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.