Age Related Cognitive Decline
Nootropic Drugs and Novel Approaches to Cognitive Decline
Although there are currently no pharmacologic interventions specifically for age-related cognitive decline, medical approaches to underlying issues such as vascular disease and systemic inflammation may help prevent progressive cognitive loss. For example, the use of certain antihypertensive medications to lower high blood pressure may slow cognitive decline and prevent dementia; however, they also pose a risk of reducing cerebrovascular blood flow and causing more cognitive harm.105,106
A number of observational studies have noted that patients using cholesterol-lowering drugs called statins (such as simvastatin [Zocor] and atorvastatin [Lipitor]) have a lower risk of mild cognitive impairment and dementia than those not using statins107; however, other studies and case reports suggest statins may impair cognitive function in some individuals,108 and other studies have found no benefit.109 Large randomized controlled trials have found statins had no impact on cognitive decline or dementia risk.108,110-114
While once thought to hold promise for patients with mild cognitive impairment, it now seems that anti-dementia drugs, like the acetylcholinesterase inhibitors donepezil (Aricept), galantamine (Razadyne), tacrine (Cognex), and rivastigmine (Exelon), have neither been shown to restore cognitive function nor protect against dementia in this population.115,116 The use of biological and genetic markers in the future may help researchers identify those most likely to benefit from certain drug therapies.115
Several other medications with potential brain-protective effects are:
- Piracetam (Nootropil) and levetiracetam (Keppra) are anti-seizure medications sometimes used as cognitive enhancers. These and several related drugs (the “racetams”) are often colloquially referred to as “nootropics.” Preclinical evidence suggests these medications may reduce neuroinflammation, improve mitochondrial function, and prevent β-amyloid-induced neuronal dysfunction.117-119 In early research, levetiracetam was found to improve cognitive performance on a memory test.120 Findings from a clinical trial in cognitive impairment and dementia patients suggest piracetam may be most effective in those with depressive symptoms.121 Whether these medications hold benefits for patients with age-related cognitive decline and mild cognitive impairment has not yet been established. Also, the regulatory status of piracetam and related compounds is vague, and legal status varies between countries.
- Zileuton (Zyflo) is an inhibitor of the pro-inflammatory enzyme 5-lipoxygenase. While its main use is as an anti-asthma medication, zileuton has demonstrated some intriguing effects on brain function in preclinical trials. In animal research, zileuton has been found to reduce brain levels of β-amyloid and tau, as well as amyloid- and tau-related neuroinflammation, neuronal dysfunction, and cognitive impairment.122-125 Other animal research suggests zileuton may reduce brain damage and cognitive losses after stroke.126-128 The possible usefulness of zileuton in age-related cognitive decline, mild cognitive impairment, and dementia awaits future investigation.
- Hydergine (co-dergocrine mesylate), a mixture of ergot alkaloids, has been found to improve cognitive function and mood in preliminary trials in elderly subjects with age-related cognitive dysfunction.129,130 Its mechanism of action is not completely understood; however, it appears to modulate neurotransmitter activity, improve cerebral metabolism, and increase antioxidant enzyme activity in the brain.131,132 Despite interesting findings, there have been no clinical trials investigating hydergine’s usefulness in age-related cognitive decline and mild cognitive impairment for decades.
- Selegiline or deprenyl (Eldepryl) is a monoamine oxidase-B inhibitor that blocks the enzymatic breakdown of certain neurotransmitters, such as dopamine and serotonin. It is used to treat Parkinson disease, Alzheimer disease, and major depressive disorder, and is thought to have anti-aging effects.133 Selegiline was found to improve cognitive performance in a six-month preliminary trial in human subjects with mild-to-moderate brain atrophy.134 Studies in animals suggest it can reduce oxidative stress, protect against brain damage due to loss of blood flow, and preserve neurotransmission and memory.135-138 More clinical trials are needed to ascertain the potential benefits of this medication in age-related cognitive decline.
- Centrophenoxine or meclofenoxate (Lucidril) enhances activation of cholinergic pathways in the central nervous system. An early trial in elderly subjects found centrophenoxine improved formation of new memory and increased subjective reports of mental alertness.139 Animal research has found that this medication may protect against cognitive losses due to aluminum toxicity,140 drug toxicity,141 and lack of blood flow.142