Alzheimer’s Disease

The B Vitamins: Reducing Homocysteine

Elevated homocysteine levels (along with reduced levels of B vitamins such as folate, vitamin B12, and vitamin B6) are persistently associated with Alzheimer’s disease and mild cognitive impairment (Quadri P et al 2005; Ravaglia G et al 2005; Tucker KL et al 2005). Based on the association between elevated homocysteine and Alzheimer’s disease, strategies that lower homocysteine levels to safe ranges, including supplementation with B vitamins, are recommended.

Vitamin B12. Research has suggested that low cobalamin (vitamin B12) levels are related to dementias in general. In a study evaluating levels of vitamin B12 in patients who had Alzheimer’s disease or frontotemporal dementia, researchers found a significant negative correlation (the lower the level of vitamin B12, the more the deterioration) between vitamin B12 and degree of cognitive deterioration (Engelborghs S et al 2004). A population-based longitudinal study in Sweden of 370 people aged 75 years or older who did not have dementia found that subjects who had low levels of vitamin B12 or folate had twice the risk of developing Alzheimer’s disease over the 3-year period of the study (Wang HX et al 2001).

Vitamin B6. A study found significantly lower consumption of vitamin B6 after age 60 years in patients with Alzheimer’s disease compared to control subjects (Mizrahi EH et al 2003). Low vitamin B6 levels are also associated with elevated numbers of lesions on the brains of patients with Alzheimer’s disease (Mulder C et al 2005).

Folate. Folic acid is needed for DNA synthesis and to make S-adenosylmethionine (SAMe). A study of 126 patients, including 30 who had Alzheimer’s disease, found that the levels of folate in cerebrospinal fluid were significantly lower in patients with late-onset Alzheimer’s disease (Serot JM et al 2001). Another longitudinal analysis of people between the ages of 70 and 79 years found that people who had high levels of homocysteine or low levels of folate had impaired cognitive function. The strongest association between abnormal levels and dementia was found in people who had low folate levels, leading researchers to suggest that folate might reduce the risk of cognitive decline (Kado DM et al 2005).

Niacin. A 2004 study (of more than 6000 people) conducted between 1993 and 2002 found that high levels of dietary niacin protect against Alzheimer’s disease (Morris MC et al 2004). The authors researched the dietary habits of initially healthy people aged 65 years or older. As the study progressed, some study participants developed Alzheimer’s disease and some remained healthy. Subjects who had the highest intake of niacin had a 70 percent reduction in risk of cognitive decline. Intake of dietary niacin was inversely related to the incidence of Alzheimer’s disease and age-related cognitive decline (Morris MC et al 2004).

Natural Hormone Replacement

Estrogen replacement therapy (ERT) has been studied in relation to Alzheimer’s disease with mixed results. Initial studies suggested that ERT protected women against developing Alzheimer’s disease. Later studies from the Women’s Health Initiative, however, suggested that combination ERT and synthetic progestin therapy increased the risk of dementia (Kasper DL et al 2004; Webber KM et al 2005). Hoping to reconcile these results, one research team suggested that estrogen has a healthy cell bias, meaning that estrogen therapy is beneficial when the cells are still healthy but can exacerbate Alzheimer’s disease once neurological health begins to degenerate (Brinton RD 2005).

When interpreting these results, however, you must consider the complex interactions among all the hormones. Newer research has examined the role of several of the hormones that act on the hypothalamic-pituitary-gonadal axis, including luteinizing hormone and follicle-stimulating hormone. Levels of these gonadotropic hormones are altered in Alzheimer’s disease. One theory suggests that increases in these hormones, rather than a decline in estrogen, may be a causative factor in Alzheimer’s disease (Webber KM et al 2005). Studies have also implicated declining levels of progesterone (Singh M 2005). In normal aging, levels of luteinizing hormone and follicle-stimulating hormone are often elevated, whereas progesterone levels decline.

Pregnenolone. Pregnenolone is a hormone that is synthesized directly from cholesterol in the cell mitochondria. The body converts pregnenolone into other important hormones, including dehydroepiandrosterone (DHEA), various estrogens, progesterone, and testosterone (Szilagyi G et al 2005). Aging causes a steep decline in the production of pregnenolone, as well as in the hormones for which it is a precursor.

