Following are short descriptions of recent research on the treatment of Alzheimer's disease. Keep in mind that hundreds of articles on Alzheimer's disease are published each month. The articles listed below are a few that have sparked our interest. We will be adding new research summaries and hope you will revisit our site to learn what is new on the treatment of Alzheimer's disease.

Aspirin in Alzheimer’s disease (AD2000): a randomised open-label trial. Ad2000 Collaborative Group. Lancet Neurology, 7(1):41-49, 2008

BACKGROUND: Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. METHODS: 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. FINDINGS: Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI -0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4.4, 95% CI 1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. INTERPRETATION: Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.

Hormonal treatment, mild cognitive impairment and Alzheimer’s disease. Ryan J, Scali J, Carriere I, et al. International Psychogeriatrics, 20(1):47-56, 2008

A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented postmenopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer's disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Apart from methodological differences, one key shortcoming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia

The role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in Alzheimer’s disease: therapeutic implications. Jiang Q, Heneka M, Landreth GE. CNS Drugs, 22(1):1-14, 2008

Alzheimer's disease is a complex neurodegenerative disorder, with aging, genetic and environmental factors contributing to its development and progression. The complexity of Alzheimer's disease presents substantial challenges for the development of new therapeutic agents. Alzheimer's disease is typified by pathological depositions of beta-amyloid peptides and neurofibrillary tangles within the diseased brain. It has also been demonstrated to be associated with a significant microglia-mediated inflammatory component, dysregulated lipid homeostasis and regional deficits in glucose metabolism within the brain. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a prototypical ligand-activated nuclear receptor that coordinates lipid, glucose and energy metabolism, and is found in elevated levels in the brains of individuals with Alzheimer's disease. A recently appreciated physiological function of this type of receptor is its ability to modulate inflammatory responses. In animal models of Alzheimer's disease, PPARgamma agonist treatment results in the reduction of amyloid plaque burden, reduced inflammation and reversal of disease-related behavioural impairment. In a recent phase II clinical trial, the use of the PPARgamma agonist rosiglitazone was associated with improved cognition and memory in patients with mild to moderate Alzheimer's disease. Thus, PPARgamma may act to modulate multiple pathophysiological mechanisms that contribute to Alzheimer's disease, and represents an attractive therapeutic target for the treatment of the disease.

Alpha-lipoic acid as a new treatment option for Alzheimer’s disease—a 48 months follow-up analysis. Hager K, Kenklies M, McAfoose J, et al. Journal of Neural Transmission Supplement, 72:189-193, 2007

Oxidative stress and neuronal energy depletion are characteristic biochemical hallmarks of Alzheimer's disease (AD). It is therefore conceivable that pro-energetic and antioxidant drugs such as alpha-lipoic acid might delay the onset or slow down the progression of the disease. In a previous study, 600mg alpha-lipoic acid was given daily to nine patients with AD (receiving a standard treatment with choline-esterase inhibitors) in an open-label study over an observation period of 12 months. The treatment led to a stabilization of cognitive functions in the study group, demonstrated by constant scores in two neuropsychological tests (the mini mental state exam, MMSE and the Alzheimer's disease assessment score cognitive subscale, ADAScog). In this report, we have extended the analysis to 43 patients over an observation period of up to 48 months. In patients with mild dementia (ADAScog < 15), the disease progressed extremely slowly (ADAScog: +1.2 points/year, MMSE: -0.6 points/year), in patients with moderate dementia at approximately twice the rate. However, the progression appears dramatically lower than data reported for untreated patients or patients on choline-esterase inhibitors in the second year of long-term studies. Despite the fact that this study was not double-blinded, placebo-controlled and randomized, our data suggest that treatment with alpha-lipoic acid might be a successful 'neuroprotective' therapy option for AD. However, a state-of-the-art phase II trial is needed urgently.

