Mild Cognitive Impairment-Alzheimer's Disease Part XVI

(6/14/09) In cognitive normal older adults, adherence to a Mediterranean diet is associated with a modestly reduced risk of developing mild cognitive impairment, and in older adults who have mild cognitive impairment (MCI), adherence to the diet is associated with a significantly reduced risk of developing Alzheimer's disease. (See: Scarmeas N., Stern Y., Mayeux R. et al. Mediterranean diet and mild cognitive impairment. Arch Neurol 2009; 66(2):216-225).

This longitudinal study followed 1393 cognitively normal subjects (mean age 76.7) and 482 subjects with mild cognitive impairment (mean age 77.5) for a mean of 4.5 years. The investigators found that 275 of the cognitively normal subjects developed MCI (about 2%).

Using diet adherence as the independent variable, the researchers found that those subjects who adhered to the diet at the highest level had a 28% lower risk of developing MCI and those original MCI subjects in the highest level of adherence to the Mediterranean diet had a 48% lower risk of progressing to Alzheimer's disease.

(5/6/08) Findings presented April 16, 2008. at the American Academy of Neurology 60th Annual Meeting suggest that men have a 67% increased risk for mild cognitive impairment (MCI) relative to women.

The abstract of this study lists the folowing researchers: Rosebud Roberts, Yonas Geda, David Knopman, Ruth Cha, Vernon Pankratz, Bradley Boeve, Walter Rocca, Ronald Petersen, Rochester, MN . The authors conclude "[T]his is one of the first studies to prospectively ascertain MCI in a population-based setting.

The higher prevalence of MCI in men is in contrast to the lack of sex difference in the prevalence of dementia or the higher prevalence in women found in some studies, which suggests a faster progression from MCI to dementia in women or a delayed progression to dementia in men." The researchers used data from the Mayo Clinic Study of Aging, a longitudinal study in Olmstead County, Minnesota, randomly selecting residents of both sexes who were between 70 and 89 years of age on October 1, 2004. They selected 2050 participants to represent equal numbers of men and women and equal numbers from 70 to 79 and 80 to 89 years of age.

"We concluded that the prevalence of MCI in the general population of 80- to 89-year-olds in our population is high," around 16.5%, Rosebud Roberts, MD, from the Mayo Clinic in Rochester, Minnesota, told a press conference. "We also concluded that the prevalence of MCI is higher in men compared to women."

(11/14/ 06) If you were to go to the Alzheimer Association site ( ), you will find a fact sheet describing mild cognitive impairment. It begins: "Mild cognitive impairment (MCI) is a general term most commonly used to describe a subtle but measurable memory disorder. According to this definition, a person with MCI has memory problems greater than normally expected with aging, but does not show other symptoms of dementia, such as impaired judgment or reasoning.

Scientists are still working to understand MCI and its relationship to Alzheimer’s disease. Because basic questions about this disorder remain to be answered, the definition of MCI continues to evolve."

Further, they state "Scientists are still working to understand MCI and its relationship to Alzheimer’s disease". We have reported on the Petersen et al study of vitamin E and donepezil for treatment of MCI, which indicated that there was a statistically significant delay in the progress of MCI to Alzheimer’s disease at 12 months but that difference did not exist at the end of three years. (NEJM 2005; 352:2379-2388). We can now report that Unverzagt and his research group (Neurology 2001; 57:1655-1662) indicated that a higher percentage of people with cognitive impairment and no dementia returned to normal (25%) annually than convert to Alzheimer’s disease. Additionally Panza et al in a population-based study completed in Italy found that up to 44% of MCI patients, diagnosed at their first visit, were estimated to return to normal a year later. (Amer J Geriatr Psychiatry 2005; 13:633-644).

Though individuals with MCI are at high risk for progressing to dementia, a large cohort of individuals can revert to normal cognitive levels. Scientists need to more definitely understand MCI to be able to develop drugs to deal with a potentially pathological process. They cannot assume that drugs that slow the progress of Alzheimer’s disease will be useful in cases of MCI.

(12/17/02)- An advisory panel to the US Food and Drug Administration ruled on Tuesday, March 13, 2001 that mild cognitive impairment, "a condition separate from Alzheimer's disease," is a valid target for new drug therapies, regardless of whether a particular drug also slows the progression to dementia. It leaves open the opportunity for drug companies to market some of the drugs they are testing for Alzheimer's disease.

The Peripheral and Central Nervous System Drugs Advisory Committee has stated that more than 80% of patients with mild cognitive impairment develop Alzheimer's disease within 10 years at a rate of 10% to 15% of patients per year. With a statistic like this, some medical experts might view mild cognitive impairment as early Alzheimer's disease rather than a distinct condition.

