Early Alzheimer's Disease

Impaired memory is typically one of the first signs of Alzheimer's
disease, but difficulty recalling the names of friends or recent events is also common among normal elderly persons. The clinician is thus faced
with the difficulty of distinguishing between normal aging and the early stages of Alzheimer's disease. Mild cognitive impairment is an
intermediate state in which persons have more memory problems than would be considered normal for their age, but their symptoms are not as severe as the symptoms of Alzheimer disease and they do not have functional impairment.


Alzheimer's disease develops at a much higher frequency
among persons with mild cognitive impairment than among those with
normal aging. Determining when patients have reached the very early stage of Alzheimer's disease is not easy, particularly because it is likely that a preclinical stage of Alzheimer's disease exists in which senile plaques, neuritic plaques, and neurofibrillary tangles occur in
sufficient numbers to meet standard neuropathological criteria for Alzheimer's disease in the absence of overt symptoms or signs of dementia. Other causes of memory impairment must also be considered, such as cerebrovascular disease, hydrocephalus, hypothyroidism, vitamin B12 deficiency, central nervous system infection, a cognitive disorder related to human immunodeficiency virus infection, adverse effects of
prescribed medications, substance abuse, and cancer.


A substantial decline in verbal memory and executive function (e.g., the ability to perform sequential tasks) typically occurs at the onset of
Alzheimer's disease but may be difficult to document without formal neuropsychological testing.

Reduced independence in daily
activities (often recognized by the patient's family) is one of the strongest predictors of disease.16 Functional status can be measured by the Clinical Dementia Rating (CDR) scale, which evaluates cognitive and
functional performance on a scale ranging from 0 to 3, with higher
scores indicating a greater severity of impairment. This assessment requires a collateral source of information gathering concerning the patient's ability to function independently but can be performed in the primary care setting and is particularly useful for clinicians who do
not have ready access to formal neuropsychological testing.

Formal neuropsychological testing that shows a substantial
decline in verbal memory and executive function supports the diagnosis of Alzheimer's disease1 but requires a trained professional for administration and interpretation.




Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and
the N-methyl-D-aspartate receptor antagonist memantine are the only
treatments for Alzheimer's disease that have been approved by the Food and Drug Administration. Randomized, placebo-controlled clinical trials of cholinesterase inhibitors have included patients with mainly mild-to-moderate Alzheimer's disease and have shown significant but clinically marginal benefits with respect to cognition, daily function, and behavior. The condition of patients who are taking
these drugs remains stable for a year or more and then may decline,
though at a rate that is slower than that among untreated patients.


Although there are few studies directly comparing the three
cholinesterase inhibitors, a systematic review and meta-analysis of data from 27 randomized trials concluded that there were no significant
differences in effects on cognitive performance among these medications.


During the study period (usually, 3 to 6 months), the use of each of
these drugs as prescribed at a standard dose resulted in a mean
improvement of 2 to 3 points on the Alzheimer's Disease Assessment Scale
for cognition (a scale ranging from 0 to 70, with higher scores
indicating better cognition) or a decreased rate of decline, as compared with the placebo group (approximately a 3-point difference, with a minimal clinically important difference of 4 points).


On the basis of 14 studies that measured daily function, donepezil was
modestly but significantly more effective than rivastigmine. Donepezil was likewise modestly but significantly better than rivastigmine and galantamine with regard to behavior, as measured by the Neuropsychiatric
Inventory (on a scale ranging from 1 to 144, with higher scores
indicating a greater severity of disease). Patients receiving donepezil had a mean reduction of 4.3 points in the baseline score, as compared with a reduction of 1.4 for those receiving the other agents. The likelihood of an overall improvement in score was 1.9 times as great with donepezil as with placebo, 1.2 times as great with rivastigmine as
with placebo, and 1.6 times as great with galantamine as with placebo. Adverse effects (including nausea, vomiting, diarrhea, dizziness, and
weight loss) were frequent with all three medications, although slightly less frequent with donepezil than with the other medications.



The author note provides the following contact info: Address reprint
requests to Dr. Mayeux at the Taub Institute for Research on Alzheimer's Disease and the Aging


New England Journal of Medicine (Volume 36Number 23, June 10),
by Richard Mayeux, M.D