Advancing Alzheimer's disease diagnosis, treatment, and care: Recommendations from the Ware Invitational Summit

Abstract

To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled “State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care,” on June 21‐22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.

Brain Insulin Resistance in Alzheimer's Disease and its Potential Treatment with GLP-1 Analogs

“…Similarly, deficiencies in the total IR content of AD brain tissues have not been found in studies explicitly using age-matched controls [14,15,27,34,35], and cell fractionation fails to reveal deficiencies in cell surface IR levels in such tissues [14]. While insulin binding of the IR may be reduced in AD brain tissue [25], insulin still manages to activate the catalytic domain of IR at 71–74% of normal levels even in the hippocampal formation of AD dementia cases [13]. As noted above, far greater reductions in insulin responsiveness are seen below the IR in the AD brain beginning with IRS-1, which is activated by insulin at only 10% of normal levels in the hippocampal formation [14].…”

“…Such microglial activation may be a critical event in AD pathogenesis given the recent finding that knocking out a gene in an animal model of AD that encodes a microglial receptor (i.e., NOD-like receptor 3), which can sense inflammatory pathogens, including Aβ, prevents development of AD pathology and cognitive deficits that normally occur in that animal model [41]. Via neuronal receptors, microglial IL-1, IL-6 and TNF-α activate IRS-1 serine kinases known by the acronyms IKK, JNK and Erk2 [13]. In this way, Aβ oligomers administered to neuronal cultures or cerebral ventricles markedly elevate IRS-1 serine phosphorylation (IRS-1 pS) at multiple sites, namely S312, S616 and/or S636 (S307, S612 and S632 in rodents) (Figure 1) [42,43].…”

“…There is consequently an urgent need to develop novel treatments of AD within the next decade [13]. Among the most promising of those now in development are treatments that target brain insulin resistance (i.e., reduced neuronal responsiveness to extracellular insulin), which is an early, common and major feature in patients with AD, with and without diabetes [14,15].…”

Validation of the Chinese Version of Addenbrooke's Cognitive Examination-Revised for Screening Mild Alzheimer's Disease and Mild Cognitive Impairment

“…With an aging population, the number of patients with Alzheimer's disease (AD) and other cognitive disorders is growing dramatically [1]. The concept of mild cognitive impairment (MCI) was first proposed by Reisberg and his colleagues in 1988 [2], and Petersen et al [3] advanced its diagnostic criteria in 1999.…”

Political drive to screen for pre-dementia: not evidence based and ignores the harms of diagnosis

“…1-3 This policy drive has been accompanied by research into early detection of dementia, including preclinical identification of underlying neurobiology that might later be associated with dementia. 4 Although the clinical features of people with established dementia are unmistakable, 5 6 the ability of these preclinical features to predict future disease is less clear. Nevertheless, the belief that there is value in screening for "pre-dementia" or mild cognitive impairment is creeping into clinical practice, with the resulting overdiagnosis having potential adverse consequences for individual patients, resource allocation, and research.…”