The use of antipsychotics is associated with increased risks of head and brain injuries among persons with Alzheimer’s disease, according to a recent study from the University of Eastern Finland.
The risk increase was highest at the initiation of antipsychotic use. The results were published in the Journal of the American Geriatrics Society (JAGS).
“As adverse effects, antipsychotics may cause sedation, orthostatic hypotension, and arrhythmias which all may lead to falls. Among older persons, falls are the most common reason for traumatic brain injuries,” Researcher Vesa Tapiainen from the University of Eastern Finland explains as a possible mechanism for the association.
Community-dwellers with Alzheimer’s disease who used antipsychotics had a 29% higher risk of head injuries and a 22% higher risk of traumatic brain injuries when compared to community-dwellers with Alzheimer’s disease who did not use antipsychotics.
Among persons with Alzheimer’s disease, antipsychotics are commonly used to treat neuropsychiatric symptoms of Alzheimer’s disease. According to clinical care guidelines, treating the cause of these symptoms, such as pain, is the first line option and secondly non-pharmacological treatments should be prioritized.
The use of antipsychotics should be restricted to most severe symptoms (such as severe aggression, agitation or psychosis). Following care guidelines and by carefully considering benefits and risks of adverse effects and events could possibly lower the incidence of head injuries and traumatic brain injuries.
The use of antipsychotics should be restricted to most severe symptoms (such as severe aggression, agitation or psychosis).
The study was conducted using the nationwide register-based MEDALZ cohort which includes Finnish community dwellers with a newly diagnosed Alzheimer’s disease in 2005-2011 (70,719 persons).
Persons were excluded if they had a prior head injury, antipsychotic use within one year prior to antipsychotic initiation or if they fulfilled other exclusion criteria of this study. The final study population was 21,795 persons who initiated antipsychotic use and 21,795 persons who did not use antipsychotics. Medicine use was extracted from the Finnish Prescription Register. Chronic diseases, use of other medications and socioeconomic position were taken into account.
Funding: The study was funded by the Academy of Finland and the Finnish Medical Society Duodecim.
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).
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive impairments in cognitive functions (Hampel et al., 2015). 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). The hippocampus is particularly vulnerable to AD-associated neuronal damage (Mu and Gage, 2011; Hollands et al., 2016).
Genetic studies of early-onset familial AD (eFAD) 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.
However, 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 and behavioral changes observed in AD patients (Selkoe and Hardy, 2016).
Although our knowledge of neuropathological and neurochemical alterations associated with AD has impressively increased in the last decades, the current treatment is limited to cholinesterase inhibitors and the N-methyl-D-aspartate (NMDA) receptor channel blocker, memantine.
None of these drugs can slow the progression of AD. Several putative disease-modifying drugs have been developed and continue to be developed with the hope of restraining the progression of the disease. Most of these drugs target either the production or the aggregation process of Aβ1-42 (Anand et al., 2017).
Results of clinical studies with all these drugs have been highly disappointing. For example, a recently concluded randomized clinical trial with an inhibitor of β-secretase (BACE1), the enzyme that cleaves APP to uncover the N-terminus domain of Aβ1-42, did not show any reduction in cognitive or functional decline in AD patients, suggesting that either disease progression does not rely exclusively on amyloid formation or, alternatively, that anti-amyloid drugs should be administered several years prior to the onset of AD to be effective (Egan et al., 2018).
The entire AD community was frustrated by the lack of efficacy of aducanumab, an anti-amyloid monoclonal antibody that was considered as highly promising based on a phase 1b clinical trial (Sevigny et al., 2016).
If these drugs fail because treatment starts too late, i.e. when pathophysiological mechanisms of AD are already established, research should be directed to the identification of risk factors that can reliably predict the development of AD. As highlighted above, a minority of patients has eFAD with autosomal dominant transmission. Children have 50% chance to inherit the same mutation, and they are natural candidates for early treatment with candidate disease-modifying drugs.
Apolipoprotein E4 (ApoE4) is the most established risk factor for sporadic AD (besides age), and subjects who are homozygous for ε4 (the gene encoding for ApoE4) and showed brain amyloidosis by PET scanning at an early age are also candidates for early treatment. The presence of ApoE4 may also predict responses to drug treatment in AD. For example, inhibitors of angiotensin-converting enzyme (ACE) improve cognition in patients affected by AD carrying ApoE4 and certain ACE polymorphisms (de Oliveira et al., 2014; de Oliveira et al., 2018). However, only about half of AD patients are ApoE4-positive, and the presence of cerebral amyloidosis is only suggestive of later development of AD (old individuals may have cerebral amyloidosis without AD).
Cardiovascular and metabolic disorders, such as hypertension, type-2 diabetes, metabolic syndrome, hypercholesterolemia, unhealthy dietary pattern, poor physical and cognitive activity, and smoking may increase the vulnerability to develop AD (Barnard et al., 2014; Xu et al., 2015).
