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Alzheimer's Disease and Related Dementias

Alzheimer's disease affects 4 million people in the United States, and by the year 2000, it is estimated that 7 million people will be afflicted. The financial burden will be staggering; 50100 billion dollars per year.

Prevalence of Alzheimer's Disease

In most of Europe, and the US, AD is twice as common as vascular dementia while in Japan and China, vascular dementia is twice as common as AD. In a review of all medical records in Rochester Minnesota from 1965 through 1974 AD was the most common cause, accounting for 64.7%. There were an additional 6.8% with AD and another contributing process. Vascular disease was the second most common diagnosis accounting for 9.4%. In most series, AD accounts for approximately 50 to 80% of the cases of dementia.

Studies of prevalence of AD worldwide often do not distinguish between Alzheimer's disease and dementia, and give figures just for dementia. Jorm et al reviewed 47 prevalence studies.

The incidence, the number of new cases among a disease free population, also rises steadily with age. In European studies, in people over 65, the incidence of moderate to severe dementia is about 1,000 per 100,000 person-years. About 600 are attributed to AD and 200 to vascular disease.

Definition of dementia

Dementia is defined as a loss of intellectual abilities which is severe enough to interfere with occupational or social functioning. The two most widely used criteria for the diagnosis of dementia are the DSM-IV, and the NINCDS-ADRDA criteria formulated in 1984 which divides AD into definite, probable, and possible. Definite AD is reserved for biopsy or autopsy proven cases. Probable AD would include patients between 40 and 90 with a progressive worsening of memory and at least one other cognitive function, documented by neuropsychological tests.

Diagnosis of Alzheimer's Disease


It is important to obtain history from both the patient and an informant whenever possible. The onset of the illness, though insidious may be pinpointed by targeted questions about function (ie. ability to do chores, handle finances, drive, bathe, dress and groom). The tempo of cognitive decline is extremely important. If the process is acute, infection, metabolic disorder, stroke or vasculitis may be more likely. If subacute, an expanding mass lesion, hydrocephalus or Creutzfeld Jakob disease (CJD) should be considered. A careful family history, with attention to both

Neurological Examination

Cranial nerve exam is normal. Focality (ie, hemiparesis, hemisensory loss, or visual field cut) may suggest other diagnoses such as stroke or mass lesion. Extrapyramidal signs, specifically rigidity may occur in 15% of mild to moderately impaired patients and increases with progression. Paratonia and primitive reflexes are common. Myoclonus is unusual, and if it occurs early in

Laboratory Evaluation

Because up to 13% of cases of dementia may be reversible (metabolic causes, medications, depression), laboratory tests recommended by the Quality Standards Committee of the American Academy of Neurology include: UA, CBC, ESR, electrolytes, BUN, Creatinine, LFTs, calcium, TFTs, B12, RPR, and HIV (if indicated).

The yield from lumbar puncture is low, but should be done in an elderly patient if the condition is rapidly progressive, if there is cancer, CNS infection, hydrocephalus, CNS vasculitis (or if there is collagen vascular disease) or if there is a positive RPR. No specific guidelines are available for younger patients.

Several groups have shown that CSF levels of the microtubule-associated protein tau, the primary constituent of neurofibrillary tangles are increased and AI342, a major component of the amyloid plaque is decreased in CSF of patients with AD compared with nondemented patients. It has been suggested that the combination of these two biomarkers may be helpful in patients whom the diagnosis of AD is suspected but clinical examination is not certain or in early cases of dementia (7)

Pathology of Alzheimer's disease

Grossly, AD is characterized by cortical atrophy which may be prominent in the frontal, parietal and temporal lobes. Microscopically, there is loss of both neurons and neuropil in the cortex. The most characteristic findings are senile plaques and neurofibrillary tangles. Plaques are found throughout the cortex and hippocampus. Neuritic plaques are composed of a core of extracellular amyloid surrounded by enlarged axonal endings (neurites). The major protein is amyloid Beta-A4 peptide, derived from the amyloid precursor protein which maps to chromosome. Neurofibrillary tangles are not unique to AD but are seen first in the hippocampus. They are composed of paired helical filaments containing the microtubule protein, tau.

Risk Factors for Alzheimer's Disease

A number of other risk factors for Alzheimer's disease have been suggested. They include family history of dementia in a first-degree relative, family history of Down's syndrome in a first-degree relative, head injury with loss of consciousness, history of depression, and history of hypothyroidism.

Genetic Risk Factors for Alzheimer's Disease

Other than age, family history of AD in a first-degree relative has been the only other risk factor consistently associated with AD. The lifetime risk of AD in relatives of affected probands has been estimated at 25-40% compared to 10% or less in relatives of unaffected controls. Recurrence risks may be as high as 40% for siblings of index cases with early onset (<60 years) AD. Additional evidence for a genetic component for AD includes the association of AD and trisomy 21; almost all people with Down's syndrome develop AD neuropathology by age 40. The concordance rate among monozygotic twins is higher than in dizygotic twins, although not 100%.

Information on the genetics of Alzheimer's disease is exploding. Four genes have now been associated with AD (10-11). Mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PS1) gene on chromosome 14, and the presenilin 2 (PS2) gene on chromosome I cause rare (<5% of all AD) autosomal-dominant forms of early onset familial AD. The fourth gene, specifically the E4 allele of the apolipoprotein E gene on chromosome 19 has been found to be a risk factorfor both late-onset familial and sporadic AD, as well as early-onset sporadic AD.

