Autosomal Dominant Alzheimer Disease: A Unique Resource to Study CSF Biomarker Changes in Preclinical AD

Abstract

Our understanding of the pathogenesis of Alzheimer disease (AD) has been greatly influenced by investigation of rare families with autosomal dominant mutations that cause early onset AD. Mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2) cause over-production of the amyloid-β peptide (Aβ) leading to early deposition of Aβ in the brain, which in turn is hypothesized to initiate a cascade of processes, resulting in neuronal death, cognitive decline, and eventual dementia. Studies of cerebrospinal fluid (CSF) from individuals with the common form of AD, late-onset AD (LOAD), have revealed that low CSF Aβ42 and high CSF tau are associated with AD brain pathology. Herein, we review the literature on CSF biomarkers in autosomal dominant AD (ADAD), which has contributed to a detailed road map of AD pathogenesis, especially during the preclinical period, prior to the appearance of any cognitive symptoms. Current drug trials are also taking advantage of the unique characteristics of ADAD and utilizing CSF biomarkers to accelerate development of effective therapies for AD.

A Bayesian Model for the Prediction and Early Diagnosis of Alzheimer's Disease

“…According to BN theory, if we assume a directed graph G with N nodes, each node n ∈ N has a number of paternal nodes pa(n) that may be linked with “child” nodes and the joint distribution for such a network given as follows: $\begin{array}{c}leftPfalse(Nfalse)={\prod }_{n\in N}pfalse(n|pafalse(nfalse)false).\end{array}$ By taking into consideration the latest calculations for the relative probabilities of AD progression due to certain brain lesions (Table 2) (Christen, 2000; de la Torre, 2002; Praticò et al, 2002; Modrego and Ferrández, 2004; Hooper et al, 2007; Cheung et al, 2008; Stone, 2008; Schuff et al, 2009; Snider et al, 2009; Wang et al, 2009; Israeli-Korn et al, 2010; Barnes and Yaffe, 2011; Nazem and Mansoori, 2011; Serrano-Pozo et al, 2011; Bird, 2012; Alzheimer's Association, 2015; Chakrabarty et al, 2015) and the majority of the published AD biomarkers (Albert et al, 2010, 2011; Besson et al, 2015; Cabezas-Opazo et al, 2015; Dong et al, 2015; Duce et al, 2015; Eskildsen et al, 2015; Jansen et al, 2015; Madeira et al, 2015; Michel, 2015; Nakanishi et al, 2015; Ossenkoppele et al, 2015; Østergaard et al, 2015; Quiroz et al, 2015; Ringman et al, 2015; Risacher et al, 2015; Sastre et al, 2015; Schindler and Fagan, 2015; Sutphen et al, 2015; Thordardottir et al, 2015; Cauwenberghe et al, 2016; Counts et al, 2016; Gaël et al, 2016; Yang et al, 2016) or calculating indirectly the relative probabilities, we designed a Bayesian model for the prediction of AD based on the abnormal testing of one or more biomarkers. The described probabilities were exported through major clinical trials globally and are continuously subject to updating and redefinition.…”

Biomarkers for Alzheimer's Disease Diagnosis

“…Individuals who inherit Presenilin-1,2 mutations present AD characteristics earlier than the age of 40-45. Families with these mutations present AD heredity which attends the autosomal dominant pattern with 50% probability for each generation to develop AD [ 11 , 33 , 34 ]. These mutations lead to plaque creation, tangles, cell loss and dementia.…”

Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease

“…Longitudinal studies of AD biomarkers therefore take many years to capture the full pathologic processes leading to dementia. Fully-penetrant autosomal dominant AD (ADAD) due to PSEN1 , PSEN2 , or APP mutations provides a valuable window for studying biomarkers across the cascade of AD pathology by taking advantage of the essentially 100% penetrance for the future development of AD with similar age of onset within families and mutation type ( Ryman et al, 2014 , Bateman et al, 2011 , Schindler and Fagan, 2015 ). Therefore, we can estimate at what point cognitive, behavioral, imaging, and biochemical changes are occurring with respect to the onset of clinical signs.…”