Progesterone is synthesized in the brain, spinal cord, and peripheral nerves from pregnenolone. Research strongly suggests that progesterone promotes the formation of myelin sheaths, the fatty layers of insulation that allow electrochemical signals to move efficiently from one neuron to another (Schumacher M et al 2004). Scientists believe that progesterone offers exciting treatment alternatives for the prevention of many degenerative brain conditions, as well as cognitive impairment during aging (Schumacher M et al 2004).

French researchers have shown that pregnenolone directly influences acetylcholine release in several key brain regions. They also demonstrated pregnenolone’s ability to promote new nerve growth. According to the study authors: “Our data demonstrate that [pregnenolone sulfate infusions] dramatically increase neurogenesis” (Mayo W et al 2003, 2005).

Testosterone. Results of studies of the association between testosterone and Alzheimer’s disease are conflicting. Some have found higher or comparable levels of testosterone in patients who have Alzheimer’s disease compared to age-matched control subjects (Almeida OP et al 2003; Pennanen C et al 2004). Others have found that patients with Alzheimer’s disease have lower levels of testosterone compared to control subjects (Hogervorst E et al 2003). However, studies have shown improved cognition in older adults who received testosterone supplementation (Cherrier MM et al 2005). Few studies have been conducted on testosterone replacement therapy in men with Alzheimer’s. One such study, however, found that testosterone therapy did not improve cognitive scores, but did result in higher quality-of-life scores for patients with Alzheimer’s disease, as rated by their caregivers (Lu PH et al 2006).

Melatonin. Known as the sleep hormone, melatonin helps establish healthy sleep patterns. However, it is also an antioxidant that has been shown to be highly effective in reducing oxidative damage to the central nervous system. Melatonin stimulates several antioxidant enzymes, including glutathione peroxidase and glutathione reductase (Reiter RJ et al 1999). In animal studies, melatonin improved cognitive function and reduced oxidative injury and deposition of beta-amyloid (Cheng Y et al 2006). Additional studies have confirmed that melatonin protects brain cells from beta-amyloid toxicity by impairing beta-amyloid generation and slowing the formation of plaque deposits (Wang JZ et al 2006).

DHEA. Various studies have indicated that patients with Alzheimer’s disease have decreased levels of DHEA and that DHEA has neuroprotective effects (Hillen T et al 2000; Polleri A et al 2002; Weill-Engerer S et al 2002). DHEA is a neuroprotective steroid and a precursor of other sex hormones, including testosterone and estrogen. In animal studies, DHEA was shown to improve memory in rats that overexpressed beta-amyloid (Farr SA et al 2004).

Huperzine to Support Acetylcholine

Huperzine A, derived from a Chinese club moss, is an NMDA-receptor blocker than can help prevent or reduce the glutamate-mediated excitotoxicity that produces beta-amyloid. It also helps block the enzyme that destroys acetylcholine, much like conventional pharmaceuticals such as acetylcholinesterase inhibitors. In animals, huperzine A improved the decrease in acetylcholine activity in the cortex and hippocampus (Bai DL et al 2000; Cheng DH et al 1996; Tang XC 1996; Wang LM et al 2000). Huperzine A was also shown to be as effective, and sometimes even more effective, than traditional acetylcholinesterase inhibitors (such as donepezil and galantamine) in porcine intrinsic cardiac neurons (Darvesh S et al 2004). These results were confirmed in a follow-up human study that found huperzine has better penetration through the blood-brain barrier, higher bioavailability, and longer duration of action than the expensive pharmaceuticals (Wang R et al 2006).

Huperzine has been extensively studied in China. One Chinese study found that 58 percent of patients with Alzheimer’s disease who were treated with huperzine showed improvement in memory and in cognitive and behavioral functions, compared with 36 percent who received placebo (Xu SS et al 1995). Chinese researchers also found that patients with Alzheimer’s disease who were treated with huperzine A performed remarkably better on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, Mini-Mental State Examination, Activities of Daily Living Scale, Clinical Global Impression Scale, and Alzheimer’s Disease Assessment Scale–Non-Cognitive Subscale than those on placebo (Zhang Z et al 2002). Huperzine is currently in phase 2 trials in the United States.