Alzheimer disease has become a major public health problem as human life span has been extended by modern medicine. It is the most common cause of dementia and is characterized by a gradual decline in memory and other cognitive functions over a period of years. The disease processes in the brain begin about 15 years prior to the appearance of symptoms, which are generally noticed later in life. Among individuals older than 65 years of age, 6% to 8% have Alzheimer disease; among persons aged 85 and older, the prevalence of Alzheimer disease is approximately 50%. Rare monogenic forms of the disease can begin in midlife.
Among the earliest symptoms of Alzheimer disease are memory impairment and problems with executive function (problem solving). As Alzheimer disease advances, the ability to learn new information is increasingly compromised. Access to distant memories, which is relatively intact in the initial stages of the disease, begins to diminish. As cognitive impairment progresses, patients may become lost while walking or driving, and become increasingly unable to perform tasks such as preparing meals, taking regular medications, or managing finances. As cognition declines, patients may experience depression and irritability and later delusions and hallucinations. Patients also may become aggressive, even toward their caretakers. The end stage of Alzheimer disease is generally characterized by a complete loss of independence. The disease exacts an enormous toll from not only affected individuals but also the friends and family members who care for them and society at large.
As the number and percentage of elderly persons increase steadily, the prevalence of Alzheimer disease almost certainly will rise. It is estimated that by the year 2040, there will be 11 million people in the United States and 80 million people worldwide with Alzheimer disease. Thus, there is an enormous need to develop effective medications to slow or halt the disease process.
Even cursory inspection reveals that the brain of a patient with mid- to late-stage Alzheimer disease is noticeably different from that of a normal person of the same age. The diseased brain appears shrunken compared with the normal brain, and has wider sulci, larger ventricles, and less overall mass. However, the pathologic hallmarks of Alzheimer disease and clues as to its etiology can be observed only at the microscopic level. In addition to loss of neurons and synapses, these hallmarks include the presence of various abnormal protein deposits. Senile plaques are dense, extracellular deposits that are composed primarily of the 38- to 43-amino-acid amyloid-β peptide (Aβ), the biochemistry of which is discussed later in this chapter. Two types of senile plaques—diffuse plaques and neuritic plaques—have been identified. Diffuse plaques are extracellular deposits of Aβ in which the Aβ peptide is aggregated but is not present in a β-sheet conformation. Neuritic plaques also consist of extracellular masses of Aβ, but are distinguished from diffuse plaques by the presence of Aβ in a β-sheet conformation as well as the presence of dystrophic dendrites and activated astrocytes and microglia. Intracellular accumulations of abnormally phosphorylated helical filaments in the form of neurofibrillary tangles and neuropil threads also are hallmarks of Alzheimer disease. The major constituent of the tangles is the microtubule-associated protein tau, a protein present in normal brain tissue that is both abnormally phosphorylated and aggregated in Alzheimer disease.
For reasons that currently are not entirely clear, tangle formation and neuron loss tend to develop preferentially in the hippocampus and medial temporal neocortex, and plaques form first in the frontal, parietal, and other association cortices. The distribution of plaques may be related to the relative amount of neuronal and synaptic activity that occurs over a lifetime. This is supported by data showing that Aβ levels are regulated by synaptic activity and that the highest levels of Aβ and subsequent amyloid plaque development occur in brain regions with the highest levels of neuronal activity such as in a cortical circuit known as the default mode network. Cholinergic nuclei such as the nucleus basalis (Chapter 6) are highly impaired while primary sensory cortices and subcortical brain regions tend to be spared. This pattern correlates with early onset memory impairment (declarative memory is dependent on the medial temporal lobe) and progressive cognitive decline (Chapter 14).
The significance of the defining pathologic features of Alzheimer disease has been the topic of intense research. Among the most important questions that investigators have attempted to answer are those related to causality. Are plaques and tangles toxic to neurons? Or are they coping mechanisms that the cell uses to detoxify other, more toxic forms of Aβ and tau? While answers to these questions are still unclear, there is increasing evidence that small, soluble oligomers of Aβ (ranging from dimers to dodecamers and larger species) are particularly pathogenic and may be a major instigator of Alzheimer disease, whereas tau aggregation and its spread to different regions of the brain may be critical in the progression of cognitive loss.
