Galantamine may be more valuable in certain countries …

Mindspan in Japan
… Especially for those aging faster
By Will Block

In the battle against aging, most of the attention to date has been on lifespan and healthspan … but now (with population aging) the focus is changing to mindspan—how long the mind can be kept agile and active. In the United States the incidence of Alzheimer’s disease is 11%, but in Japan it’s 15%. Who should be more concerned? Given that Alzheimer’s disease may be the 3rd largest cause of death in the US (see “Alzheimer’s Deaths Rival Cancer’s,” in the May, 2014 issue), you might think that the US should be.

Alzheimer’s is a Disease of Longevity

However, given that Japanese women outlive American women by 6 years (87 vs. 81) and Japanese men outlive American men by 5 years (84 vs. 79), the tables are turned by the grim fact that in Japan, the torture of losing one’s mind may be spread out over a longer period of time.

And Japan may portray the future. It has the oldest population in the world because health is viewed as precious and because its birthrate is far below the replacement rates. Too few births combined with lifespan lengthening are skewing the country into an aged society. This can be thought of as a “grey tsunami,” as it has been called by demographers.1 Moreover, back to the future, the tsunami is assuredly arriving on the shores of the US, too.


In Japan, the torture of losing one’s
mind may be spread out over a longer
period of time.


Galantamine Shows Long Term Efficacy in the Elderly

In two new studies, the “Okayama Galantamine Study (OGS)”2 and the “Okayama Late Dementia Study (OLDS),”3 Japanese researchers have taken a critical look at the use of galantamine for the treatment of Alzheimer’s disease.

In the OGS study, a long-term efficacy of galantamine (from 8 to 24 mg per day) in very elderly AD patients (80.6 ± 7.2 years old) revealed a better efficacy for males starting with lower baseline cognitive, affective, and Activity of Daily Living (ADL) functions. That fact that the subjects were substantially older than in other studies fits the Japanese model of greater longevity.


Thus, the OGS results suggests that
galantamine is more effective in older
patients and in patients switched from
other ChEIs.


Cognitive Function Well-Preserved by Galantamine

The OGS study investigated the longterm effectiveness of galantamine in 279 AD patients. In measures of cognitive function, Mini–mental state examination (MMSE) scores were well preserved and Frontal Assessment Battery (FAB) scores revealed a delayed improvement at 24 months. The MMSE test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. The FAB includes simple tests of sequencing, behavioral inhibition, planning and frontal release signs, which can be used as a screening test to elicit typical neurological and cognitive features.

Another recent study4 assessed long-term survival and drug efficacy in mild to moderate AD patients (mean age 73 years old) following 2 years of galantamine treatment, and showed that MMSE scores were maintained with galantamine compared with the placebo group. The OGS study’s patients (mean 80.6 years old) were older than those investigated in previous reports, and 25.8% of OGS patients were switched from other cholinesterase inhibitors (ChEIs) to galantamine. Thus, the OGS results suggests that galantamine is more effective in older patients and in patients switched from other ChEIs.


A higher prevalence of the ε4 allele
of the apolipoprotein E (APOE) gene
among women with AD has also
been reported.


Behavior and Planning Improvement

The improvement seen in FAB scores may be related to the specific activation of galantamine on frontal lobe metabolism. In measures of affective functions, Geriatric Depression Scale (GDS) significantly improved at 3 months, and both GDS and Abe’s Behavioral and Psychological Symptom of Dementia score (ABS) remained better than the baseline scores at 24 months. This test measures behavioral and psychological symptoms of dementia.

ABS scores were only slightly deteriorated after 12 and 24 months of galantamine monotherapy. A slight nonsignificant deterioration in ADL was noted at 12 and 24 months, probably relating to the advanced age of the patients (81.0% of the patients were over 75 years old).

The authors examined gender, cognitive function, affective status, and ADL Falalestratified groups based on their assessment at 0 months. Compared with males, Hasegawa Dementia Rating Scale-revised (HDS-R) and ABS in the female group deteriorated after 12 months of receiving only galantamine.


