Alzheimer's disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline

Abstract

Alzheimer's disease (AD) and type-2 diabetes mellitus (T2DM) are highly prevalent aging-related diseases associated with significant morbidity and mortality. Some findings in human and animal models have linked T2DM to AD-type dementia. Despite epidemiological associations between the T2DM and cognitive impairment, the interrelational mechanisms are unclear. The preponderance of evidence in longitudinal studies with autopsy confirmation have indicated that vascular mechanisms, rather than classic AD-type pathologies, underlie the cognitive decline often seen in self-reported T2DM. T2DM is associated with cardiovascular and cerebrovascular disease (CVD), and is associated with increased risk of infarcts and small vessel disease in the brain and other organs. Neuropathological examinations of post-mortem brains demonstrated evidence of cerebrovascular disease and little to no correlation between T2DM and β-amyloid deposits or neurofibrillary tangles. Nevertheless, the mechanisms upstream of early AD-specific pathology remain obscure. In this regard, there may indeed be overlap between the pathologic mechanisms of T2DM/"metabolic syndrome," and AD. More specifically, cerebral insulin processing, glucose metabolism, mitochondrial function, and/or lipid metabolism could be altered in patients in early AD and directly influence symptomatology and/or neuropathology.

Ovariectomy Activates Chronic Low-Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

“…Nearly one‐half of postmenopausal women develop osteoporosis, but menopause also increases incidence of other comorbidities including coronary artery disease, certain cancers, chronic obstructive pulmonary disease, stroke, and dementia . It is tempting to speculate that the proinflammatory T cells produced by E 2 loss also contribute to the pathogenesis of these conditions because all these conditions are known to be caused by both chronic inflammation and metabolic syndrome . In conclusion, our studies establish a new regulatory circuit between E 2 , the immune system, and the skeletal system.…”

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models

“…Next, we investigated other causative factor such as inflammatory process, mitochondrial dysfunction, or oxidative stress that may have a more critical role in the synaptic and cognitive deficits in T2DM (Carvalho et al, ; Chornenkyy, Wang, Wei, & Nelson, ; Ling et al, ; Pintana et al, ; Tumminia, Vinciguerra, Parisi, & Frittitta, ; Verdile et al, ). In addition, others authors have shown that db/db mice have reductions in brain weight and spine density, which were worsened in APP/PS1xdb/db mice, indicating a role for Aβ in these deficits (Infante‐Garcia, Ramos‐Rodriguez, Galindo‐Gonzalez, & Garcia‐Alloza, ).…”

Metabolic Syndrome and Its Biomarkers in the Development and Progression of Alzheimer’s Disease and Other Dementias

“…One of these links may lie in the fact that T2DM usually leads to atherosclerosis, which mediates cognitive decline. Another may lie in the alterations to cerebral glucose metabolism, as suggested by Chornenkyy et al [38]. Evidence from studies such as the Baltimore Longitudinal Study of Aging have shown, through autopsy, that glucose metabolism is altered in the orbital and prefrontal cortex, temporal cortex (middle gyrus, parahippocampal gyrus, and uncus), and cerebellar regions in cases of Alzheimer's disease [39,40].…”