In August 1995, the gene on chromosome 14 responsible for a number of early-onset autosomal dominant cases of AD was identified and originally named S182. It has now been renamed presenilin 1 (PS1). More than 25 mutations have been identified in 30 families. Mutations in presenilin 1 are associated with the earliest onset AD (35-55 years) of the 3 causative early-onset AD genes. The course is characterized by progressive aphasia and myoclonus which appear early in the disease and a high frequency of generalized seizures and extrapyramidal signs.

In August 1995, the gene for the Volga German form of AD (8 pedigrees in which there is a founder effect) was identified on chromosome I and named STM-2(seven Transmembrane domain). This gene which has now been renamed presenilin 2 (PS-2) shows remarkable similarities to S182. Both involve point mutations and S182 may cause an increase in the production of beta amyloid. There is a much wider age of onset in this form of familial AD and the mean age of onset is in the mid 50s. To date, only 2 distinct families have been identified. PS-1 mutations account for the vast majority of early-onset familial AD mutations; APP mutations and PS-2 mutations are much less common

Although they account for very few cases of AD, if the mechanism by which these genes cause the formation of plaques and tangles is elucidated, they may lead to new treatment strategies for all people afflicted with AD.

Apolipoprotein E

Apolipoprotein E (ApoE) is by far the most influential gene, in that it accounts for anywhere between 50 and 90% of the genetic causes of AD, and to date it is the only identified gene associated with late-onset AD (over the age of 60). Over 90 studies worldwide have shown an association between AD and the ApoE4 allele

Apolipoprotein E is a cholesterol transporting protein that is a major constituent of VLDL. There are three ApoE alleles, ApoE2, ApoE3 and ApoE4, yielding 6 possible genotypes. ApoE3/3 is the most common accounting for about 65% of Caucasians and ApoE4/E4 accounts for 2 to 3 % of the population. The allelic frequency of E4 has been reported to be as high as 40% of AD patients compared to 15% of controls. ApoE4 binds avidly to the amyloid in senile plaques

Both AD risk and age of onset appear to be dose dependent. In fact, the increased risk associated with E4 homozygosity (ORs 7.0-19.3) compared to E3/E3 or having one E4 allele compared to E3/E3 (ORs 2.8-4.4) may be explained in part by the earlier age of onset observed with increasing "dose" of E4. It is unclear whether having E4 puts one at increased risk for the development of AD because it renders the amyloid insoluble or leads to an in increase in amyloid production or whether having E2 or E3 binds tau protein better than E4 and prevents tau phosphorylation and the prevention of the formation of neurofibrillary tangles

Environmental Risk Factors for Alzheimer's Disease

Low education and head injury have been garnering a great deal of attention as risk factors for AD. Education may represent a number of other factors. It may be important prenatally or perinatally in terms of access to medical care and nutrition. In later life education may be an important confounder in the occupation one chooses, and the recreational activities and lifestyle choices one chooses. Conversely, those with higher education may be protected by environmental stimulation.

Katzman has described a reserve hypothesis- does education provide a cognitive reserve, or conversely does lack of education promote earlier onset of symptoms, constituting a true risk factor. The other theory is that low education would enable the clinician to diagnose the condition at an earlier point in time and thereby hasten diagnosis, but not be a true risk factor.


Treatment for AD has been directed at trying to improve memory or addressing the behavioral manifestations of AD which include psychosis, agitation, and sleep disturbance. The mainstay of symptomatic treatment have been the cholinesterase inhibitors.

Cholinesterase Inhibitors

Biochemically, the most consistent change is a 50-90% reduction in the activity of choline acetyl-transferase, integral for the formation of acetylcholine. Strategies to increase Ach have included precursor loading, or cholinesterase inhibition. Tacrine, a cholinesterase inhibitor is the first agent specifically for the memory impairment in AD, approved by the FDA. A 30 week, double-blind treatment with a maximum dose of 160 mg per day showed statistically significant improvement in objective neuropsychological test scores and clinical impression, but 265 of 479 tacrine treated patients withdrew early, the majority because of ALT elevations. A second cholinesterase inhibitor Donepezil, marketed under the name Aricept, was approved for use in AD in November 2006. In 15 and 24 week, randomized double-blind studies of Donepezil ( 5 or 10 mg) versus placebo, Donepezil produced significant improvement in cognitive and clinical global assessments. This medication is given once per day and does not appear to cause significant adverse events. Cholinergic side effects (diarrhea, nausea, vomiting) were reported more often in 

Metrifonate is an anti-helminth whose metabolite dichlorvos is an irreversible anticholinesterase. Metrifonate appears to be well tolerated in doses ranging form 30-60 mg and has a benefit over placebo on cognitive testing and side effect profile similar to Aricept. The only difference in side effect profile is a higher frequency of leg cramps of unknown etiology in metrifonate treated

Another drug currently under review is rivastigmine, which has been evaluated in a 26 week placebo-controlled parallel group trial of 699 patients with AD on either low 3.5 or high does 9.7 mg rivastigmine or placebo. There was a small but significant treatment effect but many does related side effects resulting in 35% of the high does group withdrawing from adverse effects compared to 15% of the low dose group and 17% on placebo.

Neuroprotective/Oxidative Stress (Slowing progression)

A number of agents that reduce oxidative stress by either reducing the rate of free radical generation (selegiline) or increasing antioxidant capacity (Vitamin E) have been studied in AD. A large multi-center trial of selegiline and vitamin E has been completed. This trial was a 2 year double blind placebo controlled study in patients with moderately severe AD. The primary outcome was the time to reach any of 4 outcomes: death, institutionalization, loss of basic activities of daily living or severe dementia. Results showed that either selegiline (5 mg. BID) or Vitamin E (1000