Two primary risk factors for Alzheimer disease have long been recognized: advanced age and genetics. Common forms of Alzheimer disease begin later in life and appear to be genetically complex. There are, however, inherited forms in which symptoms appear in middle age and follow autosomal dominant inheritance patterns. More than 100 different mutations in three known genes (amyloid precursor protein [APP], presenilin-1, and presenilin-2) can each cause early onset, familial Alzheimer disease, with some differences in age of onset and rate of progression.
In late-onset forms, the disease does not occur in a Mendelian inheritance pattern. Nonetheless, family studies have revealed that between 25% and 50% of relatives of patients with Alzheimer disease eventually are afflicted with the disease themselves, compared with approximately 10% among control groups. The apolipoprotein E (APOE) gene is the most important known genetic factor that modifies the risk for Alzheimer disease and the age at which the disease emerges. The APOE4 allele increases risk, whereas the APOE2 allele decreases risk, relative to the APOE3 allele. Numerous other genes identified in genome-wide investigations appear to modify the risk for Alzheimer disease, although none yet have been shown to exert as large an effect as APOE. Environmental factors such as sleep and exercise are probably also important in determining whether or not an individual will develop the disease.
The first major genetic advance in the study of Alzheimer disease occurred with the discovery of a linkage in some families with the region of chromosome 21 that codes for APP, whose products include Aβ peptides. Duplication of the APP locus, which increases APP gene dose, also causes early onset Alzheimer disease. Further evidence consistent with a role for APP in Alzheimer disease is that patients with Down syndrome (trisomy 21) and thus an extra copy of the APP gene develop amyloid plaques by their 30s and become demented with a mean age of ~50.
The cellular functions of APP and its metabolites in healthy individuals are unknown, but may include regulating synaptic pruning, gene expression, and neuronal growth. APP is a transmembrane protein that is expressed in many tissues, including the brain 18–4. Several different mutations of the APP gene lead to early onset Alzheimer disease 18–5. The biochemical effects of these mutations on APP processing have been studied extensively. One of these mutations, the Swedish mutation adjacent to the β-secretase site in APP, leads to increased production of all Aβ species. As Aβ aggregation is a concentration-dependent process, this likely drives earlier onset of Aβ aggregation. More common mutations in APP just distal to the N-terminus of the Aβ sequence lead to an increase in relative production of Aβ42 to Aβ40. Aβ42 is longer, more hydrophobic, and more likely to aggregate than Aβ40. Another group of mutations changes the sequence of Aβ and its aggregation properties. The mutations cause Alzheimer disease or cerebral amyloid angiopathy, a condition in which amyloid deposition in blood vessel walls leads to frequent intracerebral hemorrhages and strokes. Together with the known neurotoxic effects of Aβ, these genetic observations have led to the “amyloid hypothesis” that Alzheimer disease is caused by excessive accumulation of Aβ, particularly Aβ42, which ultimately leads to neural damage.
Diagram of APP and the production of Aβ. The APP ectodomain is shed by β-secretase cleavage. The multiprotein γ-secretase complex then cleaves APP to generate Aβ40, Aβ42, or other Aβ species. The γ-secretase complex consists of presenilin, presenilin enhancer-2 (Pen-2), nicastrin, and anterior pharynx defective-1 (Aph-1, named for its role in Notch signaling). α-Secretase cleavage prevents formation of Aβ. (Reproduced with permission from Roberson ED, Mucke L. 100 years and counting: prospects for defeating Alzheimer’s disease. Science. 2006;314(5800):781–784.)
Genetic mutations and processing of amyloid precursor protein (APP). A. Diagram of the Aβ portion of human APP (hAPP) shows sites of genetic mutations and sites of cleavage by β-, α-, and γ-secretases. B. Initial steps in the cascade leading from APP to Aβ. (Adapted with permission from Hardy J. Amyloid, the presenilins, and Alzheimer disease. Trends Neurosci. 1997;20(4):154–159.)
