Do hypoglycemic agents directly alter neuritic plaques or contribute to dementia in another way?
02 dec 2008--Prior research has suggested a link between type 2 diabetes and Alzheimer disease (AD). These studies include reports of an increased risk for dementia in people with type 2 diabetes and molecular studies describing a complex interplay between amyloid-beta — the primary component of neuritic plaques (NPs) — and insulin signaling in the brain. The specific relation between diabetes and AD pathology is unclear and is further complicated by the potential role of hypoglycemic medications in the pathophysiology of AD. To determine the relation between diabetes treatments and severity of AD pathology, researchers conducted autopsies on brains from residents of one home for elders: 124 patients with diabetes and 124 patients without diabetes matched for cognition, age at death, and sex. The diabetes group was further divided according to medication status: (1) no medication, (2) insulin, (3) oral hypoglycemics, and (4) combination therapy. Cognition was similar in all subgroups. The combination-therapy group had significantly fewer NPs in medial temporal and neocortical structures than did all the other groups. This difference remained after adjustments for fasting glucose level, other forms of neuropathology, weight, and body-mass index. Neurofibrillary tangles, the other major pathologic feature of AD, did not differ among groups. The authors speculate that these findings might support an effect of combination therapy on NPs through modulation of brain insulin signaling. Comment: This interesting work has some important limitations. The finding that patients on combination therapy had less AD pathology than did a group of controls matched for cognitive performance is curious. The authors speculate that hypoglycemic agents may modulate NPs, but an alternative explanation is that diabetes itself has other downstream effects on neuronal function that increase the degree of cognitive impairment for a given level of AD neuropathology. This explanation may be particularly relevant to patients on combination therapy, who may have had the most refractory or longest-duration diabetes. Also, despite statistical adjustments, confounding may have remained. For example, the groups might have differed in the degree of cerebrovascular disease, which is known to exacerbate cognitive impairment in AD.