In addition, the moderate to severe
AD group showed less deterioration
in ABS and ADL scores after 24
months of galantamine therapy than
the mild AD group.


The Rate of Disease Progression

One potential reason for these gender-dependent differences in galantamine’s effect on cognitive function is the rate of disease progression. Previous reports suggested that women are more likely to develop AD than men, and a higher prevalence of the ε4 allele of the apolipoprotein E (APOE) gene among women with AD has also been reported. This allele predisposes its bearers to a high incidence of AD. In regards to affective function, because galantamine can improve irritability and aggression which are more frequently seen in men, ABS scores might be well preserved in men compared with women in the OGS study.

Moderate to Severe AD Improved More than Mild AD

Of the two MMSE-dependent subgroups in the study, the moderate to severe AD group (baseline MMSE <20) improved in cognitive functions more than the mild AD group over the 24 months of the study. In addition, the moderate to severe AD group showed less deterioration in ABS and ADL scores after 24 months of galantamine therapy than the mild AD group. These data suggest that galantamine was more beneficial in treating moderate to severe AD in cognitive, affective, and ADL functions.


It did reveal the long-term efficacy of
galantamine in very elderly
AD patients.


Remarkable Improvement among Severe Group

Among the three subgroups based on ABS severity, the severe behavioral and psychological symptoms of dementia group (baseline ABS ≥5) showed a remarkable improvement in cognitive, affective and ADL (activities of daily living) functions for the 24 months studied.

These data suggest a better long-term effect of galantamine for AD patients with severe behavioral and psychological symptoms. The low ADL patients showed improvements in cognitive, affective, and ADL functions over 24 months, while there was a small deterioration in GDS and ADL scores in the high ADL patient group.

A recent report5 suggested that galantamine treatment provides a better short-term response in older AD patients with lower baseline cognitive and functional abilities. Although this retrospective study was limited by the absence of a control group, it did reveal the long-term efficacy of galantamine in very elderly AD patients.

Of great interest was the better efficacy of galantamine treatment in the patients with lower baseline cognitive, affective, and ADL functions. In addition, the subanalyses suggest that there may be a gender difference in the effectiveness of galantamine, especially in men. A previous study suggested an APOE allele-dependent response to galantamine in AD patients.

Anti-AD Drugs and a Nutrient Work for Older AD Pateints

In the OLDS study,3 which lasted 12 months, anti-AD drugs and an anti-AD nutrient (galantamine) were effective even for older AD patients, and the clinical benefits of each drug showed only a small difference with regard to gender.

In Japan, more than 4.6 million people are living with dementia (in the US it’s 5.3 million; Japan has a population of 126 million while the US total is 321 million). The number of cases in Japan is expected to rise significantly as the population ages. Worldwide, at least 44 million people are living with dementia, making the disease a global health crisis that must be addressed, especially in longer lived nations.

Destruction of Japan’s Social-Welfare Mechanisms

In a recent article in The Japan Times,6 the team leader at the Laboratory for Proteolytic Neuroscience at Riken’s Brain Science Institute responded apocalyptically to a reporter’s question about the need for more dementia research. “Alzheimer’s disease,” said team leader Takaomi Saido, “will destroy Japan’s social-welfare mechanisms in the near future. … the socioeconomical cost of Alzheimer’s disease will be greater than the government’s annual income by 2050 unless the disease becomes preventable.” Given the failure of government attempts here in the US to win any “war” on disease, we can expect no different results in Japan. The solutions lie in the marketplace, where ideas have a better chance of winning owing to the great inducement of financial success atop any “humanitarian” goal.

Not only does a diagnosis of Alzheimer’s alter the life of the person with the disease, it changes the lives of their family and friends. The OLDS study revealed that all three AD drugs (donepezil, rivastigmine, or memantine) along with the nutrient galantamine preserved cognitive functions, for 12 months, the length of the trial, with the exception of FAB with memantine.