How does Aβ42 harm neurons? Aggregation seems to be a key step. Aβ can aggregate into small oligomers that remain soluble, and also into large, insoluble filaments that form plaques. Aβ oligomers and plaques appear to be in some equilibrium. Both types of Aβ aggregates are toxic to neurons. Amyloid plaques are associated with damage to nearby neurites, potentially interfering with proper signaling. Aβ oligomers appear to be even more toxic, and data from animal models indicate that they can disrupt learning and memory. Aβ oligomers, for example, block long-term potentiation and other forms of synaptic plasticity. Aβ binds to many different cellular proteins, and it is not yet known which is the primary effector of its toxic effects. Other factors may also contribute to Aβ-induced neuronal injury. Microglial activation and inflammatory responses help clear Aβ aggregates, but release of cytokines and other mediators may disrupt normal neuronal function (Chapter 12). Aβ-initiated neurotoxic and inflammatory processes may in addition cause the generation of free radicals, which are also damaging to neurons, as outlined earlier in this chapter.
Shortly after mutations in APP were linked to the inheritance of early onset Alzheimer disease, germline mutations in two other genes, presenilin 1 (PSEN1) and presenilin 2 (PSEN2), were also found to cause Alzheimer disease. Mutations in PSEN1 account for the majority of autosomal dominant cases of early onset Alzheimer disease. PSEN1 and PSEN2 are integral membrane proteins that are widely expressed and have multiple functions.
Presenilin is the catalytically active component of the γ-secretase complex, which is formed along with other proteins including nicastrin, Aph-1, and Pen-2 (see 18–4). γ-Secretase mediates intramembranous proteolytic cleavage of type I membrane proteins with small ectodomains. One substrate is APP, after its ectodomain has been shed by β-secretase; γ-secretase cleavage of this APP carboxy-terminal fragment yields Aβ. Mutations in PSEN1 seem to increase its tendency to generate Aβ42, relative to Aβ40. In this way, the resulting increased production of more aggregation-prone Aβ42 is similar to the effect of APP mutations near the γ-secretase cleavage site. This effect is believed to be a major mechanism through which presenilin mutations cause Alzheimer disease. Thus, inhibiting γ-secretase has until recently been a leading therapeutic strategy for Alzheimer disease. However, the situation is complicated by several factors, including the fact that γ-secretase also cleaves many other proteins besides APP, including notch (see below). As well, some experts question whether increased production of Aβ42 is the predominant mechanism by which presenilin mutations cause early onset Alzheimer disease.
Apolipoprotein E (ApoE) is a 34-kDa protein that plays an important role in cholesterol transport, uptake, and redistribution in blood. The three common alleles of APOE (ε2, ε3, and ε4) are inherited in a codominant fashion and, as noted above, contribute importantly to the risk for Alzheimer disease 18–6. The inheritance of one copy of the ε4 allele increases risk of disease by ~4-fold and two copies by ~12-fold relative to the ε3 allele. One copy of the ε2 allele decreases risk by ~0.6-fold relative to the ε3 allele. Thus, APOE genotype is the strongest known risk factor for common forms of Alzheimer disease. How might a lipoprotein have such a profound influence on the risk of developing Alzheimer disease? One strong possibility is through effects on Aβ deposition and plaque formation. Three principal lines of evidence support the hypothesis that ApoE promotes amyloidogenesis. First, unlike wild-type mice, mice that lack the gene for ApoE are protected against amyloid deposition. Second, in vitro experiments have demonstrated that ApoE, especially ApoE4 (the protein product of ε4), can enhance the ability of Aβ to form fibrils. Third, ApoE influences the clearance of Aβ in vivo, with ApoE4 resulting in slower clearance than ApoE2 or ApoE3. Fourth, transgenic mice that overexpress various forms of Aβ develop more plaques when they also express ApoE4 and less when they express ApoE2.
Probability of remaining unaffected by Alzheimer disease as a function of ApoE genotype. Note that an increased incidence and decreased age of onset of the disease occurs among individuals with two copies of ApoE4, whereas those with even one copy of ApoE2 are relatively protected. The numbers on the curves designate alleles. (Adapted with permission from Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Annu Rev Neurosci. 1996;19:53.)
