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Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

ABSTRACT: During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

SUBMITTER: Dubois B

PROVIDER: S-EPMC6417794 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Dubois Bruno B Hampel Harald H Feldman Howard H HH Scheltens Philip P Aisen Paul P Andrieu Sandrine S Bakardjian Hovagim H Benali Habib H Bertram Lars L Blennow Kaj K Broich Karl K Cavedo Enrica E Crutch Sebastian S Dartigues Jean-François JF Duyckaerts Charles C Epelbaum Stéphane S Frisoni Giovanni B GB Frisoni Giovanni B GB Gauthier Serge S Genthon Remy R Gouw Alida A AA Habert Marie-Odile MO Holtzman David M DM Kivipelto Miia M Lista Simone S Molinuevo José-Luis JL O'Bryant Sid E SE Rabinovici Gil D GD Rowe Christopher C Salloway Stephen S Schneider Lon S LS Sperling Reisa R Teichmann Marc M Carrillo Maria C MC Cummings Jeffrey J Jack Cliff R CR

Alzheimer's & dementia : the journal of the Alzheimer's Association 20160301 3

During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, ver ...[more]

PMID: 27012484

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Project description:Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar “Western” diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission.

Dataset Information

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Publications

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

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