Additional Pharmacologic Therapies
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Evidence from population-based studies suggests beneficial effects of treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, although these effects have not been reproduced in clinical trials (Sastre 2010). NSAIDs affect the pathology of Alzheimer’s disease by inhibiting cyclooxygenase (COX) enzymes, which contribute to inflammation.
NSAIDs appear to prevent cognitive decline in older adults if started in midlife (prior to age 65) rather than late in life (Hayden 2007; Sastre 2010). Unfortunately, NSAIDs, even at normal dosages, have been associated with significant adverse effects. Long-term use of NSAIDs is associated with gastrointestinal, kidney, and cardiovascular complications (Sastres 2010; William 2011; Ejaz 2004). Low-dose aspirin, however, might be effective in reducing Alzheimer’s incidence and side effects are relatively rare when only 81 mg a day are taken.
Blood Pressure Lowering Drugs
It has been hypothesized that treating cardiovascular risk factors might be an effective means of preventing or treating dementia syndromes, including Alzheimer’s (Qiu 2012). Specifically, elevated blood pressure during midlife appears to be associated with Alzheimer’s development in late life. This effect may be caused by a link between high blood pressure and poor amyloid beta clearance from the brain (Shah 2012).
Drugs normally used to treat hypertension, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and calcium channel blockers, have been considered as potential Alzheimer’s therapies (Qiu 2010). Some research suggests that these drugs mildly reduce cognitive decline, and may reduce risk of Alzheimer’s development and progression (Forette 1998; Hajjar 2008; Trenkwalder 2006).
Etanercept (Enbrel®), a biological inhibitor of the cytokine TNF-α, is approved for the treatment of certain inflammatory conditions (e.g., rheumatoid arthritis, plaque psoriasis). When formulated as a perispinal injection and administered to Alzheimer’s patients, preliminary research reports suggest that Enbrel® leads to sustained improvement in cognitive function that was evident within minutes (Tobinick 2008a,b; Tobinick 2012).
Granulocyte Colony-Stimulating Factor (G-CSF)
Granulocyte colony-stimulating factor (G-CSF) is a growth factor that stimulates production of certain white blood cells. It also supports the creation of new neurons in the brain and modulates cholinergic neurotransmission (Jiang 2010). Lower levels of G-CSF have been identified in Alzheimer’s patients compared to healthy individuals (Laske 2009). An animal model of Alzheimer’s found that injections of G-CSF not only rescued compromised memory and cognitive functions, but also raised levels of acetylcholine (Tsai 2007). A study at the University of South Florida seeks to evaluate the cognitive effects of administering G-CSF to Alzheimer’s patients (Clinicaltrials.gov).
Brain-Derived Neurotrophic Factor (BDNF)
BDNF (Brain-Derived Neurotrophic Factor), a signaling protein active in the brain, facilitates the growth of new neurons and synapses and also reverses neuronal atrophy. Since BDNF levels decline with age and Alzheimer’s disease, administration of BDNF has been suggested as a potential therapy for memory loss (Li 2009). Injecting BDNF into the brains of rodents and primates reversed synaptic damage, cell death, cognitive decline, and memory deficits (Nagahara 2009). Intensive research in rodents has led to the first promising clinical trials of intracerebral neurotrophin for AD (Schulte-Herbrüggen 2008).
Lithium is a mineral used as a mood stabilizer, particularly in the treatment of bipolar disorder and major depression (Forlenza 2014). Animal and laboratory research indicate lithium may have neuroprotective effects and may preserve cognitive function in models of cognitive decline and Alzheimer’s disease (Tan 2010; Choi 2010; Cabrera 2014; De-Paula, Gattaz, 2016). In humans, lithium appears to increase brain mitochondrial functioning, reduce brain oxidative stress and markers of inflammation, promote production of BDNF, and benefit regions of the brain involved in memory and cognitive activities (Forlenza 2014; De-Paula, Kerr, 2016).
