Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease

BACKGROUND: Cholinesterase inhibitors are used to treat mild to moderate Alzheimer's disease. Their role in patients with concurrent cerebrovascular disease has been less well studied, and the influence of vascular risk factors on response to treatment is uncertain. We investigated the effect of hypertension and white matter lesions (WML) on response. METHODS: A retrospective sample of 160 consecutive out-patients who had blood pressure measured and the presence or absence of WML recorded at baseline and who completed six months treatment with a cholinesterase inhibitor was studied. Subjects scored either zero or one on the Modified Hachinski Ischaemic Scale. Subjects were assessed using the Mini-Mental State Examination (MMSE), the Digit Symbol Substitution test (DSST) and both the Instrumental Activities of Daily Living (IADL) and Social Behaviour (SB) sub-scales of the Nurses Observation Scale for Geriatric Patients (NOSGER). RESULTS: 43.9% of the total study population were classified as good responders using our criteria. Neither the presence of hypertension nor the presence of WML alone influenced outcome. However, there was a statistically significant interaction between blood pressure and WML on outcome variables on multiple analysis of variance (MANOVA) (F(4, 139) = 5.60, p < 0.0005). Subjects with both hypertension and WML deteriorate to a significantly greater extent in IADL and SB scores than any other group (p < 0.05 in each case). This effect could not be explained by age or by smoking status. CONCLUSION: Our results support the hypothesis that there is an interaction between hypertension and WML that adversely influences functional change during cholinesterase inhibitor treatment. Our results are a contrast to suggestions that subjects with vascular disease show a better response to cholinesterase inhibitors. We recommend careful exploration of factors that may influence outcome.     

The comparative efficacy and safety of cholinesterase inhibitors in patients with mild‐to‐moderate Alzheimer's disease: a Bayesian network meta‐analysis

Background

Comparative evidence for efficacy and safety of second‐generation cholinesterase inhibitors (ChEIs) is still sparse.

Objectives

The purpose of this research is to compare three ChEIs, donepezil, galantamine and rivastigmine, in patients with mild‐to‐moderate Alzheimer's disease (AD).

Methods

We conducted a systematic review for published articles and included randomised, double‐blind, placebo‐controlled trials and head‐to‐head randomised trials evaluating the efficacy and safety of ChEIs in patients with AD. We examined Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS‐Cog), Neuropsychiatric Inventory (NPI), Clinician's Interview‐Based Impression of Change plus caregiver's input (CIBIC+) and Clinical Global Impression of Change (CGIC) as efficacy endpoints. Withdrawals due to adverse events and number of patients experiencing nausea, vomiting, diarrhoea and dizziness were examined as safety profiles. Network meta‐analyses were sequentially performed for efficacy and safety outcomes based on drug/dose treatment conditions.

Results

Among the 21 trials included, network meta‐analysis showed that all treatments were significantly more efficacious than placebo in cognition measured by ADAS‐Cog. All treatments except galantamine were significantly more efficacious than placebo in global change in CIBIC+ or CGIC. Across all conditions, no significant efficacy was observed in neuropsychiatric symptoms measured by NPI. Derived hierarchies in the efficacy of treatment conditions were variables across efficacy and safety.

Conclusions

Our analysis is the first attempt to incorporate available direct and indirect evidence. The results suggest that ChEIs should have significant efficacy for cognition and global change assessment, but the efficacy on neuropsychiatric symptoms is questionable in patients with mild‐to‐moderate AD.     

Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial

BACKGROUND: There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini-Mental State Examination [sMMSE] score 5-12) within a randomized, placebo-controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5-17). METHODS: Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview-Based Impression of Change (CIBIC-plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment x disease severity interaction in the full MSAD study sample. RESULTS: CIBIC-plus scores for donepezil patients were significantly improved compared with placebo for each time-point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment x severity interactions for any of the efficacy measures. CONCLUSIONS: In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range.     

