Alzheimer Disease: Insights Into Advances in Diagnosis and Treatment

From Medscape Education Neurology & Neurosurgery

Samuel Gandy, MD, PhD

Alzheimer disease (AD) is an epidemic of brain failure affecting 5 million Americans, or about half of the population over the age of 85. Clinically, patients with AD exhibit progressive cognitive failure, including changes in personality, loss of the ability to form and retrieve new memories, and loss of the ability to navigate even the most familiar environments. Pathologically, AD is characterized by destruction of hippocampal and neocortical neurons, particularly those involving the cholinergic projections from the basal forebrain to the cerebral cortex.
The cause of the disease is well understood in only roughly 3% of cases, typically those with the rare, early-onset, familial forms of AD that can be attributed to genetic mutations.

The disease was first reported in 1907 by Bavarian psychiatrist Alois Alzheimer, who described a case that was atypical in many ways. The patient was 55 years old when symptoms of paranoia developed, and her young age may explain the long-held misconception that the disease begins in the presenilium. Until fairly recently, physicians were taught that AD was a rare disease that primarily affected people under the age of 65 years. However, the entity we call "common" or "sporadic" AD is the most common disease responsible for what has long been called "senility" in the elderly. Previously, dementia was believed to result from either vascular or degenerative processes. However, most patients with dementia have been found to have concurrent vascular and degenerative pathologies. Indeed, risk factors for stroke likewise increase the risk for AD.

The clinicopathologic syndrome, when complete, includes:

* an appropriate clinical syndrome (late life-onset amnesia, disorders of executive function [eg, organization, working memory], a psychiatric syndrome, or some combination of these);
* accumulation of abnormal proteinaceous structures; and
* neuronal and synaptic loss.

The molecular pathology of AD is defined by parenchymal and cerebrovascular amyloidosis resulting from an accumulation of amyloid-beta (A-beta), intraneuronal neurofibrillary tangles resulting from a buildup of altered tau protein, and acetylcholine deficiency. The cholinergic neurons that project diffusely from the basal forebrain to the cortex are among the earliest neurons to fail, and loss of acetylcholine content correlates well with the severity of the initial amnestic syndrome. Eventually, virtually all transmitter systems are involved to some degree and all cortical function is lost, leading to a persistent vegetative state.
Clinical Diagnosis of AD

Until very recently, the diagnosis of AD depended on careful clinical interview and mental status tests, with definitive diagnosis only available postmortem. Indeed, neuropsychological testing remains the most sensitive means of making an early clinical diagnosis. Formal testing by a neuropsychometrist is typical at research centers, but far more informal tools are used by most practitioners.

One of the most important distinctions in the diagnosis of AD is differentiating dementia and delirium (often related to metabolic dysfunction or toxic ingestion) or depressive pseudodementia. During the last decade, the concept of mild cognitive impairment (MCI) has become widely accepted. The operational definition of MCI involves demonstrable deficits in 1 domain (typically memory) or multiple cognitive domains, without a clinically important impact on the patient's function. Because patients are not functionally impaired, this level of cognitive impairment is not recognized by the US Food and Drug Administration (FDA) and no medications have been approved for use in patients with MCI. The amnestic form of MCI is the more typical harbinger of eventual progression to AD.[5]

Diagnosis begins by excluding treatable causes of cognitive dysfunction, including endocrine and metabolic disorders, vitamin deficiencies, and hydrocephalus, among others. Complete blood count, serum chemistries including liver and renal function tests, tests for syphilis, and tests of thyroid function have long been established tools in the physician's armamentarium. Computerized tomography and/or magnetic resonance imaging have become more widely used in the last decade, and CSF examination is frequently performed by neurologists, although this is by no means universal.
Biomarkers of Diagnosis and Progression

The emergence of CSF and neuroimaging biomarkers is rapidly changing the approach to dementia diagnosis. Among the most promising developments are the following:

* CSF A-beta 42 and tau levels[6,7]
o A-beta 42 levels typically fall and tau levels rise as disease progresses
o May predict which patients with amnestic MCI will progress to AD

* Fluorodeoxyglucose-positron emission tomography (FDG PET) for distinguishing frontotemporal dementia from AD[8]
o Approved by the Centers for Medicare and Medicaid Services under some circumstances