Whether MCI is really early stage Alzheimer's or a discrete disorder is still unclear. Researchers do agree that the solving the mysteries of MCI may also lead to clues in the treatment of Alzheimer's. Experts estimate that in addition to the four million Americans with Alzheimer's another eight million suffer from MCI.

The FDA has approved four drugs to treat Alzheimer's disease, but at best these drugs only provide mild relief, and do not attack the cause of AD. None of the four drugs have been approved to treat MCI, but several drugs are being tested for that purpose. The four approved drugs for the treatment of AD are: Johnson & Johnson's Reminyl; Merck & Co.'s Cognex; Novarits AG's Exelon and Pfizer's Aricept.

Where most MCI patients have trouble is with short-term recall. Tests have been developed that can evaluate the degree of impairment, but so far the drugs that are being used in the treatment of the disease only have mild, temporary effects.

Cognitive impairment is a serious medical issue that will be of increasing concern to society. Treatment strategies are needed that effectively stop or reverse the declines associated with this disorder. Some of the basic research work conducted by Goodman-Rakic and her group at Yale on the D1 receptor and working memory may have a bearing on this goal.

Mild Cognitive Impairment (MCI) is a condition characterized by mild recent memory loss without dementia or significant impairment of other cognitive functions to an extent that is beyond that expected for age or educational background. R.C. Petersen assigns the following criteria to MCI: memory complaint; normal activities of daily living; normal general cognitive functioning; abnormal memory for age; not demented.

Diagnostically oriented scales such as the Short Portable Mental Status Questionnaire (SPMSQ), the Folstein Mini-Mental Status Examination (MMSE) or the Clinical Dementia Rating scale (CDR) usually identify cognitive impairment. The MMSE includes assessments of orientation, memory, attention and calculation, language, ability to follow commands, reading comprehension, ability to write a sentence and ability to copy a drawing. Education, occupation and cultural and background factors can strongly influence MMSE scores. The CDR was designed to characterize subjects from normal function through various stages of dementia. (The problem with this scale is that a rating of 0.5 may indicate either MCI or probable AD. See below for more information on this scale.) The scores on these questionnaires do not convey any information on the etiology of the diagnosis. They are used in conjunction with a psychosocial history that includes educational, occupational, social, cultural and medical history and neuropsychological assessments to determine the existence of dementia.

In general, presence of cognitive impairment is high in elderly population. A prospective cohort study, in the primary care setting, reported that 15.7% of the subjects demonstrated evidence of MCI on the Short Portable Mental Status Questionnaire (SPMSQ). The SPMSQ is a series of ten questions aimed at probing memory, computational ability and present orientation.

The research literature suggests that many patients with MCI progress to AD. While figures vary as to the number of individuals with MCI who go on to develop AD, the percentage frequently seen in the literature is up to 40% in three years with a diagnosis of Mild Cognitive Impairment. Thus, treatment of MCI is of great interest to clinicians in that it may prevent, delay or even reverse disease-associated brain deterioration. Interestingly, memory complaint, the most common symptom of individuals carrying a diagnosis of MCI, was not predictive of conversion to AD. Other specific symptoms, such as disorientation and the total number of symptoms were associated with subsequent conversion to AD.

The assumption of a relationship between Mild Cognitive Impairment and AD is based on physiological similarities. Many MCI patients present with significant medical temporal lobe atrophy, while others have high cerebrospinal fluid and/or low CSF-ß amyloid (Aß) 42 concentrations, factors that are associated with the senile plaques common to AD. There are also genetic similarities between the conditions. The strongest physiologic predictor of familial AD, for example, may be the presence of apolipoprotein E gene (ApoE), and the E4 allele is overrepresented in both AD and MCI patients. These characteristics, in combination with the fact that the onset of AD is insidious and has a course that is gradually progressive, suggest that neuropathologies exist many years before any symptoms occur. From this scientists deduce that in many cases MCI is an early sign of AD. This boundary line is becoming the focus of much research with stress on preventative techniques for the development of AD. According to Petersen, writing an editorial in Archives of Neurology (May 2000): "This research is predicated on the notion that distinction between the cognitive changes of aging and very early AD is well delineated". There are still a lot of questions about this in the professional literature. Some question the use of the various scales to measure Mild Cognitive Impairment, which are also used to measure AD. You would tend to get more of a sampling of "mild AD" subjects leading to the conclusion that Mild Cognitive Impairment disorder is a preclinical condition for AD. Nevertheless, The National Institute of Aging (NIA) is sponsoring a three-year study involving about 30 academic institutions and 40 clinical centers. It will include 720 individuals, aged 55 to 90, who have Mild Cognitive Impairment. These individuals will be divided into three groups: One group will receive high doses of Vitamin E, the second will receive a standard dose of Donepezil (Aricept) and the third will receive a placebo. The rational for the study stated in the NIH News Release of March 15, 1999 is "Accurate and early evaluation and treatment of MCI individuals might prevent further cognitive decline, including development of Alzheimer’s disease."

