Correlating familial Alzheimer's disease gene mutations with clinical phenotype

Abstract

Alzheimer's disease (AD) causes devastating cognitive impairment and an intense research effort is currently devoted to developing improved treatments for it. A minority of cases occur at a particularly young age and are caused by autosomal dominantly inherited genetic mutations. Although rare, familial AD provides unique opportunities to gain insights into the cascade of pathological events and how they relate to clinical manifestations. The phenotype of familial AD is highly variable and, although it shares many clinical features with sporadic AD, it also possesses important differences. Exploring the genetic and pathological basis of this phenotypic heterogeneity can illuminate aspects of the underlying disease mechanism, and is likely to inform our understanding and treatment of AD in the future.

Figure 1. APP

FAD-linked mutations are marked in red while nonpathogenic mutations are marked in orange. APP: Amyloid precursor protein; CTF: C-terminal fragment; NTF: N-terminal fragment. Diagram courtesy of Richard Crook, Mayo Clinic Jacksonville, FL, USA, and John Hardy, Institute of Neurology, University College London, UK. Adapted to include current known mutations.

Figure 2. PSEN1

Familial Alzheimer's disease-linked mutations are indicated in red, while nonpathogenic mutations are marked in orange. Interaction domains with APP/TLN or NCT/APH-1/PEN-2 are marked in blue, as well as the conserved residues D257 and D385 forming the putative catalytic site. Interactions of the C-terminal domain and the hydrophilic loop domain with proteins, such as the brain G-protein Go, calsenilin, the PSAP, β- and δ-catenin, p0071 and PLD1, are shown in dark green. The endoproteolytic cleavage site separating PSEN1-NTF and -CTF in the seventh hydrophobic region, the SPP cleavage site in the ninth TMD and the caspase cleavage site in the hydrophilic loop domain are indicated by yellow arrows. APH: Anterior pharynx-defective; APP: amyloid precursor protein; CTF: C-terminal fragment; NTF: N-terminal fragment; PEN: Presenilin enhancer; PLD: Phospholipase D; PSAP: Presenilin-1-associated protein; PSEN: Presenilin; NCT: Nicastrin; SPP: Signal peptide peptidase; TLN: Telencephalin; TMD: Transmembrane domain. Reprinted with permission from [81]. Adapted to include current known mutations.

Figure 3. PSEN2

CTF: C-terminal fragment; NTF: N-terminal fragment. Diagram courtesy of Richard Crook, Mayo Clinic Jacksonville, FL, USA, and John Hardy, Institute of Neurology, University College London, UK. Adapted to include current known mutations.