* Pittsburgh compound B (PiB) PET, AV-45, and/or radiotracer 18F-FDDNP PET for imaging the neuropathologic burden of A-beta plaques and neurofibrillary tangles during life[9,10]

Apolipoprotein E (APOE) genotyping is typically performed for clinical trials and other research studies in the setting of pregenetic and postgenetic counseling. Neither the National Institute on Aging nor the Alzheimer's Association favors routine APOE genotyping because the outcome of testing positive is uncertain.[11] A patient may have an APOE epsilon 4 allele and still escape dementia, and those who lack the APOE epsilon 4 alleles are still at risk for dementia.[12]
Treatment of AD

Currently, the primary benefit of early diagnosis of AD is that it enables the patient to organize his or her affairs and participate in the planning of his or her care. The hope is that research will eventually enable the presymptomatic diagnosis of the presence of AD pathology so that those who are diagnosed can begin disease-modifying treatments to prevent or significantly delay the clinical presentation. Without an effective disease-modifying intervention, this remains an unattained goal and something of a speculation. The growing consensus in this direction is part of the driving force behind the pressure for earlier diagnosis.

Several strategies can improve quality of life at this early stage and forestall other health-related complications or risk factors such as cardiovascular disease and diabetes. Although a diet rich in a variety of vitamins and minerals and low in saturated fats (eg, the Mediterranean diet) has not been shown conclusively to improve cognitive function, such a diet will improve health by addressing obesity, lowering blood pressure, and improving glycemic control. Moreover, physical and mental activities may also mitigate cognitive decline or at the least enhance quality of life.[13] Finally, early diagnosis enables patients and their families to establish supervision and a supportive environment to maximize independence and, thus, quality of life.

Once diagnosed, the most commonly prescribed medications for AD are the cholinesterase inhibitors donepezil, galantamine, and rivastigmine. All are approved for treatment of mild to moderate stages of AD, and donepezil is indicated for severe AD. These drugs have no direct neuroactivity but provide benefit by blocking the degradation of synaptic acetylcholine, thereby sustaining neurotransmission at the presynaptic cholinergic neuron. However, as neurodegeneration progresses and those neurons fail and die, benefit from the cholinesterase inhibitors wears off. Memantine, an N-methyl-D-aspartate receptor antagonist, is believed to reduce abnormal activity in the brain by blocking the glutamatergic N-methyl-D-aspartate receptor, thus protecting against excitotoxic destruction of cholinergic neurons. Memantine is associated with modest reductions in clinical deterioration in patients with moderate to severe AD. Combining acetylcholinesterase inhibitors and memantine has been shown to slow decline and improve behavior to a greater extent than monotherapy or no therapy.[14,15]

Although meta-analyses have shown that the use of cholinesterase inhibitors and memantine in patients with dementia has resulted in only marginal clinical improvements,[16] patients and their families and caregivers do appear to have experienced meaningful benefit from them, particularly regarding quality of life and resource utilization. Moreover, anecdotal reports have described dramatic improvements with cholinesterase inhibitors. A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians, "Current Pharmacologic Treatment of Dementia,"[17] recommends that the decision to use cholinesterase inhibitors and/or memantine should be based on individualized assessments, and that tolerability, adverse effect profile, ease of use, and cost of the medication should guide the choice of agent. Because side effects of these agents are relatively benign, many clinicians will choose to prescribe them, but they must be prepared to manage the expectations of patients and families who will eventually be faced with the reality of a permanently altered life. In July, 2010, the FDA approved high-dose (23 mg) donepezil for patients with moderate to severe AD who have been established on 10 mg for at least 3 months. This approval was based on a study[18] that showed some cognitive benefit from the high dose compared with the standard dose, particularly in patients with advanced disease.
Investigational Agents

Investigational therapies target several different pathways, such as inhibition or modulation of beta- and gamma-secretases involved in A-beta formation, prevention of A-beta aggregation, and through the use of immunotherapy. Strategies to target hyperphosphorylated tau are also under investigation.

