Brain Amyloid Pathology Research Articles

P2-412: MPC-7869 (R-flurbiprofen), a selective Aβ42-lowering agent, delays time to clinically significant psychiatric events in Alzheimer’s disease (AD): Analysis from a 12-month phase 2 trial

MPC–7869 is a Selective Aβ42–Lowering Agent (SALA). In a mouse model of AD (Tg2576), MPC–7869 lowers brain levels of Aβ42 and chronic dosing in this model reduces brain amyloid pathology and prevents defects in learning and memory. These data and the Phase 2 study indicating sustained benefit in activities of daily living, global function and cognition in mild AD patients suggest a potential for MPC–7869 to have disease–modifying properties. The goal of this analysis is to explore a possible effect of MPC–7869 on time to onset of psychiatric adverse events in AD subjects. This was a placebo–controlled, double–blind, 1–year trial evaluating MPC–7869 in 207 patients with mild–to–moderate AD (MMSE 15–26, with an average MMSE score of 21). 94% of subjects were on stable acetylcholinesterase inhibitor therapy. An exploratory analysis was performed which compared time to adverse psychiatric events between treatment groups. A prespecified interaction analysis revealed that mild and moderate AD patients responded differently to MPC–7869 (P= 0.03). In mild AD patients (MMSE 20–26) there was a significant delay in time to clinically significant adverse psychiatric events in the 800 mg BID group compared to Placebo (P=0.011). The median time to event was approximately 106 days in the Placebo group among the 35% of Placebo patients who had an event. In the 800 mg BID group, the median time to event was greater than 333 days, and could not be precisely estimated since only 14% of 800 mg BID patients had an event. The most common psychiatric events reported in the placebo group were agitation, aggression, confusional state and depression. MPC–7869 has an attractive therapeutic and safety profile in patients with mild AD, the vast majority of whom were already on standard of care therapy (acetylcholinesterase inhibitors). In addition to the reported significant benefit observed in activities of daily living (P=0.033), global function (P=0.042) and a positive trend in cognition, this analysis revealed a significant delay in time to psychiatric events. These results are consistent with the hypothesis that treatment with MPC–7869 may delay progression of AD.

Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

Type II diabetes mellitus (DM2) is associated with an increased risk of cognitive dysfunction and dementia. The increased risk of dementia concerns both Alzheimer's disease and vascular dementia. Although some uncertainty remains into the exact pathogenesis, several mechanisms through which DM2 may affect the brain have now been identified. First, factors related to the 'metabolic syndrome', a cluster of metabolic and vascular risk factors (e.g. dyslipidaemia and hypertension) that is closely linked to DM2, may be involved. A number of these risk factors are predictors of cerebrovascular disease, accelerated cognitive decline and dementia. Secondly, hyperglycaemia may be involved, through adverse effects of potentially 'toxic' glucose metabolites on the brain and its vasculature. Thirdly, insulin itself may be involved. Insulin can directly modulate synaptic plasticity and learning and memory, and disturbances in insulin signalling pathways in the periphery and in the brain have recently been implicated in Alzheimer's disease and brain aging. Insulin also regulates the metabolism of beta-amyloid and tau, the building blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer's disease. In this paper, the evidence for the association between DM2 and dementia and for each of these underlying mechanisms will be reviewed, with emphasis on the role of insulin itself.

Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

Alpha-Synuclein Lesions in Normal Aging, Parkinson Disease, and Alzheimer Disease: Evidence from the Baltimore Longitudinal Study of Aging (BLSA)

Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.

The lipophilic metal chelator DP-109 reduces amyloid pathology in brains of human β-amyloid precursor protein transgenic mice

Metals such as zinc, copper and iron contribute to aggregation of amyloid-β (Aβ) protein and deposition of amyloid plaques in Alzheimer’s disease (AD). We examined whether the lipophilic metal chelator DP-109 inhibited these events in aged female hAβPP-transgenic Tg2576 mice. Daily gavage administration of DP-109 for 3 months markedly reduced the burden of amyloid plaques and the degree of cerebral amyloid angiopathy in brains, compared to animals receiving vehicle treatment. Moreover, DP-109 treatment appeared to facilitate the transition of Aβ from insoluble to soluble forms in the cerebrum. These results further support the hypothesis that endogenous metals are involved in the deposition of aggregated Aβ in brains of AD patients, and that metal chelators may be useful therapeutic agents in the treatment of AD.