Long-term efficacy and safety of celecoxib in Alzheimer’s disease. Soininen H, West C, Robbins J, et al. Dementia and Geriatric Cognitive Disorders, 23(1):8-21, 2007

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) may play an important role in the neuropathology of Alzheimer's disease (AD). The efficacy and safety of celecoxib (200 mg bid), a COX-2 selective inhibitor, were assessed in patients > or =50 years with established mild-to-moderate AD to determine whether treatment was effective in retarding deterioration of cognitive function. METHODS: This was a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The primary efficacy end points were the change from baseline to week 52 in the Alzheimer's Disease Assessment Scale-Cognitive Behavior (ADAS-cog) composite score and the week 52 Clinician's Interview-Based Impression of Change Plus (CIBIC+). RESULTS: At 52 weeks, change in ADAS-cog scores from baseline was similar for placebo and celecoxib 200 mg bid groups (5.00 and 4.39, respectively). CIBIC+ scores were also similar (4.83 and 4.92). Two extension studies were conducted but were terminated early based on these efficacy results. Safety data from all 3 studies indicated that celecoxib was generally well-tolerated. CONCLUSION: Celecoxib 200 mg bid did not slow the progression of AD in this study, and the occurrence of adverse events was as expected for an elderly population with a complex chronic medical condition.

Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer’s disease: a 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients. Sun Y, Lu CJ, Chien KL, et al. Clinical Therapeutics, 29(10):2204-2214, 2007

BACKGROUND: Elevated serum homocysteine levels have been associated with the development of Alzheimer's dementia (AD). The combined use of a mecobalamin capsule preparation, which contains vitamin B12 0.5 mg with an active methyl base, and an over-the-counter nutritional supplement that contains folic acid 1 mg and pyridoxine hyperchloride 5 mg may be effective as a homocysteine-lowering vitamin regimen. OBJECTIVE: The aim of this study was to determine whether oral multivitamin supplementation containing vitamins B6 and B12 and folic acid would improve cognitive function and reduce serum homocysteine levels in patients with mild to moderate AD. METHODS: This randomized, double-blind, placebocontrolled trial was conducted at En Chu Kong Hospital, Taipei, Taiwan. Male and female patients aged >50 years with mild to moderate AD and normal folic acid and vitamin B12 concentrations were enrolled. All patients received treatment with an acetylcholinesterase inhibitor and were randomized to receive add-on mecobalamin (B12) 500 mg + multivitamin supplement, or placebos, PO QD for 26 weeks. The multivitamin contained pyridoxine (B6) 5 mg, folic acid 1 mg, and other vitamins and iron. Serum homocysteine level was measured and cognitive tests were conducted at baseline and after 26 weeks. The primary efficacy outcome was change in cognition, measured as the change in score from baseline to week 26 on the Alzheimer's Disease Assessment Scale 11-item Cognition subscale. Secondary efficacy outcomes included changes in function in performance of activities of daily living (ADLs) and concentrations of homocysteine, B12, and folic acid. Tolerability was assessed by comparing the 2 study groups with respect to physical examination findings, including changes in vital signs, laboratory test abnormalities, concomitant medication use, and compliance of study medication was assessed using an interview with the patient's caregiver, as well as the monitoring of adverse events (AEs) throughout the study. RESULTS: Eighty-nine patients (45 men, 44 women; all Taiwanese; mean [SD] age, 75 [7.3] years) were enrolled and randomized. Overall, there were no significant differences in cognition or ADL function scores between the 2 groups. At week 26, the mean (SD) between-group difference in serum homocysteine concentration versus placebo was -2.25 (2.85) micromol/L (P = 0.008), and the mean serum concentrations of vitamin B12 and folic acid were significantly higher (but within normal range) in the multivitamin group compared with placebo (., +536.9 [694.4] pg/mL [P < 0.001] and +13.84 ng/mL [11.17] [P = 0.012] at 26 weeks, respectively). The 2 most common AEs were muscle pain (11.1% and 6.8%) and insomnia (8.9% and 9.1%) in the multivitamin and placebo groups, respectively. CONCLUSIONS: In this population of patients with mild to moderate AD in Taiwan, a multivitamin supplement containing vitamins B(6) and B(12) and folic acid for 26 weeks decreased homocysteine concentrations. No statistically significant beneficial effects on cognition or ADL function were found between multivitamin and placebo at 26 weeks.

IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Winblad B, Grossberg G, Frolich L, et al. Neurology, 69(4 Suppl 1):S14-S22, 2007

The rivastigmine patch is the first transdermal treatment for Alzheimer disease (AD). By providing continuous delivery of drug into the bloodstream over 24 hours, transdermal delivery may offer benefits superior to those of oral administration. This study compared the efficacy, safety and tolerability of rivastigmine patches with capsules and placebo. IDEAL (Investigation of transDermal Exelon in ALzheimer's disease) was a 24-week, double-blind, double-dummy, placebo- and active-controlled study. Patients with AD were randomized to placebo or one of three active treatment target dose groups: 10-cm(2) rivastigmine patch (delivering 9.5 mg/24 hours); 20-cm(2) rivastigmine patch (17.4 mg/24 hours); or 6-mg BID rivastigmine capsules. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Secondary outcome measures assessed a range of domains, including behavior, cognitive performance, attention, executive functions, and activities of daily living. A total of 1,195 AD patients participated. All rivastigmine treatment groups showed significant improvement relative to placebo. The 10-cm(2) patch showed similar efficacy to capsules, with approximately two-thirds fewer reports of nausea (7.2% vs 23.1%) and vomiting (6.2% vs 17.0%), incidences statistically not significantly different from placebo (5.0% and 3.3% for nausea and vomiting, respectively). The 20-cm(2) patch showed earlier improvement and numerically superior cognitive scores vs the 10-cm(2) patch with similar tolerability to capsules. Local skin tolerability was good. The transdermal patch with rivastigmine may offer additional therapeutic benefits and may prove to be the best delivery system for this drug to treat AD.

Donepezil for the treatment of agitation in Alzheimer’s disease. Howard RJ, Juszczak E, Ballard CG, et al. New England Journal of Medicine, 357(14):1382-1392, 2007

BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease.

Pharmacological treatment of the psychosis of Alzheimer’s disease: what is the best approach? Madhusoodanan S, Shah P, Brenner R, et al. CNS DRUGS, 21(2):101-115, 2007

Psychosis of Alzheimer's disease (PAD) forms part of the behavioural and psychological symptoms of dementia (BPSD). PAD includes symptoms of psychosis such as hallucinations or delusions, and may be associated with agitation, negative symptoms or depression. Even though the US FDA has not approved any medication for the treatment of PAD, atypical antipsychotics have been widely used and favoured by geriatric experts in the management of the condition in view of their modest efficacy and relative safety. However, the recent FDA warnings regarding the cardiac, metabolic, cerebrovascular and mortality risks associated with the use of these drugs in elderly patients with dementia have caused serious concerns regarding their use. Nevertheless, until an effective and safe medication is approved by the regulatory agencies for PAD, clinicians do not have a better choice than atypical antipsychotics for the management of the serious symptoms of this condition.

A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. van Dyck CH, Tariot PN, Meyers B, et al. Alzheimer Disease and Associated Disorders, 21(2):136-143, 2007

This study examined the efficacy and safety of memantine monotherapy in patients with moderate-to-severe Alzheimer disease (AD). Patients not receiving a cholinesterase inhibitor (N=350) were randomized to receive memantine (20 mg/d) or placebo during this 24-week, double-blind, placebo-controlled trial. Prospectively defined analyses failed to demonstrate a statistically significant benefit of memantine treatment compared with placebo on the Severe Impairment Battery (SIB) at week 24 end point, although a significant advantage was observed for memantine at weeks 12 and 18. The 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL19) did not differ significantly between groups in any analysis. Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus) did not significantly favor memantine at week 24 despite a significant advantage for memantine at weeks 12 and 18. Other secondary outcomes showed no significant treatment differences. Post hoc analyses of potentially confounding covariates and alternative methods of imputing missing data did not substantially alter the results. Because of the violations of normality assumptions for the SIB and ADCS-ADL19, nonparametric analyses were performed; statistically significant benefit of memantine over placebo was demonstrated at week 24 for the SIB but not the ADCS-ADL19. The type and incidence of adverse events were similar in both groups.

Antioxidant vitamin supplement use and risk of dementia or Alzheimer’s disease in older adults. Gray SL, Anderson ML, Crane PK, et al. Journal of the American Geriatrics Society, November 2007 [Epub ahead of print]

