Genetic discoveries as the basis of personalized therapy: rosiglitazone treatment of Alzheimer's disease

Hsueh, Willa A.

doi:10.1038/sj.tpj.6500383

Cited by 11 publications

(4 citation statements)

References 31 publications

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“…The only stratification variable was the presence or absence of APOE-ε4 genotype. The rationale for this stratification was that observational studies have shown that APOE-ε4 genotype modifies the association of hyperinsulinemia and diabetes with AD (risk is much higher in those with APOE-ε4)[27-29] and a pilot randomized trial of the insulin sensitizer rosiglitazone reported that this medication was only efficacious among persons without APOE-ε4 [30]. Allocation concealment was maintained by randomly alternating block sizes.…”

Section: Methodsmentioning

confidence: 99%

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Luchsinger

Perez

Chang

et al. 2016

JAD

218

129

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Diabetes and hyperinsulinemia may be risk factors for Alzheimer's disease (AD). We conducted a pilot study of metformin, a medication efficacious in treating and preventing diabetes while reducing hyperinsulinemia, among persons with amnestic mild cognitive impairment (AMCI) with the goal of collecting preliminary data on feasiblity, safety, and efficacy. Participants were 80 men and women aged 55 to 90 years with AMCI, overweight or obese, without treated diabetes. We randomized participants to metformin 1000 mg twice a day or matching placebo for 12 months. The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake (rCMRgl) in the posterior cingulate-precuneus in brain Fluorodeoxyglucose Positron Emission Tomography. Change in plasma Aβ42 was an exploratory outcome. The mean age of participants was 65 years. Fifty % of participants were women. The only baseline variable that was different between the arms was the ADAS-Cog. Metformin could not be tolerated by 7.5% of participants; 15% tolerated 500 mg/day, 35% tolerated 1000 mg/day, 32.5% tolerated 1500 mg/day, and only 10% tolerated the maximum dose. There were no serious adverse events related to metformin. The 7.5% of persons who did not tolerate metformin reported gastrointestinal symptoms. After adjusting for baseline ADAS-cog, changes in total recall of the SRT favored the metformin group (9.7 ± 8.5 vs. 5.3 ± 8.5; p = 0.02). Differences for other outcomes were not significant. A larger trial seems warranted to evaluate the efficacy and cognitive safety of metformin in prodromal AD.

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Section: Methodsmentioning

confidence: 99%

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Luchsinger

Perez

Chang

et al. 2016

JAD

218

129

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“…In consideration of the underlying pathological mechanisms, researches are being conducted with treatments for insulin resistance such as Rosiglitazone ® (Hsueh 2006) and gene therapy targeting insulin degrading enzyme (Qiu and Folstein 2006).…”

Section: Diabetus Mellitus and Cognitive Declinementioning

confidence: 99%

Vascular risk factors, cognitve decline, and dementia

Duron

Hanon²

2008

VHRM

250

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Dementia is one of the most important neurological disorders in the elderly. Aging is associated with a large increase in the prevalence and incidence of degenerative (Alzheimer's disease) and vascular dementia, leading to a devastating loss of autonomy. In view of the increasing longevity of populations worldwide, prevention of dementia has turned into a major public health challenge. In the past decade, several vascular risk factors have been found to be associated with vascular dementia but also Alzheimer's disease. Some longitudinal studies, have found signifi cant associations between hypertension, diabetus mellitus, and metabolic syndrome, assessed at middle age, and dementia. Studies assessing the link between hypercholesterolemia, atrial fi brillation, smoking, and dementia have given more confl icting results. Furthermore, some studies have highlighted the possible protective effect of antihypertensive therapy on cognition and some trials are evaluating the effects of statins and treatments for insulin resistance. Vascular risk factors and their treatments are a promising avenue of research for prevention of dementia, and further long-term, placebo-controlled, randomized studies, need to be performed.

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“…Plasma insulin concentration is elevated in patients with type 2 DM because of peripheral insulin resistance. Hyperinsulinaemia is one of the predictors of memory impairment and AD [24]. Large population's studies on vascular risk factors have demonstrated that an increase in brain insulin is found to be associated with poor performances on the MMSE.…”

Section: Hyperinsulinaemia and Insulin Resistancementioning

confidence: 99%

Alzheimer′s Disease and Type 2 Diabetes Mellitus: Risk Factors and Effectiveness of Antidiabetic Agents in Treatment of Alzheimer′s Disease

Myint¹

2013

SJCM

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The aim of this review is to highlight the association between type 2 diabetes mellitus (DM) and cognitive impairment/Alzheimer's disease (AD) and provide an updated summary of the evidence related to various potentially modifiable risk factors such as hyperinsulinaemia,insulin resistance,hypo-and hyperglycaemia, vascular risk factors like hypertension and obesity, micro and macrovascular complications, depression in AD.Treating modifiable risk factors can reduce the prevalence of AD.In addition we provide the information about potential benefits of antidiabetic agents for slowing of cognitive decline and AD in patients with type2 DM. There were studies demonstrating the novel effects of antidiabetic agents on neuronal functions by increased insulin signaling in an AD brain with a neuroprotective and neurotrophic effect. In this regard insulin, metformin and thiazolidinediones (in particular, rosiglitazone and pioglitazone) would have potential protective effect for the development of AD.

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Genetic discoveries as the basis of personalized therapy: rosiglitazone treatment of Alzheimer's disease

Cited by 11 publications

References 31 publications

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Metformin in Amnestic Mild Cognitive Impairment: Results of a Pilot Randomized Placebo Controlled Clinical Trial

Vascular risk factors, cognitve decline, and dementia

Alzheimer′s Disease and Type 2 Diabetes Mellitus: Risk Factors and Effectiveness of Antidiabetic Agents in Treatment of Alzheimer′s Disease

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