Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because its incidence and prevalence increase with age, more and more people are expected to be affected by this common condition with the increasing longevity of populations and the large cohort of baby boomers coming to maturity. Fortunately there has been a rapid increase in understanding of the clinical presentation, natural history, and pathophysiology of AD. Furthermore, there are encouraging results in symptomatic therapy and there is hope for long-term stabilization and preventive treatment.

Clinical presentation

In 1982 Professor Barry Reisberg proposed a Global Deterioration Scale that summarizes seven steps in the progression of AD and serves as an excellent means to describe its natural history (see Table 1).

The symptoms of AD are thus a combination of progressive decline in intellectual abilities and functional autonomy, very often with psychiatric features such as anxiety and depression (mostly in stages 3 and 4), followed by delusions, hallucinations, and wandering (mostly in stages 5 and 6). The latter symptoms cause a severe burden for the families and lead to nursing home placement in most countries. In the final stage of AD (stage 7), there are changes in motor tone and walking ability similar to those in Parkinson's disease. Death occurs within six to eight years after diagnosis, usually from pneumonia.

There is currently a great interest in the very early symptoms of AD, since early treatment with agents that modify the disease process can significantly delay progression from normal (stage 1) to minimal symptoms (stages 2 and 3), or from minimal symptoms to diagnosable AD (stage 4 and beyond). It appears that late onset depression with loss of interest, energy, or concentration; a long postoperative delirium; or subjective memory complaints with changes in abilities to handle finances, medication, phone, or transportation suggests the possibility of incipient AD.

Diagnosis

Most commonly family members initiate the diagnostic process by bringing the affected person to the attention of the family doctor. The progressive loss of memory for current or recent events is highlighted, with examples of missed appointments, bills paid late, and repeating stories on the phone. A decreased initiative and planning ability is often quite striking, with reduced participation in conversation. The diagnosis of AD is done primarily by a structured history with the patient and a knowledgeable informant. In addition to memory decline, the diagnosis of dementia requires a change in one other intellectual domain (such as language, recognizing objects and people, using tools, planning and adjusting to circumstances) that interferes with daily life and represents a decline from a previous level of functioning. The typical progression of AD as described in the previous section and a normal neurologic examination strongly support the diagnosis of probable AD (90 percent probability if a microscopic examination of the brain is made from a biopsy or autopsy, in which case the diagnosis can be definite). Other features can be found through history and physical examination that suggest alternative diagnosis: history of strokes or high blood pressure with asymmetric reflexes (vascular dementia or mixed AD and vascular dementia), visual hallucinations and gait instability early in the course (dementia with Lewy bodies), social disinhibition and loss of speech early in the course (fronto-temporal dementia). A concomitant disorder, such as depression, malnutrition, or hypothyroidism, would change the diagnosis of AD to "possible."

A mental status assessment is required when AD is suspected, and can range from the simple but short and reliable Mini Mental State Examination of Martial, Folstein, et al. to a structured and complete neuropsychological examination performed by a psychometrician. This may be required in highly educated individuals suspected of early stage AD, for whom the diagnosis is of some urgency because of occupational or social responsibility. Most often these tests need to be repeated within six to twelve months in order to conclusively demonstrate a decline in two cognitive domains.

The laboratory assessment of AD is currently done to support the clinical impression based on a careful history and physical examination. A minimum workup includes blood count of red and white cells; markers of thyroid, liver, and renal function; and blood sugar levels. In some countries routine additional tests include markers of nutritional deficiencies (B12, folic acid) and of previous infection with syphilis. Brain imaging using computer tomography or magnetic resonance imaging without infusion is most often performed in order to demonstrate brain atrophy and rule out tumors, blood clots, and strokes large or small. It is unusual for a brain scan to change the clinical diagnosis or management.

A number of putative biological markers of AD are under study as adjuncts to the clinical diagnosis. The best known are the blood apolipoprotein E genotype and spinal fluid levels of beta-amyloid fragments and tau. None of these markers has the specificity and sensitivity required for routine use, but this research is important for the day when individuals at risk of AD who are in presymptomatic stages will seek advice for preventive therapy.

Pathophysiology

The core pathology of AD was described by Alois Alzheimer early in 1907: extracellular senile or neuritic plaques made up of an amyloid core, surrounded by cell debris, and intracellular neurofibrillary tangles. More recently Robert Terry has emphasized the importance of neuronal cell loss, and Patrick McGeer has documented a strikingly enhanced cellular immune response in the brain of persons with AD. Peter Whitehouse has demonstrated a relatively selective loss of cholinergic neurons in basal forebrain structures, particularly the nucleus basalis of Meynert. This observation, coupled with the reduction in levels of the acetylcholinesynthesizing enzyme choline acetyltransferase, suggested a neurotransmitter deficiency amenable to pharmacotherapy, similar to dopamine deficiency in Parkinson's disease.

