British Geriatrics Society Newsletter November 2004

Encouraging developments in understanding the progression from cognitive impairment to Alzheimer’s disease, positive outcomes with therapeutic interventions and growing evidence of importance of lifestyle factors were reported at the 9th International Conference on Alzheimer’s Disease and Related Disorders in Pennsylvania, USA.

Evidence for progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) was reported from a major, population-based study carried out in Sweden. The study examined 379 non-demented subjects aged 75-95 years on two occasions over three years. Study subjects were assessed at baseline for MCI – defined as having a subjective memory complaint that was self-reported or reported by a close informant, normal levels of general cognition but impairment in different cognitive domains, including episodic memory, visuospatial ability and verbal fluency. They were reassessed after three years for presence of dementia, according to DSM-III-R criteria.

The prevalence of MCI-amnestic (impairment in memory only) was 2.6%, while that for MCI-single non-memory domain was 6.0% and for MCI-multidomains it was 3.4%. Results revealed that people with MCI-amnestic at baseline were nearly eight times more likely to progress to dementia (relative risk 7.7; 1.8-32.4) compared to those with no subjective or objective cognitive deficits. Of the 55 subjects who developed AD at follow-up, just over a quarter (25.5%; n=14) had MCI three years before diagnosis. People with deficits on a global cognitive test (MMSE) had a much greater risk of dementia than those with no impairment (relative risk 7.7; 2.1-28.9).

Reporting the results, Katie Palmer, Karolinska Institute, Stockholm, Sweden, said: “We found strong evidence of a degenerative aetiology in people with MCI-amnestic and MCI-multidomain.” However, she noted that the low prevalence of MCI at the general population level would result in the identification of a relatively low number of people at high risk of progressing to dementia. “A broader evaluation of signs and symptoms, and consideration of global cognitive deficits even of the absence of domain-specific cognitive impairment may increase predictivity in the general population,” she suggested.

Slowed Progression
Encouraging results were reported indicating that the acetyl cholinesterase inhibitor donepezil slowed progression from mild cognitive impairment (MCI) to AD by about six months compared to placebo, in the first study to show a positive treatment effect on progression. The study randomised 769 people with mild cognitive impairment to vitamin E (up to 2000IU/day), donepezil (5mg per day for six weeks, increasing to 10mg) or placebo. They were followed up for three years and evaluated every six months. Reporting the results, Ronald Petersen, Mayo Clinic, Rochester, Minnesota, USA, said: “Progression to AD was slower with donepezil during the first 18 months of the study, but was then similar to placebo.” Vitamin E had no effect.

Progression from MCI to AD was significantly slower with donepezil at 6 months (p<0.001), 1 year (p<0.009) and 18 months (p<0.035). The average delay in disease progression was about six months in people who progressed to AD. This risk reduction was lost at three years, when progression to AD was similar in all three treatment groups. “It appears there is protection against progression to AD for the first 18 months of treatment,” Dr Petersen noted, adding: “Perhaps we can intervene at an earlier stage of disease than previously thought – pre-AD.”

Slowing conversion to dementia
An open label extension a study of patients with MCI treated with flexible dosing of galantamine (up to 24mg/day) showed similar results, with a reduction in conversion to dementia during the first few months of treatment but no significant difference at two years. However, Michael Gold, Johnson & Johnson Pharmaceutical Research and Development, Titusville, USA, said there was a treatment effect of about 20% reduction in new conversions to dementia in favour of galantamine. He added that there was also a significant reduction in whole brain atrophy in favour of galantamine (0.619 for placebo vs 0.413 for galantamine).

The benefit of longer-term trials of AChEIs was suggested in results from the AWARE (Aricept Washout and Rechallenge) study showing behavioural benefits in patients continuing treatment compared to those discontinuing therapy. The study randomised 193/619 patients who showed unclear benefit with 12 weeks’ donepezil (10mg/day) to continue with the drug or switch to placebo. Results showed significant improvement in behaviour after a further 12 weeks’ treatment with donepezil (p<0.05) – with particular improvement in depression and dysphoria.

Reporting the findings, Peter Johannsen, Righospitalet, Copenhagen, Denmark, said: ”Behavioural symptoms should be considered when evaluating the treatment response in patients with mild to moderate AD.” A UK delegate commented: “It is great to see a study that I feel I can use in the clinic.”

Treatment with the antipsychotic quetiapine showed some control of agitation in a study of elderly patients with AD, without increasing risk of cerebrovascular events. A total of 333 patients with probable AD and/or vascular dementia and who were living in nursing homes were randomised to 100mg per day (n = 124), 200mg per day (n = 117), or placebo (n = 92).

Treatment with the highest dose of quetiapine (200mg daily) achieved a mean reduction of 8 points on the Positive And Negative Syndrome Scale Excited Component (PANSS-EC) – used as a measure of agitation - compared to a reduction of 5 points in the placebo group (p= 0.022). On the Clinical Global Impression of Change (CGI-C), 60% of patients in the 200mg per day group were rated as being ‘very much improved’, which was significantly higher compared with placebo (p< 0.05). Quetiapine was generally well tolerated, with no increase in cerebrovascular events.

Pierre Tariot, University of Rochester in New York, noted that this was the first prospective, randomised, placebo-controlled study to demonstrate safety and efficacy of an antipsychotic in agitation associated with AD – although quetiapine is not currently licensed for this indication. He added: “While this drug has now been shown to be effective in a randomised trial, I think pharmacological interventions should be the last choice in treating agitation — not the first choice.”

Prevention studies
The importance of lifestyle factors in AD was illustrated in several studies showing that body weight, blood pressure, cholesterol level, lung function, leisure activity and dietary intake of vegetables were all linked to the risk of developing the disease.

Body weight
A 10-year study from the Karolinska Institute, Stockholm, showed that individuals who were obese in middle age were twice as likely to develop dementia later as those of normal body weight. For those who also had raised cholesterol and blood pressure, the risk of dementia was six times higher.

Activity
Another study suggested that leisure pursuits involving mental, social or physical activity all seemed to offer some protection against dementia. The greatest benefit came from complex pursuits combining two or three types of activity.

Diet
Findings from the long-running Nurses’ Health Study demonstrated that high intake of leafy, green (such as spinach), or cruciferous (e.g. broccoli), vegetables was associated with less decline on cognitive tests than lower intake. “The difference amounted to being about one to two years younger in terms of cognitive ageing,” reported Jae Hee Kang, Harvard Medical School, Boston.

“Although Alzheimer’s is a complex disease with complex causes, studies at the conference bolstered evidence that we may be able to influence at least some factors in the mix,” said William Thies, vice-president of medical and scientific affairs with the Alzheimer’s Association.