Affective functions were also preserved with all four agents in older AD patients for 12 months. OLDS also showed a gender-dependent difference, as male MMSE scores became worse at 12 months in the donepezil group and female GDS scores at 6 months. In contrast, female HDS-R and ABS scores in the galantamine group became worse at 12 months while male scores were preserved for 12 months.

In another recent report, the same researchers showed that AD is an age-dependent disease, as 72.5% were older patients, among which 69% had AD.7 Because the world population is aging, the number of older individuals with AD is also increasing. The OLDS study is the first report describing the clinical effects of four anti-AD agents for older AD patients, which also reveals gender differences.


Of great interest was the better
efficacy of galantamine treatment in
the patients starting with lower
baseline cognitive, affective, and
ADL functions.


The data from the OLDS study suggests that ChEIs (cholinesterase inhibitors) preserve or even improve cognitive function in older AD patients for 12 months, the length of the trial, and can improve affective function within 3 months.

OLDS also revealed a small but significant difference between genders. Effects of ChEI for cognitive, affective, and ADL functions between males and females were different. Other recent reports have suggested that women are more likely than men to develop AD, and a higher prevalence of the ε4 allele in women with AD has also been reported.

However, vascular dementia is more common in males. In addition, the brain reserve is reported higher in males than females. These gender differences could account for the differences in the effects of anti-AD agents. However, there remained some mysterious parts about gender differences of AD, and the basic mechanism is expected to be clarified in the future. The present results from OLDS also suggest that galantamine was better for male cognitive and affective functions.

Selective Forgetting and Alzheimer’s

In most instances of Alzheimer’s, it is probable that the willful control of recollection and selective forgetting has been ongoing since early childhood. Initially, Alzheimer patients as young children likely began refusing to remember painful and humiliating childhood abuses. Do Alzheimer’s Japanese patients have anything to forget (in the OGS study, the mean age was 80.6 years; born about 1935)?

In conclusion, the present results from OGS and OLDS suggest that galantamine is effective even for older AD patients, but the difference in effects for other anti-AD agents is small with regard to cognitive, affective, and ADL functions, and between genders. The present data provide useful information for the selection of anti-AD agents, especially galantamine, for older AD patients, a path the US is following albeit belatedly.

References

  1. Mander T. Longevity and healthy ageing - Will healthcare be drowned by the grey Tsunami or sunk by the demographic iceberg? Post Reprod Health. 2014 Mar 13;20(1):8-10.
  2. Nakano Y, Matsuzono K, Yamashita T, Ohta Y, Hishikawa N, Sato K, Deguchi K, Abe K. Long-Term Efficacy of Galantamine in Alzheimer’s Disease: The Okayama Galantamine Study (OGS). J Alzheimers Dis. 2015 Aug 3;47(3):609-17.
  3. Matsuzono K, Yamashita T, Ohta Y, Hishikawa N, Sato K, Kono S, Deguchi K, Nakano Y, Abe K. Clinical Benefits for Older Alzheimer’s Disease Patients: Okayama Late Dementia Study (OLDS). J Alzheimers Dis. 2015 Jun 25;46(3):687-93.
  4. Hager K, Baseman AS, Nye JS, Brashear HR, Han J, Sano M, Davis B, Richards HM. Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease. Neuropsychiatr Dis Treat. 2014;10:391-401.
  5. Wallin AK, Wattmo C, Minthon L Galantamine treatment in Alzheimer’s disease: Response and long-term outcome in a routine clinical setting. Neuropsychiatr Dis Treat. 2011;7:565-em76.
  6. Hooper R. Now is the time to research Alzheimer’s. The Japan Times, April 19, 2014. http://www.japantimes.co.jp/news/2014/04/19/national/science-health/now-is-the-time-to-research-alzheimers/#.VjTSEqRVsbG Accessed: October 31, 2015.
  7. Hishikawa N, Fukui Y, Sato K, Kono S, Yamashita T, Ohta Y, Deguchi K, Abe K. Characteristic features of cognitive, affective and daily living functions of late-elderly dementia. Geriatr Gerontol Int. 2015 May 8. doi: 10.1111/ggi.12492. Epub ahead of print] PubMed PMID: 25952646.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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