Cholinesterase inhibitors for Alzheimer's disease: variations in clinical practice in the north-west of England

BACKGROUND: In the UK, the National Institute for Health and Clinical Excellence (NICE) is currently reviewing cost-effectiveness of cholinesterase inhibitors (ChEIs) for Alzheimer's disease (AD) in the NHS. The implementation of the original NICE (2001) guidance that made these drugs available in the UK was not examined in this review process, and was the objective of this study. METHOD: Ten hospitals in and around Manchester participated in the audit. Case records of all patients who were started on ChEIs between January 2002 and the date of the audit (November 2003 to December 2004) were examined to assess adherence to the NICE (2001) guidance. Information about available resources was gathered from lead clinicians of each hospital. RESULTS: A total of 1,092 case records were examined. The treatment of AD with ChEIs varied considerably with regard to pre-treatment investigations, waiting period for treatment, scales used to assess efficacy, adherence to the NICE (2001) guidance, and available resources. The actual number of patients with mild to moderate AD receiving ChEIs was much lower than that expected from known prevalence rates. Non-uniformity of clinical practice and missing data were the main limitations of the audit. CONCLUSION: There is a need to harmonise the use and monitoring of ChEIs for AD in the NHS so that the data from routine clinical practice could feed into future clinical and cost-effectiveness analyses.     

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia

OBJECTIVE: To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). METHOD: MEDLINE (1966--December 2004), PsychINFO (1972--December 2004), EMBASE (1980--December 2004), CINHAL (1982--December 2004), and the Cochrane Collaboration were searched in December 2004. RESULTS: Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. CONCLUSION: Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms--in particular tremor--may limit the utility of cholinesterase inhibitors.     

The economic consequences of Alzheimer's disease in the context of new drug developments

The first national symptomatic treatment for Alzheimer's disease has received a very mixed and perhaps ageist reception from purchasers of health care in the UK. This is largely because detailed information on the long-term effects of this class of drugs is scarce. However, by looking at the published evidence on the economic burden of Alzheimer's disease, some observations and assumptions can be made as to the influence of the new drug treatments. The drug therapies available and those most likely to become licensed are reviewed and the potential economic impact is discussed. Long-term outcome studies would properly address this, but as these drugs have now demonstrated efficacy, particularly in non-cognitive behaviours, it will be ethically more difficult to maintain patients on placebo for long periods. Some assumptions therefore have to be made from long-term open-label studies. Those drugs currently available, and those in development, may offer effective treatment for some of the core symptoms of Alzheimer's disease, slowing the rate of cognitive decline and preserving competence in activities of daily living for longer. If handled correctly, these treatments have the potential to offer cost savings for many patients, and cost-effectiveness improvements look probable. © 1998 John Wiley & Sons, Ltd.     

A multinational, randomised, 12-week study comparing the effects of donepezil and galantamine in patients with mild to moderate Alzheimer's disease

OBJECTIVES: To compare directly, in the same patient cohort, the ease of use and tolerability of donepezil and galantamine in the treatment of Alzheimer's disease (AD), and investigate the effects of both treatments on cognition and activities of daily living (ADL). METHODS: Patients with mild to moderate AD from 14 European centres were randomised to receive open-label donepezil (up to 10 mg once daily) or galantamine (up to 12 mg twice daily) for 12 weeks, according to the approved product labelling. Physicians and caregivers completed questionnaires rating satisfaction with treatment/ease of use in daily practice. Secondary assessments were the ADAS-cog, the MMSE, and the DAD scale to assess ADL. Tolerability was evaluated by reporting adverse events (AEs). RESULTS: Both physicians and caregivers reported significantly greater overall satisfaction/ease of use for donepezil (n = 64) compared with galantamine (n = 56) at weeks 4, 12, and endpoint (week 12 LOCF; all p-values <0.05). Significantly greater improvements in cognition were also observed for donepezil versus galantamine on the ADAS-cog at Week 12 and endpoint (p-values <0.05). ADL improved significantly in the donepezil group compared with the galantamine group at weeks 4, 12, and endpoint (p-values <0.05). Most AEs were mild to moderate, however, 46% galantamine-treated patients reported gastrointestinal AEs vs 25% donepezil patients. CONCLUSIONS: Physician and caregiver ease of use/satisfaction scores, and assessments of cognition and ADL, showed significant benefits for donepezil compared with galantamine in this direct comparative trial. Both treatments were well tolerated, with more gastrointestinal AEs reported for galantamine vs donepezil.     

Ten years of cholinesterase inhibitors

In this editorial we have summarised ten years of evidence relating to the use of cholinesterase inhibitors in Alzheimer's and other dementias. We have presented this evidence in the context of the evolution of public and professional awareness of dementia and its management and prescribing patterns over this time frame. We also briefly outline recent political and legal events surrounding the 2007 NICE guidance and the possible long‐term impact of cholinesterase inhibitors on clinical practice. Whilst cholinesterase inhibitors continue to play a part in the management of Alzheimer's disease, it is possible that their most important legacy will be their contribution to the increased awareness and recognition of dementia as a neurodegenerative disease and the resulting transformation of old age psychiatry services. Copyright © 2009 John Wiley & Sons, Ltd.     

