Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of acquired dementia. The biggest risk factor for the development of AD is age, and with increasing longevity, a feature of modern healthcare, the prevalence of dementia and most particularly AD is set to double over the next 20 years. The disease is characterized most commonly by memory, language, and executive dysfunction although other presentations such as visuospatial dysfunction, agnosia, and behavioral disturbance are common in younger onset and familial forms. The pathology is a unifying feature and much progress has been made in understanding the pathogenesis. It is hoped that the next generation of therapeutic interventions will act upon the underlying mechanisms and truly modify the onset and progression of this prevalent disease.

4.1 Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain characterized by an insidious onset of memory impairment, progressive cognitive deterioration, emergence of neuropsychiatric symptoms, and functional decline. Pathologically, it is characterized by the accumulation of amyloid plaques and intraneuronal neurofibrillary tangles, which are associated with neuronal dysfunction and eventual cell death. It is the most common form of dementia accounting for between 50 and 60 % of all cases. The global prevalence of dementia is increasing and it has been projected that the number of people affected will double every 20 years to an estimated 81.1 million by 2040. AD is therefore the most common neurodegenerative disorder affecting between 20 and 30 million individuals worldwide. It is primarily an age-related disorder. The prevalence of dementia is low (approximately 1 %) in individuals aged 60–64 but increases exponentially with age so that in individuals aged 85 years or over, the prevalence in the Western world is between 24 and 33 %. AD has a complex multifactorial etiology and apart from age, genetic and environmental factors play important roles in the onset and progression of disease.

4.2 Risk Factors

4.2.1 Genetic Factors

From a genetic point of view, Alzheimer’s disease is a heterogeneous disorder with both familial and sporadic forms. The vast majority of Alzheimer’s disease is sporadic and of late onset (≥65 years), while a small proportion of all cases (<2 %) may inherit the disease in autosomal dominant fashion. These variants are generally of early onset (<65 years). Autosomal dominant forms are mostly related to mutations in one of three genes: amyloid precursor protein gene (APP) on chromosome 21, presenilin 1 gene (PS1) on chromosome 14, and presenilin 2 gene (PS2) on chromosome 1 (Table 4.1). PS1 accounts for the majority of mutations while APP and PS2 mutations occur less frequently. All of these genes impact upon the production of the beta amyloid protein (Aß), which is the principal component of senile plaques hypothesized to play a central role in the evolution of Alzheimer’s pathology. The vast majority of AD patients, however, have sporadic late-onset disease, which has a complex etiology attributed to interactions between environmental risk factors and individual genetic susceptibilities. Twin studies have estimated the heritability of late-onset sporadic AD to be approximately 76 %.

Table 4.1 Established Alzheimer’s genes and their functional relevance

The most well-established genetic risk factor for late-onset AD is the apolipoprotein E gene (APOE). Three APOE alleles have been identified: e2, e3, and e4. The APOE e4 allele has been linked to the development of AD, whilst epidemiologic as well as pathologic studies have suggested a possible protective effect for the e2 allele. There is an apparent gene-dosing effect according to the actual genotype. One meta-analysis reported the odds of developing AD in heterozygous carriers of the APOE e4 allele as threefold, while the odds for homozygous carriers was almost 15-fold.

The APOE e4 allele operates mainly by decreasing the age of onset with each allele copy lowering the age of onset by almost 10 years. It is therefore a marker of susceptibility rather than a determinative gene. The mechanism whereby APOEe4 influences the development of AD is complex and may be modified by other genes and environmental factors. APOE acts as a cholesterol transporter in the brain, which mediates neuronal protection and repair and is believed to participate in early Aß deposition. The APOE e4 allele has been associated with increased severity of illness including faster cognitive decline, increased risk of conversion from mild cognitive impairment to AD, more neuropsychiatric symptoms, decreased survival time, and increased amyloid load at autopsy. The use of APOE genotype as a diagnostic tool has been examined in several studies but low sensitivity and specificity limit its usefulness and it is not currently recommended for diagnostic use. Table 4.1 summarizes established Alzheimer’s genes and their functional relevance.

Although the APOE e4 allele has been calculated to account for most of the genetic risk in late-onset alzheimer’s disease, a number of candidate genes of smaller effect have also been identified. The advent of large Genome Wide Association Studies (GWAS) has allowed identification of several genes of small effect and findings are collated in the online AlzGene database which allows researchers to compare results and search for consistency between international groups. It is hypothesised that genetic mutations of modest effect in concert with other genetic and environmental factors, may precipitate clinical disease in vulnerable individuals. For example, variant of genes for CLU (clusterin/apolipoprotein J), CR1 (complement receptor 1), and PICALM (phosphatidylinositol-binding clathrin assembly protein) have achieved genome-wide significance in independent GWAS studies. These genetic variants may be involved in reduced clearance of Aß. It is hoped that improved understanding of underlying mechanisms of action may lead to new therapeutic targets to delay the onset and progression of disease.