Although its effect on amyloid deposition is probably the most well-studied role of ApoE in Alzheimer disease, there are other mechanisms that may contribute. Possible mechanisms include effects of ApoE on synaptic plasticity, inflammation, and tau aggregation. More work needs to be done in these areas to understand their relevance in mediating the role of ApoE in Alzheimer disease.
The microtubule-associated protein tau is involved in several neurodegenerative diseases. Some, including certain forms of FTD (discussed later), can be caused by tau gene mutations and are termed primary tauopathies. Alzheimer disease is a secondary tauopathy; tau mutations apparently do not cause the disease, but tau protein nonetheless accumulates and plays an important pathogenic role.
The tau gene on chromosome 17 is very complex and alternatively spliced to generate six different isoforms 18–7. Three of the isoforms contain three microtubule-binding domains (3R tau), while the other three have four such domains (4R tau). Tau is expressed primarily in neurons and at lower levels in glia. It is involved in neurite outgrowth and regulates axonal transport, yet tau knockout mice have no dramatic defects.
Structure of the tau gene and isoforms, and their pathogenic mutations. A. The tau gene (top) is transcribed into a primary RNA (middle) that is alternatively spliced and translated to produce six mRNA and protein isoforms. The isoforms contain either zero (ON), one (1N), or two (2N) amino-terminal inserts, and either three (3R) or four (4R) carboxy-terminal microtubule-binding domains. (Adapted with permission from Buée L, Bussière T, Buée-Scherrer V, et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev. 2000;33(1):95–130.) B. Summary of mutations in MAPT, the tau gene, that cause familial forms of frontotemporal dementia and related neurodegenerative disorders. (Used with permission from Michel Goedert, MRC Laboratory of Molecular Biology, Cambridge, UK).
Interest in tau has focused on neurofibrillary tangles, which are composed primarily of aberrantly phosphorylated and aggregated tau. Several protein kinases are thought to contribute to tau hyperphosphorylation, including cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β) (Chapter 4). The amount of tangle pathology is highly correlated with the degree of neuronal loss and the severity of cognitive impairment in Alzheimer disease patients. This suggests that pathologic aggregation of tau may be a final pathway leading to neurodegeneration in Alzheimer disease. There is abundant evidence that Aβ can stimulate modification and aggregation of tau, although mechanisms linking the two are not clear. Aβ activates many of the kinases that phosphorylate tau, and also increases pathologic tau cleavage. Mouse models expressing high levels of both Aβ and human tau develop plaques and tangles, and treatments aimed at Aβ reverse some aspects of the tau pathology. Thus, one model for Alzheimer pathogenesis postulates that Aβ triggers downstream changes in tau, leading to tangle formation and neuronal death, thereby causing cognitive impairment.
While many aspects of this model have been validated, other mechanisms undoubtedly also contribute. For example, animal models indicate that, much like soluble oligomers of Aβ, soluble forms of tau contribute to neuronal dysfunction and cognitive deficits, even apart from any role in tangle formation and cell death. Other important questions about tau’s role in Alzheimer disease remain, such as which phosphorylation sites are most important in the disease, the extent to which various tau posttranslational modifications contribute to pathogenesis, and the extent to which tau aggregates may spread from cell to cell in the brain and propagate in a prion-like manner 18–2. Recent experiments that demonstrate protective effects of antitau antibodies in animal models of tauopathy suggest the potential importance of the latter mechanism.
18–2 Prion Disorders
The term prion disorder refers to both a distinct disease entity and a pathophysiologic mechanism of neurodegeneration. Creutzfeldt–Jakob disease (CJD) and its variants (vCJD) belong to a group of diseases that until recently defied easy classification in that they display features of both infectious and neurodegenerative mechanisms. CJD and vCJD patients demonstrate rapidly progressive dementia associated with diffuse myoclonic jerks and other neurologic abnormalities. The major neuropathologic changes occur in the cerebral and cerebellar cortices, which show marked neuronal loss, gliosis, and spongiform changes. The time from symptom onset to death is commonly a matter of weeks or months. Other mammalian forms of this condition include scrapie in sheep, chronic wasting disease in deer and elk, and mad cow disease. Concern about the possibilities of zoonotic transmission of these disorders (transmission from animals to humans) constitutes a major public health issue.