A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil

OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.     

Mechanism of action of cholinesterase inhibitors in Alzheimer's disease

Cholinesterase inhibitors, such as physostigmine and tacrine, have lately gained interest as potential drugs in the treatment of Alzheimer's disease. Already in the 1950ths, it was discovered that physostigmine and tacrine were potent inhibitors of acetylcholinesterase and butyrylcholinesterase. However, later studies have shown that cholinesterase inhibitors also interact with cholinergic receptors, with sodium and potassium ion channels and effect the uptake, synthesis and release of neurotransmitters. In summary, cholinesterase inhibitors are drugs with many modes of action, which may be of advantage in the treatment of a complex disorder such as Alzheimer's disease.     

Velnacrine for the treatment of Alzheimer's disease: A double-blind,placebo-controlled trial

Summary The present study examines the safety and efficacy of the centrally acting cholinesterase inhibitor, velnacrine, in treating the cognitive symptoms of Alzheimer's disease. Seven hundred thirty-five patients with mild-to-severe Alzheimer's disease were treated in a double-blind, placebo-controlled study. Following the screen visit, patients were treated with velnacrine (10, 25, 50 and 75 mg t.i.d.) or placebo in a double-blind dose-ranging study to identify velnacrine-responsive patients and their best dose. Following placebo washout velnacrine responsive patients were randomly assigned to their best dose of velnacrine (N=153) or placebo (N=156) in a six week double-blind dosereplication study. Primary efficacy measures were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS) and the Physician's Clinical Global Impression of Change.Statistically significant improvement was observed in both primary efficacy measures in velnacrine-treated patients during the dose-replication study. Velnacrine patients scored better on the cognitive subscale of the ADAS than placebo patients (P < 0.001), with patients receiving the highest velnacrine dose averaging a 4.1-point improvement with respect to screen values. Clinical Global Impression of Change scores of velnacrine-treated patients were significantly improved at the end of the 6 weeks of treatment when compared to those of placebo patients (P < 0.05). The most common side effect was asymptomatic elevation in liver transaminase levels, which occurred among 29% of patients. These data suggest that velnacrine produces modest clinical improvement in a subset of patients with mild-to-severe Alzheimer's disease.     

Potential treatment effects of donepezil not detected in Alzheimer's disease clinical trials: a physician survey

OBJECTIVES: Clinical trials of the cholinesterase inhibitor donepezil have used standard psychometric tools to evaluate treatment efficacy. These trials, however, appear not to capture clinically demonstrable, but otherwise unmeasured, beneficial treatment effects. We sought to identify and categorize clinically recognizable effects of donepezil treatment in Alzheimer's disease. METHODS: A list of potential effects was developed using clinical trials data and the experience of an expert panel. These were incorporated in a questionnaire, which was tested with a focus group, revised and then used in a postal survey of physicians. Data were classified by cognitive domain, and reviewed by a second panel. RESULTS: Items that were most often rated as being improved were related to frontal systems function, including attentional capacity and initiative. Behavioral symptoms that were among the highest rated items were apathy, mood, and agitation. The top two other items were social interactions and involvement in domestic activities. Of the top ten symptomatic treatment effects, only four appeared to be readily identified by current standard measures. CONCLUSIONS: Physicians recognize as important several treatment effects that are not well captured by current standard measures. New methods are needed to capture such effects, which also have the potential to offer insight into the neurobiology of the human cholinergic system.     

