Alzheimer's disease: clinical trials and drug development

Mangialasche, Francesca; Solomon, Alina; Winblad, Bengt; Mecocci, Patrizia; Kivipelto, Miia

doi:10.1016/s1474-4422(10)70119-8

Cited by 1,024 publications

(783 citation statements)

References 148 publications

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“…These g-secretase modulators (GSMs) were initially shown to bind to APP, although some more recent studies demonstrated that they also can target g-secretase 21,22 . Although the precise molecular mechanism of action remains poorly understood, a number of these molecules have advanced to clinical trials 23 .…”

mentioning

confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical g-secretase modulators affect the processing of APP by the g-secretase complex and the production of the amyloid-beta peptide Ab42, the accumulation of which is considered causative of Alzheimer's disease. Here we demonstrate that mutations in the transmembrane domain of APP causing aggressive early-onset familial Alzheimer's disease affect both g-and e-cleavage sites, by raising the Ab42/40 ratio and inhibiting the production of AICD50-99, one of the two physiological APP intracellular domains (ICDs). This is in sharp contrast to g-secretase modulators, which shift Ab42 production towards the shorter Ab38, but unequivocally spare the e-site and APP-and Notch-ICDs production. Molecular simulations suggest that familial Alzheimer's disease mutations modulate the flexibility of the APP transmembrane domain and the presentation of its g-site, modifying at the same time, the solvation of the e-site.

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confidence: 99%

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

et al. 2013

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“…There is a large body of evidence on the beneficial effects of a healthy lifestyle including physical exercise and vascular risk control against AD onset and development which has been recently extensively summarized (see the 2012 special issue of the Zeitschr. Gerontol Geriatr and European Journal of Geriatrics on dementia and of the Journal of Alzheimer's Disease, Physiopathology of vascular risk factors in Alzheimer's Disease; Mangialasche et al 2010). Their recapitulation would be redundant and goes beyond the scope of this special section.…”

Section: Why Do We Need To Care About Dementiamentioning

confidence: 99%

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

Polidori

Schulz

2014

Genes Nutr

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There is an impressing body of evidence supporting the beneficial role of balanced nutrition in lowering the risk of dementia and its commonest form, Alzheimer's disease. Nevertheless, and despite worldwide dementia epidemic, there is much unfounded skepticism and lack of information among physicians. As a result, the diagnosis of cognitive impairment occurs still far too late, at best symptomatic drugs keep being prescribed and patients and caregivers are left with little concrete support in the hands of the natural history of the disease. This review summarizes knowledge about the impact of nutrition as part of a healthy lifestyle and of micronutrients in particular on delaying and avoiding dementia onset.Why do we need to care about dementia Dementia is the most prevalent neurodegenerative disorder, and it is characterized by progression, multiple etiology, complex symptomatology including that related to a disturbance of cognitive performance and absence of a cure. During the course of the disease, the cognitive symptoms of dementia persist and steadily worsen and behavioral disturbances appear and progress and as a result intellectual and social abilities are affected enough to obstacle the performance of activities of daily living. According to dementia definition, a diagnosis of dementia can be done when the impairment of more cognitive domains lasts long enough and is associated with behavioral disturbances both affecting activities of daily living. Dementia is indeed associated with disability and a high grade of dependence on caregivers-usually family members. This condition of disability and dependence brings along an enormous social and economic burden which is linked to the epidemics of dementia and its commonest, untreatable form, Alzheimer's disease (AD). The major risk factor for dementia and AD is advanced age, and therefore, the societal impact of AD is increasing according to aging demographics (http:// ec.europa.eu/health/reports/european). Life expectancy at birth in the EU increased from 72 years in 1980 to 78 years in 2007. The population of industrialized countries progressed from a mean life expectancy of 35 years at the beginning of the last century, to currently over 80 years of age. People aged 65 years or older are expected to double between 1995 and 2050 to reach 135 million in the EU, with very old people, aged 80 years and older, being projected to grow as much as eight to ten times on the global scale by 2050. This will strongly impact the already challenging number of ten million AD cases in the EU. As a cure against dementia has not been found yet, health care professionals all over the world are predicted to face the diagnostic, therapeutic and socioeconomical challenges of over 115 million people with dementia by 2050 (Prince et al. 2013). This perspective might be even underestimated, particularly due to inadequate diagnosis, lack of awareness and low education. The dramatic loss of synapses and cholinergic neurons, accumulation of extracellular b amyloid (Ab) plaqu...

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“…Eight years on, multiple therapies are in late-stage testing (see 'Selected drugs in clinical trials 2011'), including four that have the potential to modify the biological roots of Alzheimer's disease 1 . And yet, despite these seemingly imminent improvements in Alzheimer's therapeutics, a vague pall of scepticism hangs over the field.…”

Section: By L a U R E N G R Av I T Zmentioning

confidence: 99%

Drugs: A tangled web of targets

Gravitz¹

2011

Nature

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Alzheimer's disease: clinical trials and drug development

Cited by 1,024 publications

References 148 publications

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

Drugs: A tangled web of targets

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