The DIAN‐TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

Bateman, Randall J.; Benzinger, Tammie L.S.; Berry, Scott M.; Clifford, David B.; Duggan, Cynthia; Fagan, Anne M.; Fanning, Kathleen; Farlow, Martin R.; Hassenstab, Jason; McDade, Eric; Mills, Susan; Paumier, Katrina L.; Quintana, Melanie; Salloway, Stephen; Santacruz, Anna; Schneider, Lon S.; Wang, Guoqiao; Xiong, Chengjie

doi:10.1016/j.jalz.2016.07.005

Cited by 239 publications

(281 citation statements)

References 65 publications

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“…Preventive clinical trials on presymptomatic carriers of highly penetrant variants of APP , PSEN1 , or PSEN2 belonging to EOAD families are currently ongoing (e.g., DIAN-TU). The study of such presymptomatic individuals indeed revealed that disease mechanisms, including Aβ aggregation, begin years before the clinical onset [116] . The prevention of Aβ aggregation or toxicity is therefore a promising solution to delay AD onset or prevent the disease in these very rare families.…”

Section: Resultsmentioning

confidence: 98%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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Section: Resultsmentioning

confidence: 98%

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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“…With respect to preventive therapies, two clinical trialsthe DIAN-TU (Dominantly Inherited Alzheimer Network Trial Unit) and API (Alzheimer's Prevention Initiative)-are ongoing to test the efficacy of passive immunotherapy among normal or mildly symptomatic FAD mutation carriers. 5,6 Thus, it is important to enhance local doctors' knowledge of FAD.…”

Section: Resultsmentioning

confidence: 99%

“…Asymptomatic carriers are also potentially valuable for future clinical trials. [4][5][6] In terms of cognitive symptoms, patients with FAD tended to present slightly less frequently with amnesia than those with LOAD, although amnesia remained their main presenting cognitive symptom. This is in agreement with previous studies that reported EOAD patients to have more prominent frontoparietal dysfunction than medial temporal dysfunction.…”

Section: Discussionmentioning

confidence: 98%

The first case series of Chinese patients in Hong Kong with familial Alzheimer’s disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer’s disease

Shea

Chu

et al. 2017

Hong Kong Med J

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“…These unfortunate 0.5 million people in 517 families in the world are destined for developing Alzheimer at the early age of 22-55, at about the same age as their mother or father, and their mother or father. The exact timing of dementia onset is dictated by the particular mutation in the APP, PS1 or PS2 gene [85][86][87][88]. To me, the DIAN people are the best 'human model' to study and understand the mind and what the brain does as time goes by, to uncover the molecular details and cellular mechanisms at work in the mind and body many decades before Alzheimer begins.…”

Section: Prevention Is the Only Curementioning

confidence: 99%

The amyloid hypothesis is too good to be true

Kurkinen¹

2017

Alzheimers Dement Cogn Neurol

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The DIAN‐TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

Cited by 239 publications

References 65 publications

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

The first case series of Chinese patients in Hong Kong with familial Alzheimer’s disease compared with those with biomarker-confirmed sporadic late-onset Alzheimer’s disease

The amyloid hypothesis is too good to be true

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