Risperidone for psychosis of Alzheimer's disease and mixed dementia: results of a double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of low-dose risperidone in treating psychosis of Alzheimer's disease (AD) and mixed dementia (MD) in a subset of nursing-home residents who had dementia and aggression and who were participating in a randomized placebo-controlled trial of risperidone for aggression. METHOD: This post-hoc analysis included only patients diagnosed with AD or MD with psychosis, defined by a score of >or= 2 on any item of the Behavioral Pathology of Alzheimer's Disease (BEHAVE-AD) psychosis subscale at both screening and baseline. Co-primary efficacy endpoints were changes in scores on BEHAVE-AD psychosis subscale and Clinical Global Impression of Change (CGI-C). RESULTS: Overall, 93 patients (46 risperidone and 47 placebo) fulfilled the psychosis of AD criteria. Mean change at endpoint in BEHAVE-AD psychosis subscale with risperidone was superior to placebo (-5.2 vs -3.3; p = 0.039). Distribution of CGI-C at endpoint also favoured risperidone (p < 0.001). The superior improvement with risperidone compared with placebo occurred as early as the first two weeks and persisted to the end of the treatment period. At endpoint, 59% of risperidone-treated patients were responders (i.e. were 'very much' or 'much' improved) compared with 26% of patients receiving placebo. The mean risperidone dose was 1.03 +/- 0.61 mg/day. Twelve weeks of treatment were completed by 37 patients treated with risperidone (80%) and 35 with placebo (74%). A total of 46 (98%) placebo- and 44 (96%) risperidone-treated patients experienced at least one adverse event, with only somnolence occurring more frequently in the risperidone group. CONCLUSION: Risperidone effectively reduces psychosis and improves global functioning in elderly patients with moderate-to-severe psychosis of AD and MD.     

TNF alpha inhibitors in Alzheimer's disease: A systematic review

Objectives

The objective of this study was to evaluate the effect of tumour necrosis factor‐alpha inhibitors (TNF‐αI) on Alzheimer's disease‐associated pathology.

Design

A literature search of PubMed, Embase, PsychINFO, Web of Science, Scopus, and the Cochrane Library databases for human and animal studies that evaluated the use of TNF‐αI was performed on 26 October 2016.

Results

The main outcomes assessed were cognition and behaviour, reduction in brain tissue mass, presence of plaques and tangles, and synaptic function. Risk of bias was assessed regarding blinding, statistical model, outcome reporting, and other biases. Sixteen studies were included, 13 of which were animal studies and 3 of which were human. All animal studies found that treatment with TNF‐αI leads to an improvement in cognition and behaviour. None of the studies measured change in brain tissue mass. The majority of studies documented a beneficial effect in other areas, including the presence of plaques and tangles and synaptic function. The amount of data from human studies was limited. Two out of 3 studies concluded that TNF‐αI are beneficial in Alzheimer's disease patients, with one being an observational study and the latter being a small pilot study, with a high risk of bias.

Conclusion

It was concluded that a large‐scale randomized controlled trial assessing the effectiveness of TNF‐αI on humans is warranted.     

Endogenous antioxidants predicted outcome and increased after treatment: A benzoate dose-finding,randomized, double-blind,placebo-controlled trial for Alzheimer's disease

Aim

Previous pilot studies suggest that sodium benzoate may be a potential cognitive enhancer for patients with Alzheimer's disease (AD), schizophrenia, or late-life depression. Especially for AD treatment, a confirmatory trial with predictive biomarkers is urgently needed. This study aimed to confirm benzoate as a novel treatment for AD and to discover its optimal dose and biomarkers.

Methods

A 24-week, dose-finding, randomized, double-blind, placebo-controlled trial, with clinical measurements at weeks 0, 8, 16, and 24, was conducted in three major medical centers in Taiwan. Among 154 patients screened for AD, 149 were eligible and randomized to one of the four treatments: (i) benzoate 500 group (fixed 500 mg/day); (ii) benzoate 750 (500 mg/day for the first 4 weeks, 750 mg/day from the 5th week); (iii) benzoate 1000 (500 mg/day for the first 4 weeks, 1000 mg/day from the 5th week); and (iv) placebo. The primary outcome measure was AD assessment scale-cognitive subscale (ADAS-cog).

Results

The benzoate 1000 group performed best in improving ADAS-cog (P = 0.026 at week 24), with female advantage. Higher plasma catalase at baseline predicted better outcome. Benzoate receivers tended to have higher catalase and glutathione than placebo recipients after treatment. The four intervention groups showed similar safety profiles.

Conclusions

By enhancing two vital endogenous antioxidants, catalase and glutathione, sodium benzoate therapy improved cognition of patients with AD, with higher baseline catalase predicting better response. Supporting the oxidative stress theory, the results show promise for benzoate as a novel treatment for AD.     