Because of the implied relationships, traditional treatment strategies for MCI thus far are based on those for AD. However, there is no treatment at this time for vulnerable genes such as ApoE. The FDA recommends acetylcholinesterase inhibitors (AChEI’s), that focus on cognitive symptomatology rather than the pathology of dementia as a treatment for AD and the treatment for MCI.

The full pathological process is not fully understood at this time. What follows is the result of much research in this area. It is not the full picture of the disease. The temporal lobe contains the hippocampus that plays significant role in learning and memory and contains a nucleus responsible for acetylcholine, a factor that has been highly correlated with intellectual impairment. AChEI may slow the enzyme lysis (rupture of the cell’s plasma membrane, leading to the release of cytoplasm and the death of the cell) of acetylcholine to help ameliorate the cognitive impairment brought on by the condition. Braak and Braak suggested that there are 6 histological stages in AD. The preclinical phase includes stages I and II and occurs in the transentorhinal cortex. MCI involves stages III and IV in the hippocampus and limbic cortex and fully developed AD stages V & VI occur in the isocortical areas. However, all groups, including healthy controls, demonstrate some atrophy in the hippocampus.

Monty de Leon and his group has demonstrated that dilation of the perihippocampal fissure can predict the diagnosis of AD with over 90% accuracy. He also showed that visual ratings of hippocampal atrophy indicated 70% of people with mild cognitive impairment were affected, rising to 96% in those with moderate or severe dementia compared to 29% in normal controls.

(See articles in our Alzheimer’s disease file on this web site especially part VI.)

While figures vary, the average conversion rate from MCI to AD is 12% per year. In contrast, the conversion rate to MCI or AD in healthy elderly control subjects is approximately 1-2% per year. In elderly subjects (60-64 years), from a community sample, the prevalence rate was 13.5% for a diagnosis of AAMI, but was 23.5% for aging-associated cognitive decline (AACD), a category related to AAMI, but differing in that it is manifested as gradual cognitive decline without dementia rather than nonprogressive cognitive impairment. Obtaining an "undiluted" sampling of any of these categories and would seem like a conjurers feat of magic. It would prove helpful if specific biologically markers existed that distinguished pure situations of each disorder.

Petersen et al, in a National Institute on Aging (NIA) funded study, characterize MCI as a condition of measurable memory loss without dementia that is abnormal for age and educational background. It is distinguished from age-associated memory impairment (AAMI), which consists of a mild decline in memory that is nonprogressive, some deterioration in learning, attention and concentration, thinking, use of language and is consistent with age-associated norms of cognitive performance. This type of decline in memory has also been called Benign Senescent Forgetfulness, Age-Consistent Memory Decline, Cognitive Decline (Age Related), Forgetfulness (Benign Senescent), Memory Decline (Age-Consistent), and Mild Neurocognitive Disorder. Risk factors for these impairments include advancing age, prior heart attack, heart failure and female gender.

Patients with MCI have been distinguished from healthy subjects on memory tests, such as delayed recall tasks of verbal and nonverbal stimuli. On these tests, patients with MCI performed similarly to those with AD; however, the AD patients were impaired on a variety of other cognitive measures. In contrast, patients with MCI demonstrated comparable performance to healthy subjects on global measures of cognitive function, including the Mini Mental State Exam and Dementia Rating Scale (DRS). Many of these studies will have to be duplicated in larger population samplings to be useful to the practitioner in their individual office.

DRS rate the severity of dementia as absent (0), questionable (0.5), mild (1), moderate (2), or severe (3). Typical patient with MCI would score 0.5. While AD patients may have the same score, they are more likely to be impaired in other areas of cognition, such as those measured by verbal intelligence quotient, performance intelligence quotient, MMSE and DRS and are functionally impaired.

The neuropathologic correlates of MCI are still not known. The memory deficit suggests that structures within the temporal lobe, specifically, the hippocampus, are prime suspects for involvement, due to their cognitive responsibilities such as learning and memory.