Genetic factors clearly play a major role in AD. Presenilin genes carried on chromosomes 1 and 14, and genes on chromosome 21 modifying beta-amyloid metabolism, cause AD at relatively young ages in a Mendelian dominant pattern. Other genes, such as apolipoprotein E on chromosome 19, increase the risk of AD but do not cause it. Many other genes related to late-onset AD (the most common type) remain to be identified.

Acquired factors over a lifetime can positively or negatively modify the genetic risks. Epidemiological studies have confirmed and found risk factors (see Table 2) and protective factors for AD (see Table 3). Caution should be exerted, since the relative importance of such factors varies between studies. For instance, smoking was considered alternatively a risk and a protective factor; it is now considered neutral as far as AD (but a major risk factor for many other health conditions). High aluminum water content and closed head trauma have been considered risk factors, but the current consensus is that this is not the case. There is currently uncertainty as to the preventive value of hormone replacement therapy (HRT) in postmenopausal women.

Some of these factors clearly make biological sense: systolic hypertension increases the risk of strokes, an additional burden to the aging brain with plaques and tangles; apolipoprotein E4 carriers have a reduced ability to maintain synaptic plasticity (or repair) abilities; NSAIDs suppress the chronic brain inflammatory response associated with neuronal loss; higher education increases the density of synaptic connections; red wine contains a natural antioxidant. Some of these factors interact: higher education and longer HRT (if confirmed to be of value in ongoing randomized studies) will lead to a reduction in the risk of AD associated with female gender. It is hypothesized that a careful weighing of these risk and protective factors for individuals could lead to a preventive strategy in which advice would be proportional to the risk. For example, a person carrying a double apolipoprotein E4 mutation (from both parents) and a positive family history of AD may want to take NSAIDs chronically. Other risk factors can be modified for all individuals, such as systolic hypertension. This strategy needs to be validated in prospective studies but offers hope of delaying onset of symptoms of AD by five to ten years for the population as a whole, thus significantly reducing the prevalence of AD within one generation.

Treatments

The global management of AD includes a number of steps (see Table 4). In most countries the family practitioner handles them all, in consultation with a variety of health professionals and other community resources throughout the course of AD. For instance, an atypical presentation or pattern of progression may suggest a diagnosis of dementia other than AD, and an expert diagnostic opinion may be needed. Depression or cognitive or behavioral symptoms unresponsive to standard pharmacotherapy may require a trial of another class of drug, with input from experienced clinicians.

Many patients in early stages of AD require treatment with an antidepressant, preferably of the selective serotonin reuptake inhibitor class, for six to twelve months. Most will want to try a cholinesterase inhibitor (CI) in an attempt to increase brain acetylcholine levels and improve symptoms. Randomized clinical trials and clinical experience have shown that in mild to moderately severe stages of AD (stages 3 to 6), therapeutic doses of CI cause an initial improvement, variable between individuals. After nine to twelve months the improvement above the starting point is followed by a slower decline in cognition and functional autonomy relative to patients not on CI, for periods lasting up to three years. It is likely but not yet fully established that CI delays the emergence of neuropsychiatric symptoms seen in stages 5 and 6. There has been some disappointment at the modest size of improvement, the relatively short duration of benefit, and the lack of predictability of who will improve. A more realistic expectation is a delay in progression of symptoms until drugs (currently in various phases of experimental testing) acting on the pathophysiology of AD are proven safe and effective, leading to a combination of symptomatic and stabilization therapy.

A number of possible treatments to delay progression of AD, based on data generated from large-scale epidemiological studies, human brain banks, and the transgenic animal models of AD (see Table 6), are available for evaluation. Largescale randomized studies are required to test these, some as long as five years, depending on the therapeutic target (for instance, delaying emergence of cognitive symptoms in healthy elderly persons, or conversion from mild cognitive impairment to diagnosable AD).

Conclusion

Although the human and societal cost of AD is staggering, there is hope that earlier and better diagnosis, increased knowledge of its natural history with support of the patient and family throughout the disease stages, effective symptomatic drugs, and potentially effective disease modification strategies will have a dramatic impact on the number of persons affected in the future, and the quality of life of persons currently affected. The fast pace of research and development in AD is unique in neurological history, and should lead to a better future for aging populations.