Effects of cholinesterase inhibitors appear greater in patients on established antihypertensive therapy

INTRODUCTION: There is increasing evidence that hypertension may contribute to development of dementia. Studies show that blood pressure lowering therapy might protect against cognitive deterioration and that antihypertensive treatment reduce the incidence of dementia. AIM: We hypothesize that administration of cholinesterase inhibitors (AChEis) to patients with Alzheimer's Disease (AD) receiving antihypertensive medications therapy would result in clinical benefits for a period of 40 weeks in routine clinical practice. METHODS AND MATERIALS: Patients with possible or probable AD were enrolled from 16 Alzheimer evaluation units (UVA) of Brescia and Cremona (Northern Italy). Patients treated with donepezil, rivastigmine and galantamine for 40 weeks independently of dosages were selected. Patients were evaluated at baseline (T0), 4 weeks (T1), 16 weeks (T2) and 40 weeks (T3). RESULTS: 416 patients completed the study at 40 weeks; of these 255 were 'non users' while 161 utilized antihypertensive drugs ('users'). The mean change in MMSE score from baseline to week 40 demonstrate that antihypertensive-treated patients improved by 0.7 points while patients receiving only AChEis remain stables. Analyzing separately patients (n = 183) that ameliorate (responders) on cognition at T3 ( >/= 1 point MMSE score increase) a significant differences in favor of 'users' antihypertensive drugs over 'non users' on cognition at weeks 16 and 40 has been demonstrated. In particular, at T2 the mean change of MMSE from baseline in 'users' was 3.2 +/- 2.6 vs 'non users' 2.2 +/- 2.3 ( p = 0.016) and at T3 was 3.5 +/- 2.5 vs 'non users' 2.0.2.7+/-1.6 ( p = 0.018). Antihypertensive drugs were independently associated with cognitive improvement in responder patients treated with AChEis (95% CI: 0.41-1.79; p = 0.002). CONCLUSION: Antihypertensive medications in AD patients treated with AChEis are associated with an independent improvement on cognition after 40 weeks of treatment.     

Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease

OBJECTIVE: To evaluate the efficacy and safety of donepezil, an acetylcholinesterase inhibitor, as a treatment for cognitive impairment and dementia in patients with Parkinson' s disease (PD). METHODS: Using a randomized, double-blind, placebo-controlled design, nine patients received placebo and seven patients received donepezil (2.5-10 mg/day) for a mean (SD) duration of 15.2 (3.4) weeks. The primary efficacy outcomes were derived from a neuropsychological battery that assessed global cognitive status as well as memory, attention, psychomotor speed, and visuospatial and executive functions. Secondary efficacy outcomes were psychiatric symptom and activities of daily living ratings. Primary safety measures were motor signs and assessments of adverse effects. RESULTS: Patients on donepezil showed selective and significant (p<0.05) improvement on the memory subscale of the Dementia Rating Scale. There was also a trend toward improvement on a measure of psychomotor speed and attention. There were no group differences in psychiatric status, motor function, or activities of daily living as measured at baseline or end-point. Adverse effects resulted in premature withdrawal of four patients on donepezil, two for peripheral cholinergic effects and one for increased parkinsonism. Side effects were associated with dosage increases. CONCLUSION: Donepezil has a beneficial effect on memory and may improve other cognitive deficits in patients with PD and cognitive impairment. However, variable tolerability in our sample underscores the need for careful monitoring when prescribing donepezil to patients with PD, especially with dosage increases.     

A feasibility and tolerability study of lithium in Alzheimer's disease

OBJECTIVE: To assess the safety and feasibility of prescribing long term lithium to elderly people with mild to moderate Alzheimer's disease (AD). METHODS: An open label treatment group with low dose lithium for up to 1 year with the Lithium Side Effects Rating Scale as the primary outcome measure. A comparison group matched for cognition and age not receiving lithium therapy. RESULTS: Twenty-two people with AD initiated lithium. Fourteen participants discontinued therapy after a mean of 16 weeks of treatment compared to the 39 weeks for those continuing to take treatment at the end of the study. Three patients discontinued treatment due to possible side effects that abated on ceasing therapy. The reports of side effects on the primary outcome scale did not differ between those discontinuing therapy and those remaining in the study. Two patients died whilst receiving lithium--in neither case was the treatment felt to be related to cause of death. There was no difference in deaths, drop outs or change in MMSE between those receiving lithium and the comparison group. CONCLUSIONS: Lithium treatment in elderly people with AD has relatively few side effects and those that were apparently due to treatment were mild and reversible. Nonetheless discontinuation rates are high. The use of lithium as a potential disease modification therapy in AD should be explored further but is not without problems.