As a pathophysiologic mechanism, a prion refers to a normal protein that acquires an alternative conformation that becomes self-propagating. All mammalian prion proteins adopt a β-sheet-rich conformation and appear to readily oligomerize and self-propagate. The prototype is prion protein (PrP) itself, first described as the cause of scrapie and several other spongiform encephalopathies. However, other neurodegenerative conditions may involve a prion-like process in which altered conformations in other proteins play a significant role in disease pathogenesis, although this remains controversial. Possible examples include Alzheimer disease (Aβ and tau), variants of FTD (tau), Parkinson disease (α-synuclein), and ALS (TDP-43 and the fused in sarcoma gene product or FUS). Consistent with the concept that these other neurodegenerative disease-causing proteins act as prions is the finding that Aβ plaques and neurofibrillary tangles in Alzheimer disease spread from certain parts of the brain to others, possibly even via transsynaptic mechanisms. Recent studies, for example, have traced the spread of tau-related pathology across several brain regions. Further work is needed to prove this pathogenetic mechanism.
Efforts are under way to develop agents that can prevent or reverse pathologic protein misfolding. One recent successful example is the approval of tafamidis in Europe for familial transthyretin amyloid polyneuropathy, which involves the deposition of a non-Aβ form of amyloid in peripheral nerves.
Because Alzheimer disease is so disabling and yet so common, intense research efforts in the pharmaceutical industry and in academic settings have been devoted to developing agents that will prevent or retard the disease process. Currently used agents focus on symptomatic improvement only and include drugs that increase cholinergic neurotransmission or block glutamate receptors. Still in development are several strategies aimed at altering the disease processes themselves, such as regulating Aβ or tau.
Because cholinergic neurons of the nucleus basalis are prominently affected in Alzheimer disease, and because cholinergic activity regulates memory processing, enhancement of cholinergic functioning was one of the earliest treatment goals. The initial attempts to increase cholinergic functioning involved administration of the acetylcholine precursors, choline and lecithin. Although the analogous strategy has proven effective for Parkinson disease—L-dopa, a precursor of dopamine, improves symptoms of the illness (see below)—multiple studies have established that cholinergic precursors are not effective in the treatment of Alzheimer disease.
Subsequent efforts met with partial success by inhibiting the cholinesterase activity that clears acetylcholine from the synaptic cleft (see Chapter 6 for a general discussion of cholinergic systems). Four cholinesterase inhibitors are currently approved for the treatment of Alzheimer disease in the United States: tacrine, donepezil, galantamine, and rivastigmine 18–8. These agents do not reverse the course of the disease, nor are they dramatically effective at restoring cognitive function, but in some patients they can temporarily improve attention and memory, delaying the inevitable symptomatic deterioration.
Structures of clinically used cholinesterase inhibitors.
Other cholinergic treatment strategies include agonists or positive allosteric modulators at particular muscarinic or nicotinic cholinergic receptors (Chapter 14). Still another strategy is targeting the nerve growth factor (NGF) signaling pathway, which provides trophic support for cholinergic neurons. However, as discussed in Chapter 8, it is challenging to deliver growth factors directly into the brain and to design small molecules that activate endogenous growth factor signaling pathways. Nevertheless, there are clinical trials under way in which NGF is being delivered via gene therapy directly into the brain in patients with Alzheimer disease.
NMDA receptor antagonists
In addition to cholinesterase inhibitors, the other approved treatment for Alzheimer disease is memantine. Memantine is a low-affinity antagonist of the NMDA glutamate receptor, which is integrally involved in synaptic plasticity (Chapter 14) but also mediates excitotoxic injury as discussed earlier. Because its effects are voltage dependent, it has been proposed that memantine preferentially inhibits excessive NMDA receptor activation associated with excitotoxicity, without blocking the receptor’s function under most normal conditions. However, this speculation is counter to our knowledge of NMDA receptor function in brain and the use of memantine to treat the cognitive symptoms of Alzheimer disease: one would predict that NMDA agonists might improve cognitive function, while NMDA antagonists might reduce longer-term excitotoxicity. Hence, the use of an NMDA antagonist for symptomatic improvement, not as a disease-altering agent, does not make sense based on the reasoning above. It is, of course, quite possible that memantine’s modest clinical effects are mediated via alternative mechanisms not yet identified.
