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.

Keywords: VCID; epidemiology; mitochondria; neuropathology; pathogenesis; preclinical.

Figure 1

Relationship between T2DM and AD and cognitive decline. Diabetes, specifically T2DM, has a strong association with CVD that causes dementia through generation of subcortical and cortical infarcts. T2DM has been linked with dementia and AD, however, the mechanism(s) are uncertain. Amyloid plaques and neurofibrillary tangles have a strong association with cognitive status and to date, T2DM has not been associated with increased levels of plaques and tangles. T2DM, type 2 diabetes mellitus; CVD, cerebrovascular disease; AD, Alzheimer's Disease.

Figure 2

Mitochondrial autophagy in AD. Mitochondrial dysfunction could play key roles in AD pathogenesis. Damaged mitochondria not only compromise the production of cellular energy and lose the capacity for Ca2+ buffering, they also release harmful ROS and cytochrome C resulted in activation of destructive pathways. Mitophagy is a mechanism for removing aged or damaged mitochondria, however, this mechanism is impaired in AD. Functionally defective mitochondria and insufficient clearance of the damaged organelles and macromolecules may synergistically intensify the detrimental pathways of AD. ATP, adenosine triphosphosphate; ROS, reactive oxygen species.

Figure 3

Lipid metabolism dysfunction in Alzheimer's Disease. A. Inhibition of cholesterol synthesis enzymes decreases plasma membrane cholesterol levels, β‐secretase and γ‐secretase activities, and β‐amyloid production. B. Cholesterol can be converted to 24‐(S)‐hydroxycholesterol or cholesteryl ester by CYP461A or ACAT‐1, respectively. Increased ACAT‐1 activity causes production of cholesteryl esters and increased β‐amyloid levels. Inhibition of ACAT‐1 by CP‐113,818 reduces β‐amyloid. C. Glycerophospholipids (GP) stabilize plasma membrane proteins such as ion channels and affect plasma membrane fluidity. Lower levels of GP are found in AD as evidenced by increased levels of GP degradation products, which are proinflammatory. Recruited astrocytes and microglia release IL1β, IL6, and TNFα and cause subsequent neuroinflammation. CYP461A, 24‐hydroxylase; ACAT‐1, sterol O‐acyltransferase 1; GP glycerophospholipids; AD, Alzheimer's Disease; IL1β, interleukin‐1β; IL6, interleukin‐6; TNFα tumor necrosis factor alpha.