Lithium supplementation may enhance cognitive function (Tsaltas 2009; Rybakowski 2016). In a pilot study, patients with Alzheimer’s disease treated with 300 micrograms lithium per day (at least 3000 times lower than typical doses used to treat bipolar disorder) for 15 months experienced no change in cognitive performance versus their untreated counterparts who experienced significant cognitive losses (Nunes 2013). In a pilot trial in 45 subjects with amnestic mild cognitive impairment (a condition that frequently progresses to Alzheimer’s disease), those who received lithium were less likely to develop Alzheimer’s disease over a 12-month period compared with placebo, although this difference was small and not statistically significant (Forlenza 2011). Findings from a study using a mouse model of Alzheimer’s disease suggest pyrroloqinoline quinone may enhance the benefits of lithium (Zhao 2014).
The neuroprotective effect of lithium appears to be related to its ability to inhibit an enzyme called glycogen synthase kinase 3. By inhibiting glycogen synthase kinase 3, which catalyzes reactions that join phosphates to tau proteins, lithium helps regulate tau protein phosphorylation and prevent neurofibrillary tangle formation (Houck 2016; Alvarez 2002; Engel 2008). Glycogen synthase kinase 3 inhibition has also been associated with reduced amyloid production (Zhang 2011; Rockenstein 2007). Furthermore, animal and laboratory research show lithium treatment may increase brain levels of a neuroprotective protein called beta-cell lymphoma 2 (Bcl-2) (Manji 2000).
Because doses of lithium used to treat bipolar disorder (typically 900–1800 mg per day) can cause a number of side effects (Gitlin 2016), including kidney toxicity (Azab 2015) and brain cerebellar toxicity and atrophy (shrinking) (Adityanjee 2005), researchers have been monitoring the effects of long-term use of lower doses. A preliminary, randomized, controlled trial in 61 older subjects with mild cognitive decline receiving low-dose lithium found no significant evidence of kidney damage after four years of treatment; however, lithium-treated subjects had higher incidence of weight gain, decreased thyroid function, new-onset diabetes, and abnormal heart rhythms. The lithium doses used in this study were ≥ 150 mg per day, and individualized to maintain serum levels between 0.25 and 0.50 mmol/L (Aprahamian 2014). While lithium appears to hold potential for people with Alzheimer’s disease, these findings point to more research needed to determine ideal dosing and long-term safety.
Selective Estrogen Receptor Modulators (SERMs)
Selective estrogen receptor modulators are drugs that either increase or decrease estrogen signaling, depending on the tissue type (McDonnell 2002). Currently, the most studied and clinically relevant SERMs are tamoxifen and raloxifene. Tamoxifen is best recognized as a potent antagonist (blocker) of estrogen action in breast tissue. However, low concentrations of tamoxifen have been noted to protect cultured neurons from amyloid beta and glutamate toxicity (O’Neill 2004). In postmenopausal women, raloxifene, at a dose of 120 mg/day, has been linked with reduced risk of cognitive impairment and development of Alzheimer’s disease (Yaffe 2005).
Vaccines are being developed in hopes of clearing amyloid beta from the brains of Alzheimer’s patients immunologically (Upadhyaya 2010). Initial research suggests a mechanistic possibility that this approach could work (Holmes 2008), but many obstacles still impede the development of clinically effective vaccines for Alzheimer’s disease (St. George-Hyslop 2008). For example, some studies suggest that simply eliminating amyloid beta may not be sufficient, and that targeting other aspects of Alzheimer’s pathology in conjunction with amyloid beta vaccination may have a better chance of success (Aranda-Abreu 2011).
As mentioned above, the theory that Alzheimer’s disease could be cause by infectious organisms is gaining traction within the scientific community. Based upon these findings, it has been proposed that antibiotics may represent a viable treatment for Alzheimer’s disease (Miklossy 2011).
Early clinical trials have noted marked improvements in Alzheimer’s patients following antibiotic treatment. In one such trial, 100 subjects with probable Alzheimer’s disease were treated with the antibiotics doxycycline and rifampin for three months and followed for a year. At six months post-treatment, subjects who received antibiotics displayed significantly less cognitive decline than those who received a placebo, and the effect was even more pronounced at 12 months. Antibiotic recipients also showed less behavioral dysfunction at three months. The researchers concluded that “therapy with doxycycline and rifampin may have a therapeutic role in patients with mild to moderate [Alzheimer’s disease] (Loeb 2004). Another smaller trial found Alzheimer’s patients treated with 100 mg daily of the antibiotic D-cycloserine displayed significantly improved scores on a standardized assessment of cognitive function (Tsai 1999).