Anti-inflammatory agents and antioxidants
The buildup of Aβ into plaques causes some local microglial and astrocytic activation, with concomitant release of cytokines and acute-phase proteins (Chapter 12). Thus, inflammatory processes are implicated in the neurodegeneration that is characteristic of Alzheimer disease. Consistent with this suspicion, retrospective epidemiologic studies suggest that patients taking nonsteroidal anti-inflammatory drugs (NSAIDs), for example, ibuprofen, on a regular basis—for example, for arthritis—have a reduced risk of developing Alzheimer disease. Unfortunately, prospective trials for people with symptomatic Alzheimer disease have failed to support the efficacy of several different NSAIDs. Future trials of anti-inflammatory agents as preventive measures may prove more fruitful. It is likely that inflammation can in some ways be beneficial, perhaps by contributing to plaque clearance, and that anti-inflammatory therapies will need to be specifically targeted to the harmful aspects of these processes.
A related treatment strategy involves the use of antioxidants and free radical scavengers. Activated microglia secrete hydrogen peroxide, superoxides, and hydroxyl radicals; these are useful in combating foreign cells or organisms but can damage neurons. It is therefore possible that antioxidants and free radical scavengers may serve a protective function in Alzheimer disease and in other neurodegenerative disorders. Vitamin E (α-tocopherol) has been extensively investigated, with recent studies suggesting that it might slow progression of the illness. There has been considerable interest in several natural products called polyphenols, such as resveratrol and curcumin, which are reported to have anti-inflammatory effects and be neuroprotective in cell culture and in animal models of Alzheimer and Parkinson disease. Resveratrol activates sirtuins, which are categorized as Class III histone deacetylases (HDACs), although they deaceylate numerous non-histone substrate proteins as well. Resveratrol is also reported to inhibit the mTOR and TNF-α signaling pathways (Chapters 4 and 8). Curcumin is an inhibitor of histone acetyltransferases (HATs), among several other actions (Chapter 4). Despite the attention given to these agents, there is no convincing evidence for their therapeutic efficacy in humans, although clinical trials continue for several CNS and peripheral disorders.
Disease-altering strategies: targeting Aβ
Much effort has been devoted to strategies aimed at decreasing the production, enhancing the clearance, or neutralizing the neurotoxic properties of Aβ. Several different compounds, including cyclohexanehexols and tramiprosate, are able to block aggregation of Aβ into oligomers or fibrillar plaques in vitro and in animal models. However, studies in humans with mild-to-moderate Alzheimer disease showed no positive effects.
Immune-based approaches to stimulate Aβ clearance are also under clinical investigation. Vaccination with Aβ plus adjuvant was highly effective in mouse models, profoundly reducing amyloid plaque load and improving cognitive performance. However, a clinical trial in patients was terminated early because a subset of patients developed encephalitis related to the immune reaction. Because the trial still gave hints of benefit in at least some patients, second-generation approaches using different immunologic strategies (namely, passive immunization) are under investigation. In two large phase 3 trials, systemic administration of anti-Aβ monoclonal antibodies bapineuzumab and solanezumab did not meet their primary end points in patients with mild-to-moderate Alzheimer disease. However, solanezumab treatment resulted in significant slowing of cognitive decline in patients with mild impairments. An additional phase 3 trial with solanezumab in such patients is therefore now under way. In addition, two prevention trials in early onset familial Alzheimer disease have started in which anti-Aβ antibodies are being assessed. Also, a large prevention trial in cognitively normal elderly individuals who have amyloid deposition in their brains based on new amyloid imaging agents (eg, Amyvid) is slated to further assess the effects of solanezumab in still earlier phases of the illness. A challenge with immunotherapies is determining their mechanism of action. Several models have been proposed. One hypothesis holds that peripherally administered anti-Aβ antibody acts as a “sink,” altering the equilibrium between Aβ in the blood and that in the cerebrospinal fluid (CSF) and brain parenchyma. An alternative hypothesis is that anti-Aβ antibodies, like all other immunoglobulins (IgGs) in the blood, get into the CNS at concentrations of 0.1% to 0.2% of plasma concentrations and contribute to microglial-mediated phagocytic clearance of amyloid plaque. A third hypothesis is that antibodies that enter the CNS alter Aβ aggregation and neutralization of Aβ toxicity. Since only a small fraction of systemically administered antibody crosses the blood–brain barrier, efforts are under way to develop methods to increase delivery of antibodies directly into the brain.
