Risk Factors for Alzheimer's Disease: Focus on Stress.

Alessandra Caruso,Alessandra Gaetano,Ferdinando Nicoletti,Sergio Scaccianoce

doi:10.3389/fphar.2019.00976

Alessandra Caruso, Alessandra Gaetano + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2019.00976

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Abstract

In vulnerable individuals, chronic and persistent stress is an established risk factor for disorders that are comorbid with Alzheimer’s disease (AD), such as hypertension, obesity and metabolic syndrome, and psychiatric disorders. There are no disease-modifying drugs in the treatment of AD, and all phase-3 clinical trials with anti-amyloid drugs (e.g., β- or γ-secretase inhibitors and monoclonal antibodies) did not meet the primary endpoints. There are many reasons for the lack of efficacy of anti-amyloid drugs in AD, the most likely being a late start of treatment, considering that pathophysiological mechanisms underlying synaptic dysfunction and neuronal death begin several decades before the clinical onset of AD. The identification of risk factors is, therefore, an essential step for early treatment of AD with candidate disease-modifying drugs. Preclinical studies suggest that stress, and the resulting activation of the hypothalamic–pituitary–adrenal axis, can induce biochemical abnormalities reminiscent to those found in autoptic brain samples from individuals affected by AD (e.g., increases amyloid precursor protein and tau hyperphosphorylation). In this review, we will critically analyze the current knowledge supporting stress as a potential risk factor for AD.

Highlights

According to the World Health Organization, “a risk factor is any attribute, characteristic or exposure of an individual that increases the likelihood of developing a disease or injury”
Genetic studies of early-onset familial Alzheimer’s disease (AD) have demonstrated that the formation of Aβ1-42 aggregates, rather than tau hyperphosphorylation, lies at the core of AD. eFAD is caused by mutations in the genes encoding for amyloid-ß precursor protein (APP) (Goate, 2006), presenilin 1 (PSEN1) (Sherrington et al, 1995), and presenilin 2 (PSEN2) (Levy-Lahad et al, 1995; Rogaev et al, 1995) inherited as an autosomal dominant trait (Guerreiro et al, 2012)
PSEN1 mutations account for most eFAD, while APP and PSEN2 are rarer

Summary

Introduction

According to the World Health Organization, “a risk factor is any attribute, characteristic or exposure of an individual that increases the likelihood of developing a disease or injury” (www.who. int/topics/risk_factors). According to the World Health Organization, “a risk factor is any attribute, characteristic or exposure of an individual that increases the likelihood of developing a disease or injury” AD is characterized by loss of neurons and synapses in the cerebral cortex and hippocampus (Nisticò et al, 2012). Formation of aggregates of the β-amyloid peptide (Aβ1-42) and neurofibrillary tangles resulting from tau protein hyperphosphorylation are the major hallmarks of AD. These histopathological processes occur in brain regions that are involved in memory formation and emotional regulation (Gómez-Isla et al, 1996; Murray et al, 2006; Holtzman et al, 2011). These findings have constituted the bases that led to the proposal of the so-called “amyloid cascade hypothesis,” which posits that dysregulation of amyloid-ß (Aß) peptide production and/or proteolytic degradation plays a key role in triggering the pathological

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