Although larger trials with longer follow-up periods are needed to more thoroughly asses the therapeutic value of antibiotics in Alzheimer’s disease, evidence continues to mount that the most common cause of dementia may be the result of an infection, and early treatment with inexpensive antimicrobial drugs might represent an advance in the management of this devastating condition (Miklossy 2011).
Piracetam has been studied in a wide-range of patient populations and has demonstrated small benefits in a variety of models of neurological disorders. Multiple mechanisms for the observable effects of piracetam on brain function have been proposed, though a precise description of its mode of action has yet to be elucidated. Preliminary studies suggest that piracetam may modulate the signaling of multiple neurotransmitter receptors, and improve neuronal membrane fluidity (Malyka 2010; Muller 1997).
A comprehensive review that assessed the efficacy of piracetam in older subjects suggests that the drug may provide appreciable benefits for cognitive dysfunction. The reviewers concluded that “…the results of this analysis provide compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment” (Waegemans 2002). Additionally, a piracetam analog called levetiracetam was shown to reverse synaptic and cognitive deficits in an animal Alzheimer’s model (Sanchez 2012).
5-lipoxygenase (5-LO) is an enzyme that produces several pro-inflammatory lipid molecules, most of which are known as leukotrienes (Poeckel 2010; Hedi 2004). 5-LO and some of the leukotrienes it produces have been implicated in the inflammation that accompanies various chronic diseases, including Alzheimer’s disease (Vagnozzi 2017; Joshi 2014; Chinnici 2007). These inflammatory mediators have also been implicated in other tauopathies, which are neurodegenerative conditions in which toxic protein deposits, known as tau protein, accumulate inside neurons. Alzheimer’s disease is a type of tauopathy (Giannopoulos 2018a; Chu 2016).
A 2018 study suggests zileuton (Zyflo), a leukotriene inhibitor approved over two decades ago to treat asthma, may have the potential to reduce neurodegeneration associated with tau protein accumulation (Israel 1996; Watkins 2007). Using an animal model of neurodegeneration, the study tested whether inhibiting leukotriene synthesis could help after cellular damage in the nervous system has already started. Twelve-month-old mice with a tauopathy were randomized to receive zileuton or placebo for 16 weeks (Giannopoulos 2018b). As expected, at the beginning of the study memory and spatial learning were impaired in the mice with the tauopathy compared with control mice (Giannopoulos 2018b). Zileuton reduced these behavioral impairments. When the brains of the animals were examined, mice that received zileuton had about 90% fewer leukotrienes in their brains and about 50% less tau protein. The animals treated with zileuton also had decreased neuroinflammation and increased levels of three biochemical markers that reflect synaptic integrity (Giannopoulos 2018b).
Other studies also report benefits with zileuton treatment in neurodegenerative diseases. In a mouse model of Alzheimer’s disease, three months of zileuton treatment significantly decreased amyloid-beta levels between the neurons and improved cognitive function (Di Meco 2014). Another study on the same mouse model of Alzheimer’s disease showed that zileuton treatment led to a significant improvement in working memory and communication among brain cells (Giannopoulos 2014). Similar findings have been reported in other preclinical studies as well (Chu 2013; Chu 2011). Moreover, in rodent models of stroke, zileuton decreased inflammation, protected against brain damage, and improved neurological deficits (Tu 2016; Silva 2015). Zileuton also inhibited 5-LO activation and cell injury in a laboratory model of Parkinson’s disease (Zhang, Zhang 2011). In a laboratory study, zileuton protected mouse neurons against chemical toxicity caused by exposure to glutamate (Liu 2015).
Additional Emerging Therapies
The following compounds hold promise, but more research is needed before their potential therapeutic value in Alzheimer’s disease can be deciphered:
- Rapamycin (Cai 2012) – An immunosuppressive drug that also improves removal of cellular debris, including amyloid beta, via enhancing a process called autophagy.
- Secretase inhibitors (used only in preliminary human trials) (Fleisher 2008). These drugs target the enzymes that cleave amyloid precursor protein into amyloid beta fragments. In theory, blocking secretase activity would slow accumulation of amyloid beta.