Considerable effort is being devoted to inhibiting Aβ production by blocking β- or γ-secretase. Challenges in the chemical synthesis of β-secretase inhibitors (termed BACE inhibitors) initially slowed their development. However, there are now several such inhibitors in phase 1 to phase 3 clinical trials. This approach holds a great deal of promise, especially if initiated early in the course of illness. However, there is some concern over potential side effects in that, during development, β-secretase regulates myelin thickness as well as other processes.
It has proven easier to block γ-secretase, but concerns over side effects related to substrate specificity have been the limiting issue. Besides APP, γ-secretase cleaves many other type I transmembrane proteins with small extracellular domains. One of the most important is Notch, a signaling molecule with critical roles in differentiation and development. Notch cleavage by γ-secretase releases the Notch intracellular domain (NICD), which acts in the nucleus to regulate gene expression. Presumably through inhibition of Notch cleavage, γ-secretase inhibitors have demonstrated adverse effects on lymphoid and gastrointestinal tissues, which have large populations of rapidly dividing cells. Attempts to create γ-secretase inhibitors that are more selective for APP have thus far not been successful. A related approach is to develop modulators of γ-secretase rather than direct inhibitors of the enzyme’s catalytic activity. These compounds cause γ-secretase to produce less Aβ42 and more shorter Aβ species, essentially the reverse purported effect of presenilin mutations, and thus may lessen Aβ aggregation and toxicity.
Additional approaches to reducing Aβ levels are being considered. α-Secretase cleavage of APP initiates a nonamyloidogenic pathway by cleaving within the Aβ sequence (see 18–4), so increasing α-secretase activity should reduce Aβ levels. In addition, many endogenous peptidases that serve to degrade Aβ have been identified, including neprilysin and insulin-degrading enzyme. Activating either α-secretase or one of these peptidases may be effective in lowering Aβ levels and treating Alzheimer disease.
Other disease-altering strategies
Pharmaceutical approaches to directly target tau or ApoE are not as advanced as approaches toward Aβ. However, recent work by several laboratories has demonstrated the potential effectiveness of antitau antibodies in animal models of tauopathy. This is a promising approach that is expected to move into human trials over the next 1 or 2 years. Other attempts are focused on identifying specific conformations or posttranslational modifications of tau, or interactions between tau and other proteins, which might be pathogenic and could be targeted to treat the disease 18–9. For example, because tau phosphorylation is such a hallmark of Alzheimer disease, inhibitors of the several protein kinases that are known to phosphorylate tau (eg, CDK5, GSK3β) are being investigated, but the multiple roles of these protein kinases raise significant challenges for developing drugs that are safe. Inhibitors of tau aggregation or agents that stimulate tau clearance are also under investigation. Examples include drugs that would increase tau acetylation or O-linked N-acetylglucosamination (O-GlcNAc), among others. Finally, there are efforts to develop drugs that increase the lipidation state of ApoE, which has been shown to be protective in animal models.
Strategies for antitau therapies. Tau normally functions as a microtubule-associated protein. Numerous approaches are being considered to reduce either total levels of tau or its pathogenic forms. (Used with permission from J Gestwicki, University of California San Francisco, San Francisco, CA.)
The FTDs are a group of related neurodegenerative disorders that are distinguished in several ways from Alzheimer disease, perhaps foremost because of their heterogeneity, both clinically and pathologically.