This review aims to comment on preclinical and clinical data on stress and glucocorticoids as risk factors for AD. Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, with an ensuing increase in blood levels of glucocorticoid hormones (cortisol in humans and corticosterone in rodents).
Hypothalamic corticotrophin-releasing hormone (CRH) is the main secretagogue of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH, in turn, stimulates the production of glucocorticoids from the adrenal cortex. Glucocorticoids exert a crucial role in the adaptive physiological and behavioral responses to stress.
Moreover, glucocorticoid hormones exert a negative feedback signal capable of inhibiting the activation of the HPA axis: the main targets of glucocorticoid-induced negative feedback are the anterior pituitary, the hypothalamus, and the hippocampus. Glucocorticoid binds to two receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR).
Both are ligand-dependent transcription factors. Of the two receptors, MRs have one order of magnitude higher affinity for glucocorticoids than GRs. At low levels of circulating glucocorticoids, e.g., during the circadian nadir, MRs are fully occupied; in contrast, GR activation occurs at the circadian peak of glucocorticoids or in response to stressful events. Interestingly, both MRs and GRs are highly expressed in pyramidal neurons of CA1 and CA2 and in granule cells of the dentate gyrus of the hippocampus (Han et al., 2005), which is a vulnerable brain region in AD (Henneman et al., 2009).
It has been hypothesized that long-lasting stress and the resulting sustained hypocortisolemia could be a potential neurodegenerative factor for the hippocampus (Angelucci, 2000). However, recent findings have depicted a more complex relationship between stress and neurodegeneration.
Hypothalamic–Pituitary–Adrenal Axis Dysfunction In Alzheimer’s Disease
Clinical reports of hypercortisolism in AD patients suggest a causal role for glucocorticoids in AD (Bruno et al., 1995; Hatzinger et al., 1995; Greenwald et al., 1986; Peskind et al., 2001; Rasmuson et al., 2001; Wilson et al., 2003; Hoogendijk et al., 2006; Johansson et al., 2010; Curto et al., 2017; Ouanes and Popp, 2019).
However, it should be considered that some degree of stress could be present in a condition involving bodily or psychic suffering, especially when patients are cognitively able to perceive memory impairment, which is among the first symptoms reported by patients suffering from AD (Saydak et al., 1987). Dysregulation of the corticotropic axis is present in individuals suffering from depression, diabetes, and metabolic syndrome.
These clinical conditions have been hypothesized to increase the risk to develop AD later in life (Ownby et al., 2006; Huang et al., 2014; Rojas-Gutierrez et al., 2017). In particular, it has been reported that patients who experienced late-life, but not early- or mid-life, depression had a two-fold increased risk for AD (Barnes et al., 2012; Singh-Manoux et al., 2017). Single nucleotide polymorphism (SNP) analysis in patients affected by AD supports the hypothesis that elevated glucocorticoid levels increase the risk to develop AD. de Quervain et al. (2004) analyzed SNPs in 10 glucocorticoid-related genes in 814 AD patients.
They found an association between AD and a rare haplotype in the 5’ regulatory region of the gene encoding for type-1 11ß-hydroxysteroid dehydrogenase (11ß-HSD1). 11ß-HSD1, also known as cortisone reductase, catalyzes the conversion of cortisol into the biological inert 11-keto derivative (cortisone).
Thus, subjects carrying this rare haplotype with reduced 11ß-HSD1 transcription show less inactivation of glucocorticoids, which, in turn, is associated with an increased vulnerability to the clinical manifestation of AD. On the contrary, subjects bearing a polymorphism of the GR gene (NR3C1) are characterized by a reduced risk to develop AD (van Rossum et al., 2008). More precisely, carriers of the ER22/23EK allele (approximately 7% of the entire population) were associated with a decreased risk of developing dementia. The presence of the ER22/23EK allele leads to a decreased sensitivity of GRs to glucocorticoids (Russcher et al., 2005).
Several lines of evidence suggest a tight connection between neuroinflammation and AD (see Nichols et al., 2019 for a recent review). In a double-blind, placebo-controlled trial, 138 AD patients received prednisone (10 mg daily for 1 year).
Glucocorticoid treatment not only failed to ameliorate cognitive decline as assessed by the Alzheimer’s Disease Assessment Scale but also caused a greater behavioral decline, as measured by the Brief Psychiatric Rating Scale (Aisen et al., 2000).
These findings suggest a detrimental effect of glucocorticoids in AD. Some clinical trials have investigated the effects of the glucocorticoid receptor antagonist, mifepristone, in AD patients (Belanoff et al., 2002; DeBattista and Belanoff, 2005). Although a significant improvement of cognitive function was observed in AD patients after a 6-week treatment with 200 mg of mifepristone (Pomara et al., 2002), there are no ongoing clinical trials with glucocorticoid