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.

Keywords: Alzheimer disease; autosomal dominant; biomarkers; cerebrospinal fluid; familial.

Figure 1

A time course of changes in ADAD mutation carriers versus non-carriers. Cross-sectional data obtained in the DIAN cohort demonstrates that CSF Aβ42 (yellow) declines as Aβ deposition increases as shown by amyloid PET imaging (orange). CSF tau (green) increases as hippocampal volume (blue) and glucose metabolism as shown by FDG PET (purple) decreases. CDR-SOB (Clinical Dementia Rating-Sum of Boxes) (black), which quantifies clinical symptoms of dementia, increases (indicating worse performance) relatively late in the disease course. Reproduced with permission from Bateman et al. (11).