Whereas the signature cognitive deficit in Alzheimer disease usually begins with memory impairment, FTD patients classically have preserved memory initially, but severe problems in other cognitive domains. Several different syndromes can be diagnosed, depending on which symptoms occur earliest or are most severe. In the behavioral variant of FTD, patients withdraw from their friends and families and lack normal emotional responses, such as empathy when a loved one is injured. They often develop unusual compulsions, personality changes, altered food preferences, and disinhibited behaviors, and lack insight into their own illnesses. Another variant of FTD is semantic dementia. These individuals show some of the same behavioral abnormalities, but are affected primarily by a loss of semantic knowledge, or information about what things are. This leads to problems in naming objects that are shown to them, and eventually with being able to describe anything about the item. A third variant of FTD is characterized by progressive aphasia. These patients show problems primarily in language expression. Finally, some patients with tauopathies present not with FTD but with parkinsonism and other motor symptoms and are diagnosed with progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) (see the section “Parkinson disease”). Patients who present with one of these syndromes often go on to develop one or more of the others as their disease worsens.
FTD tends to occur in somewhat younger patients than Alzheimer disease, with an average age of onset in the late 50s. In fact, among patients under 65, FTD is as common as Alzheimer disease.
The neuropathology of FTD syndromes is also more heterogeneous than that of Alzheimer disease. Amyloid plaques are not observed, and Aβ is not believed to play a prominent role in causing these diseases. About half of patients show some type of tau-positive inclusions, although usually not the classic neurofibrillary tangles seen in Alzheimer disease. The tau pathology can occur in glial cells or takes the form of spherical neuronal inclusions termed Pick bodies. (FTDs were originally referred to as Pick disease.) The other half of FTD patients do not have tau-positive inclusions, but most have inclusions composed of certain ubiquitinated proteins. For years, the identity of the protein accumulating in FTD was unknown, but it has now been identified as TDP-43 (TAR DNA-binding protein of 43 kD). TDP-43 is a nuclear protein, the exact role of which in neuropathogenesis remains to be determined.
Mutations in the tau gene are one cause of FTD. Because these cases often have parkinsonism and the tau gene is on chromosome 17, these cases are often referred to as FTDP-17. Many different tau mutations have been described, most of which are around the microtubule-binding domains of the protein 18–7. Many mutations seem to increase the proportion of 4R tau, while others seem to favor tau aggregation. Current research is aimed at understanding precise molecular mechanisms through which tau mutations cause FTD.
The other major genetic cause of FTD is mutations in the progranulin gene. Patients with progranulin mutations develop TDP-43 pathology. Progranulin is a secreted growth factor, and the many different mutations that have been described lead to a destabilization of its mRNA and resulting haploinsufficiency of progranulin. The leading hypothesis is that a ~50% loss of progranulin function leads to neurodegeneration; however, possible mechanisms remain unknown. Less common genetic forms of FTD are caused by mutations in valosin-containing protein (VCP) or charged multivesicular body protein 2B (CHMP2B), both of which have roles in protein handling.
There are no approved drugs for FTD. Cholinesterase inhibitors used for Alzheimer disease are not effective, although memantine may be. Serotonergic systems seem to be strongly affected by FTD, and selective serotonin reuptake inhibitors are commonly utilized as symptomatic therapies. Tau-based therapeutics, discussed above under treatments for Alzheimer disease, have yet to be tested in FTDs.
Vascular disease is a major cause of cognitive impairment in the elderly. Both large infarctions and chronic ischemia due to changes in small vessels, as occurs with long-standing hypertension, can lead to dementia. These cases are termed vascular dementia or multi-infarct dementia. They are usually diagnosed based on a combination of stepwise (as opposed to steadily progressive) decline, the presence of cardiovascular risk factors, and neuroimaging evidence of vascular disease. The primary form of treatment is prevention (see Chapter 20).
Dementia with Lewy bodies may clinically resemble Alzheimer disease. Distinguishing features include parkinsonism, frequent fluctuations, and the occurrence of visual hallucinations. Pathologically, Lewy bodies containing α-synuclein, identical to those seen in Parkinson disease, are found throughout the neocortex. Treatment is similar to that for Alzheimer disease.