OBJECTIVES: To examine whether use of vitamins C or E alone or in combination was associated with lower incidence of dementia or Alzheimer's disease (AD). DESIGN: Prospective cohort study. SETTING: Group Health Cooperative, Seattle, Washington. PARTICIPANTS: Two thousand nine hundred sixty-nine participants aged 65 and older without cognitive impairment at baseline in the Adult Changes in Thought study. MEASUREMENTS: Participants were followed biennially to identify incident dementia and AD diagnosed according to standard criteria. Participants were considered to be users of vitamins C or E if they self-reported use for at least 1 week during the month before baseline. RESULTS: Over a mean follow-up+/-standard deviation of 5.5+/-2.7 years, 405 subjects developed dementia (289 developed AD). The use of vitamin E was not associated with dementia (adjusted hazard ratio (HR)=0.98, 95% confidence interval (CI)=0.77-1.25) or with AD (HR=1.04; 95% CI=0.78-1.39). No association was found between vitamin C alone (dementia: HR=0.90, 95% CI=0.71-1.13; AD: HR=0.95, 95% CI=0.72-1.25) or concurrent use of vitamin C and E (dementia: HR=0.93, 95% CI=0.72-1.20; AD: HR=1.00, 95% CI=0.73-1.35) and either outcome. CONCLUSION: In this study, the use of supplemental vitamin E and C, alone or in combination, did not reduce risk of AD or overall dementia over 5.5 years of follow-up.

Oxidative stress and transcriptional regulation in Alzheimer disease. Shi Q, Gibson GE. Alzheimer Disease and Associated Disorders, 21(4):276-291, 2007

Alzheimer disease (AD) is defined by progressive impairments in memory and cognition and by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. However, oxidative stress and impaired mitochondrial function always accompany AD. Mitochondria are a major site of production of free radicals [ie, reactive oxygen species (ROS)] and primary targets of ROS. ROS are cytotoxic, and evidence of ROS-induced damage to cell membranes, proteins, and DNA in AD is overwhelming. Nevertheless, therapies based on antioxidants have been disappointing. Thus, alternative strategies are necessary. ROS also act as signaling molecules including for transcription. Thus, chronic exposure to ROS in AD could activate cascades of genes. Although initially protective, prolonged activation may be damaging. Thus, therapeutic approaches based on modulation of these gene cascades may lead to effective therapies. Genes involved in several pathways including antioxidant defense, detoxification, inflammation, etc, are induced in response to oxidative stress and in AD. However, genes that are associated with energy metabolism, which is necessary for normal brain function, are mostly down-regulated. Redox-sensitive transcription factors such as activator protein-1, nuclear factor-kappaB, specificity protein-1, and hypoxia-inducible factor are important in redox-dependent gene regulation. Peroxisome proliferators-activated receptor-gamma coactivator (PGC-1alpha) is a coactivator of several transcription factors and is a potent stimulator of mitochondrial biogenesis and respiration. Down-regulated expression of PGC-1alpha has been implicated in Huntington disease and in several Huntington disease animal models. PGC-1alpha role in regulation of ROS metabolism makes it a potential candidate player between ROS, mitochondria, and neurodegenerative diseases. This review summarizes the current progress on how oxidative stress regulates the expression of genes that might contribute to AD pathophysiology and the implications of the transcriptional modifications for AD. Finally, potential therapeutic strategies based on the updated understandings of redox state-dependent gene regulation in AD are proposed to overcome the lack of efficacy of antioxidant therapies.

Effects of exercise on brain function: role of free radicals. Radak Z, Kumagai S, Taylor AW, et al. Applied Physiology, Nutrition, and Metabolism, 32(5):942-946, 2007

Reactive oxygen species (ROS) are continuously generated during aerobic metabolism. Certain levels of ROS, which could be dependent on the type of cell, cell age, history of ROS exposure, etc., could facilitate specific cell functions. Indeed, ROS stimulate a number of stress responses and activate gene expression for a wide range of proteins. It is well known that increased levels of ROS are involved in the aging process and the pathogenesis of a number of neurodegenerative diseases. Because of the enhanced sensitivity of the central nervous system to ROS, it is especially important to maintain the normal redox state in different types of neuro cells. In the last decade it became clear that regular exercise beneficially affects brain function as well, and can play an important preventive and therapeutic role in stroke and in Alzheimer's and Parkinson's diseases. The effects of exercise appear to be very complex and could include neurogenesis via neurotrophic factors, increased capillarization, decreased oxidative damage, and increased proteolytic degradation by proteasome and neprilysin. Data from our and other laboratories indicate that exercise-induced modulation of ROS levels plays a role in the protein content and expression of brain-derived neurotrophic factor, tyrosine recepetor kinase B, and cAMP response element binding protein, resulting in better function and increased neurogenesis. The enhanced activities of proteasome and neprilysin result in decreased accumulation of carbonyls and amyloid beta-proteins, as well as improved memory. It appears that exercise-induced modulation of the redox state is an important means by which exercise benefits brain function, increases the resistance against oxidative stress, and facilitates recovery from oxidative stress.