Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer's Disease Patients

Abstract

This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer's disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual's mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aβ peptides brain catabolism and brain clearance.

Keywords: Alzheimer’s disease; ageing; animal models; human studies; memory impairment; neuroinflammation; physical exercise.

Figure 1

Chronic low grade sterile inflammation promotes AD-related changes in APP processing. Abbreviations: 99-CTF (99-amino acid membrane bound C-terminal fragment), AβF (amyloid β fibrils), Aβn (amyloid β peptides with 37 to 44 amino acid residues), AβO (amyloid β oligomers), AβPF (amyloid β protofibrils), APP (amyloid precursor protein), DAMPS (damage-associated molecular patterns), ER (endoplasmic reticulum), IFITM (interferon-induced transmembrane protein), IL -1β, -6, (interleukins -1β, -6), JNK (c-Jun N-terminal Kinase), MITO, NFκB/GSK3β (nuclear factor kappa-light-chain-enhancer of activated B cells/glycogen synthase kinase 3β), P38 (Mitogen-activated protein kinase 38), TNFα (tumour necrosis factor α), VAT.

Figure 2

Modulation of neuroinflammation and Aβ peptides processing by regular, structured physical exercise. Abbreviations: Aβ42 (amyloid β peptide with 42 amino acid residues), AβO (toxic amyloid β oligomers), AMPK (5′ AMP-activated protein kinase), DAMPS (damage-associated molecular patterns), BDNF (brain-derived neurotrophic factor), CDK5 (cyclin dependent kinase 5), DAMPS (damage associated molecular patterns), GSK3 glycogen synthase kinase 3), IDE (insulin-degrading enzyme), IGF1 (insulin-like growth factor 1), IL -1β, -6, (interleukins -1β, -6), TNFα (tumour necrosis factor α).