How important is this disorder of memory impairment to drug manufacturers? We would like to quote from a release issued by an investment organization on 10/17/00 and have our readers make their own conclusions. "…This freedom will allow them (the company) to participate in the accelerated development of a ‘proof of principle’ trial in MCI, mild cognitive impairment, an enormous market and one which blurs with the even more ubiquitous ‘age-related cognitive decline’, which we all experience from age forty on. Establishing consensual criteria for MCI disorder and its assessment opens the door for (omitted) to sidestep the traffic jam in the Alzheimer’s drug arena, one which continues to invoke contention as to etiology and optimal treatment strategies."

There is no question that cognitive dysfunction represents one of the greatest health problems affecting the elderly. We would urge researchers to be sure of their classification system before they proceed to open the gates to a treatment that may have questionable value as to the existence of that disorder. This could be a gold mine for all kinds of pharmaceutical/drug companies, but may not live up to the expectations of the user, and would raise hopes in one of the most vulnerable populations in our society.

The precise causes of cognitive disorders remain a mystery. A proper understanding of the disorder would be more effective in developing a treatment. There is no question that individuals are only interested in "what will make them better" and just want a quick cure. The treatments available today do not eliminate the cause. Memory loss is a persistent phenomenon during aging. Removing the symptoms may provide palliative care, but what is really needed is a cure for a totally disabling disorder of the elderly. The future will tell us if the answer is there.


Daly E., Zaitchik D., Copeland M., Schmahmann J., Gunther J., Albert M. Predicting conversion to Alzheimer’s disease using standardized clinical information. Archives of Neurology 2000; 57: 675-680.

Frisoni, G. B., Rozzini, R., Bianchetti, A., & Trabucchi M. Principal lifetime occupation and MMSE score in elderly persons. Journal of Gerontology: Social Sciences 1993; 48: S310-S314

Hanninen T., Hallikainen M., Koivisto K., Helkala EL., Reinkainen RJ, Soininen H., et al. A follow-up study of age-associated memory impairment: neuropsychological predictors of dementia. J Am Ger Soc 1995; 43: 1007-1015.

Morris JC. The clinical dementia rating (CDR); current version and scoring rules. Neurology 1993; 43:2412-2414.

Petersen RC., Smith GE., Waring SC., Ivnik RJ., Tangalos E., Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology 1999;56: 303-308.

Peterson RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characteristics and outcome. Arch Neurol 1998; 56:303-308.

Peterson, Ronald C. Mild Cognitive Impairment or Questionable Dementia? Archives of Neurology 2000; 57(4)

De Leon MJ., Ferris SH., Golomb J., Tarshish C., Convit A., et al Frequency of hippocampus atrophy in normal elderly and Alzheimer’s disease patients. Neurobiology of Aging. 1997; 18:1-11.

The following other sources of information are recommended:

Flicker C., Ferris SH., & Reisberg B. A longitudinal study of cognitive function in elderly persons with subjective memory complaints. Journal of the American Geriatrics Society. 1993; 41: 1029-1032

Drevets WC., & Rubin EH. Psychotic symptoms and the longitudinal course of senile dementia of the Alzheimer type. Biological Psychiatry 1989;25:39-48.

Collie A. & Maruff P. Neuropsychology of preclinical Alzheimer’s disease and mild cognitive impairment Neuroscience & Behavioral Review 2000;24:365-374. (Suggests that the biochemical changes that precede AD may be present up to 20 years before the disease manifests itself.)

Small GW. Differential diagnosis and early detection of dementia. American Journal of Geriatric Psychiatry 1998; 6(Suppl 1): 389-403. (Suggest that patients with mild cognitive impairment display a number of structural and functional imaging abnormalities.)

 See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients.
See: Alzheimer's Disease PartIV-Alternative Treatment.
See: Alzheimer's Disease Part V-Possible New Drugs for Alzheimer's Disease Treatment.
See: Alzheimer's Part VI -Early Diagnosis.
See: Alzheimer's Part VII -New Medication-Metrifonate
See:Alzheimer's Disease PartVIII - Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII-Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See: Alzheimer's Disease Part XV-Cerebrolysin
See: Alzheimer's Disease Part XVII-Summary
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease Part XXI-The Brain
See Dementia with Lewy Bodies- Part XXII-by Gourete Broderick
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV-Psychosis
See: Alzheimer's Disease-Part XXVI-Amyloid-beta Hypothesis Controversy
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD


Harold Rubin, MS, ABD, CRC, Guest Lecturer
updated June 14, 2009

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