New Insights into the Molecular Bases of Familial Alzheimer's Disease.

Valeria D’Argenio,Daniela Sarnataro

doi:10.3390/jpm10020026

Abstract

Like several neurodegenerative disorders, such as Prion and Parkinson diseases, Alzheimer’s disease (AD) is characterized by spreading mechanism of aggregated proteins in the brain in a typical “prion-like” manner. Recent genetic studies have identified in four genes associated with inherited AD (amyloid precursor protein-APP, Presenilin-1, Presenilin-2 and Apolipoprotein E), rare mutations which cause dysregulation of APP processing and alterations of folding of the derived amyloid beta peptide (Aβ). Accumulation and aggregation of Aβ in the brain can trigger a series of intracellular events, including hyperphosphorylation of tau protein, leading to the pathological features of AD. However, mutations in these four genes account for a small of the total genetic risk for familial AD (FAD). Genome-wide association studies have recently led to the identification of additional AD candidate genes. Here, we review an update of well-established, highly penetrant FAD-causing genes with correlation to the protein misfolding pathway, and novel emerging candidate FAD genes, as well as inherited risk factors. Knowledge of these genes and of their correlated biochemical cascade will provide several potential targets for treatment of AD and aging-related disorders.

Highlights

Alzheimer’s disease (AD) is responsible for about 60–70% of cases of dementia, equivalent to an estimated population of 40–50 million persons worldwide
Recent genetic studies have identified in four genes associated with inherited AD, rare mutations which cause dysregulation of APP processing and alterations of folding of the derived amyloid beta peptide (Aβ)
While late onset AD is usually sporadic and doesn’t show any segregation within the families, it has been highlighted that early onset AD is featured by a high recurrence rate within the affected families, suggesting the presence of inherited forms of AD [3]

Summary

Introduction

Alzheimer’s disease (AD) is responsible for about 60–70% of cases of dementia, equivalent to an estimated population of 40–50 million persons worldwide. This more than doubled from 1990 to 2016 [1]. Early onset AD cases, characterized by the occurrence of clinical signs between 30 and 65 years old, have been reported [3,4]. Even if atypical phenotypes have been described, clinical and pathological features seem to be the same between early and late onset AD, so that it may be difficult to distinguish these 2 groups [4]. Iens.thiIsncothnitsexct,otnhteext, the rerlealatitoionnsshhiipp bbeettwweeeenn mmuutatatitoinosnsafafeffceticntginAgDA-rDel-arteeldatgeednegsenanesd apnrodtepinros’tetrinafsf’ictkrianffig,cfkoilndgin,gfoalndding and aaggggrreeggaattiioonn pprrooppeerrttieiesswwilillbl ebehihgihglhiglhigtehdt,ewd,itwh istphescpiaelcaitatel nattitoennttiooAnPtoP.ANPePx.t,Nnoexvte,l,neomveerlg, ienmg earngding and ccgaaennnddeitididcaattteeesFtFiAnAgDDmggeanyeenbsee,sau,ssawesfeuwlllieansllFinAahsDeirnfiathemedirlriitieseskdinfarocistrokdresfrawtcoitloilmrbsepwraolsivloledbthiesecauidlssesonedtdi,fiisscucagutigsoesnsetadinn,dgstumhgaagtneeansgtleiamnrggeentdthat enlargoef dthge eant-eritsick steusbtjiencgts.may be useful in FAD families in order to improve the identification and management of the at-risk subjects

Methods

Apolipoprotein E ε4 Risk Allele and Familial Alzheimer Disease

Findings

Conclusions