Japanese-American men. Diagnosis of neurocognitive disorder was performed through physical exam and MRI according to the NINCDS-ADRDA and DSM-IV criteria	T2DM was significantly associated with AD diagnosis [RR = 1.8 (95%CI: 1.1-2.9) P < 0.05]
McIntosh et al[118]	Prospective study that examined the relationship between T2DM, biomarkers, and the risk for suffering from neurocognitive disorders in 1289 dementia-free participants. AD biomarker levels were measured from the CSF. Neurocognitive disorders were evaluated through the CDRSB	Untreated diabetic individuals had higher levels of p-tau, p-tau/Aβ1-42, and t-tau/Aβ1-42 in their CSF than normoglycemic or prediabetic individuals (P < 0.05). The untreated group did not progress to neurocognitive disorder in higher rates than normoglycemic individuals [HR = 1.602 (95%CI: 1.057-2.429); P = 0.026]

AD: Alzheimer’s disease; T2DM: Type 2 diabetes mellitus; RR: Relative risk; HR: Hazard ratio; DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, revised third edition; CSF: Cerebrospinal fluid; CDRSB: Clinical Dementia Rating Sum of Boxes; p-tau: Phosphorylated tau; t-tau: Total tau; Aβ1-42: β-amyloid 1-42; MRI: Magnetic resonance imaging; NINCDS: National Institute of Neurological and Communicative Disorders and Stroke; ADRDA: Alzheimer’s Disease and Related Disorders Association; CI: Confidence interval; OR: Odds ratio.

Table 2 Summary of key evidence and ongoing trials on Alzheimer’s disease and type 2 diabetes mellitus

Ref.	Antidiabetic drug	Methodology	Results
Craft et al[137]	Intranasal insulin	Randomized, double-blind, placebo-controlled trial which evaluated the effects of intranasal insulin administration in 104 adults with amnestic mild cognitive impairment or mild to moderate AD	Treatment with 20 UI of insulin improved delayed memory (P ≤ 0.05). According to caretakers, a functional improvement was observed in the groups receiving 20 and 40 UI of insulin, respectively (P ≤ 0.01)
Alp et al[164]	Beta-glucan and gliclazide	Preclinical assay including mice with induced diabetes. These were subdivided into six groups among which two groups received treatment with beta-glucan or gliclazide. Different parameters were used to determine the level of oxidative stress, including paraoxonase-1, total antioxidative status, and malondialdehyde	Mice with induced diabetes with no treatment presented high levels of malondialdehyde with a decrease in paraoxonase-1. Groups treated with beta-glucan and gliclazide presented a return of these values to normal levels after treatment, showing a decrease in brain oxidative stress (P ≤ 0.05)
Mostafa et al[174]	Metformin	Preclinical study in mice in which a group received scopolamine and metformin at and the other group received scopolamine and rivastigmine. Malondialdehyde, Akt, phosphorylated Akt, phosphorylated tau, and acetylcholinesterase levels were determined	The functionality of mice receiving scopolamine and a dose of metformin of 100 mg/kg per day was better than the group that was not administered with metformin. They also presented less inflammation and oxidative stress compared with the group receiving rivastigmine. An increase in phosphorylated Akt was observed
Qi et al[188]	Liraglutide	Forty mice were divided into four groups. The group with amyloid beta-induced AD was administered with liraglutide for 8 weeks and their cognitive performance was evaluated using a Morris water labyrinth	A protective effect in cognitive performance was observed in mice administered with liraglutide. Likewise, less structural changes in pyramidal neurons were observed, as well as a decrease in tau phosphorylation
Adler et al[209]	Amylin	The amylin levels in AD patients, patients with mild cognitive dysfunctions, and the control group were determined. Likewise, pramlintide, an amylin analog, was administered in AD mice in which oxidative stress and cognition were evaluated	Lower levels of amylin in patients with AD and mild cognitive dysfunction were observed compared with the control group. Mice administered with pramlintide showed improvement in cognition and synaptic markers as well as a decrease in oxidative stress in the hippocampus
NCT01843075[190]	Liraglutide	Multicenter, randomized, double-blind, placebo-controlled Phase IIb study in patients with mild AD	-
NCT03980730[208]	Azeliragon	Multicenter, randomized, double-blind, placebo-controlled, Phase II/III studies to evaluate the safety and efficacy of azeliragon as a treatment for subjects with mild AD	-
NCT02462161[142]	Intranasal insulin aspart	Pilot phase I clinical trial that will examine the effects of intranasal insulin aspart on cognition, daily function, blood, and cerebral spinal fluid markers of AD	-
NCT02503501[143]	Intranasal insulin glulisine	A phase II, single center, randomized, double-blind, placebo-controlled study that will evaluate the safety and effectiveness of intranasal glulisine in patients with probable AD	-

AD: Alzheimer’s disease.