The anti-amyloid aggregation agent tramiprosate and the gamma-secretase modulator tarenflurbil were examined in trials that included no central nervous system amyloid endpoint, thus preventing any conclusions about the amyloid hypothesis.[19,20] The immunotherapeutic bapineuzumab, when infused for approximately 80 weeks, lowered brain burden of PiB-positive amyloid by 25% but was associated with no cognitive benefit.[21] Questions remain regarding whether the duration was long enough, whether initiation was early enough, and/or whether brain levels of toxic A-beta oligomer were reduced.[22] A gamma-secretase inhibitor trial was terminated because of complications characterized as an increased rate of both cognitive decline and skin cancers, both apparently attributable to the gamma-secretase inhibitor.[23] Because of the failure and complications of this high visibility trial, gamma-secretase inhibitors are somewhat out of favor, and attention has turned toward gamma-secretase modulators, alpha-secretase activation, beta-secretase inhibitors, and amyloid immunotherapeutics.

Other novel targets include those that affect mitochondrial function, serotonin receptors, receptors for advanced glycation end products, and nerve growth factor, among other pathways. Many of these targeted agents are in phase 2 or 3 clinical development, bringing hope for further development.[24]
The A-Beta Oligomer Hypothesis of AD: Potential New Targets?

Decades of bench science are now providing insights that may result in new avenues of treatment. As mentioned, the neurodegenerative process in AD is characterized by the accumulation of interstitial A-beta plaques and cerebrovascular amyloid. A-beta 40 is the predominantly produced species; only a trace amount of A-beta 42 is produced, in a ratio of approximately 99 to 1. A-beta 42 spontaneously aggregates, making this peptide more likely to form small "n" aggregates (known collectively as oligomers or A-beta-derived diffusible ligands).[25]

A popular current concept regarding the pathogenesis of cognitive failure in AD is that A-beta oligomers are especially neurotoxic. This formulation contrasts with the traditional concept that the key toxins are the highly structured A-beta fibrils that comprise amyloid plaques. Further, the current formulation is that the oligomer pathway and the amyloid fibril pathway are separate and distinct. The advent of amyloid imaging with PiB has confirmed neuropathologic reports that many healthy adults accumulate numerous A-beta deposits with few signs of contemporaneous dementia.[9]

The amyloid precursor protein (APP) is a transmembrane protein that contains 3 sites for cleavage by proteinases, designated alpha, beta, and gamma secretases. The alpha-secretase pathway is nonamyloidogenic. The most compelling line of evidence linking A-beta to AD is genetic, because rare mutations in either APP or gamma-secretase can cause hereditary forms of AD that are clinically and pathologically indistinguishable from the more common, so-called sporadic form of the disease. These mutations apparently exert their actions by modulating APP processing. Some mutations cause quantitative or qualitative changes in the cleavages that generate A-beta. Other mutations are localized within the A-beta sequence of APP and cause generation of A-beta peptides that bear enhanced inherent predisposition toward oligomerization.[25]

Several approaches have converged to implicate soluble oligomeric A-beta in AD. One such approach has employed a well-known electrophysiologic correlate to learning and memory known as hippocampal long-term potentiation (LTP). Several studies have shown that hippocampal LTP can be inhibited by both synthetic and naturally secreted human A-beta oligomers. Some investigators have reported that the oligomeric A-beta levels needed to disrupt LTP correlate well with the amounts observed in cerebrospinal fluid in patients with AD. Furthermore, the effects of A-beta oligomers on LTP can be reduced through application of anti-A-beta antibodies in vivo.[26-29] New mouse models have shown that A-beta oligomers are sufficient to cause behavioral deficits, even in the absence of amyloid plaques.[30]

Defining the importance of A-beta oligomers is critical because oligomers cannot be visualized by PiB PET scans. In addition, there is some surprising evidence from laboratory mouse models that converting oligomers to fibrils and plaques might even be beneficial.[31] Obviously, oligomer research is still in its early days, but if fibrils and plaques prove to be inert or even beneficial, the goals of much amyloid research would be upended.
Conclusion

The future of AD diagnosis and management appears significantly brighter than the past. Nonetheless, early recognition and lifestyle interventions including healthier diet and exercise regimens, creation of a supportive environment, and medications including cholinesterase inhibitors and memantine can enhance quality of life. Investigational agents may improve outcomes by providing interventions at multiple pathophysiologic pathways. The seeds of basic science are bearing fruit and may provide new therapeutic targets through novel insights into the neural mechanisms underlying this fascinating, devastating disease.

Supported by an independent educational grant from Forest.