4.2.2 Lifestyle and Vascular Risk Factors

Although several AD risk factors are genetic in nature, others are determined by environmental or lifestyle influences and may be amenable to modification. Recent years have seen an expansion in the number of epidemiological studies in AD and several risk factors that were traditionally considered as “vascular” have been associated with increased risk of AD (Table 4.2). Longitudinal studies such as the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study have found midlife hypertension, hypercholesterolemia, and obesity to be associated with increased risk of dementia and AD in later life.

Table 4.2 Potentially modifiable risk factors found to be associated with Alzheimer’s disease in population studies

Clustering of risk factors was observed to increase the risk in an additive fashion. A dementia risk score using data gathered during the CAIDE study predicted dementia with a sensitivity of 0.77, specificity of 0.63, and negative predictive value of 0.98 over 20 years of follow up. This score included variables such as age (≥47 years), low education (<10 years), hypertension, hypercholesterolemia, and obesity. There is now a great deal of interest in developing approaches to help reduce the risk of AD in later life through identifying individuals who might benefit from intensive lifestyle consultations and pharmacological interventions in earlier life. However, not all studies have replicated these findings and one systematic review concluded that the evidence for single clinically defined vascular risk factors was inconsistent at best while the strength of the association was increased by identifying interactions between risk factors such as hypertension and diabetes. In addition, the relationship between cognition and blood pressure is complex with hypertension in midlife and hypotension in later life both associated with increased risk of AD. Although initial case control studies reported a protective effect for smoking, longitudinal studies have now established that smoking is associated with increased risk of AD. Longitudinal studies show that stroke increases the subsequent risk of AD and hyperhomocysteinemia has similarly been reported to increase risk.

Other factors, that have been reported to be protective from population studies, include regular fish consumption, moderate wine intake, and higher educational status. There is also now a significant amount of epidemiological data, which suggests that individuals who are more socially and physically active and engage in more cognitively stimulating activities are at decreased risk of developing dementia and AD. In fact, a recent review concluded that after accounting for non-independence between risk factors, around a third of Alzheimer’s diseases cases worldwide might be attributed to potentially modifiable risk factors. Psychological risk factors are also important. In particular, depression has been found to behave as both a risk factor for and prodromal symptom of AD. Late onset depression may occur as part of the prodrome of early AD but depression, which occurs decades in advance of cognitive decline, is also known to increase risk of AD in a dose-dependent fashion. Psychological distress and loneliness have similarly been reported to increase risk. A number of mechanisms for the association between depression and AD have been proposed. Depression has been independently associated with increased risk of cerebrovascular disease and the chronic neurotoxic effects of elevated glucocorticoids upon hippocampal neurogenesis and repair may also diminish cognitive reserve. Finally, depression may have a more direct neuropathological effect as stress and exogenous glucocorticoids have been shown to increase β-amyloid production in animal models of AD. Having a greater sense of purpose in life and conscientiousness appear to be protective and have both been independently associated with reduced risk of AD. Sleep disturbances, particularly reduced sleep duration, sleep fragmentation, and sleep-disordered breathing, have been implicated as potentially remediable causes of cognitive decline. However, further research is needed to better define the nature of these associations and determine mechanisms which might allow further exploration of preventive and therapeutic strategies. There are already many good reasons why maintaining good psychological health and promoting a physically, cognitively, and socially active lifestyle may be advisable and beneficial for patients.

4.2.3 Other Risk Factors

Data from epidemiological studies reported an association between nonsteroidal anti-inflammatory (NSAID) use and decreased risk of AD while interventional studies in this area have been negative to date. Lipid-lowering medications have similarly been reported to be associated with decreased risk while interventional studies of statins have been largely negative to date. Hormone replacement therapy (HRT) was associated with decreased risk of AD while an interventional study reported an increased risk of dementia, again highlighting the caution with which observational findings must be interpreted. Severe head injury and exposure to toxins such as defoliants and fumigants have been associated with increased risk. Static risk factors include a family history of trisomy 21. Female gender has also been associated with increased prevalence AD. There are many possible reasons for this variable observation although a number of investigators have concluded that it is due to the longer life expectancy in females rather than gender-specific risk factors for the disease.

4.2.4 Pathogenesis

The exact cellular mechanisms leading to neuronal cell death in AD remain uncertain but multiple etiological and pathogenetic hypotheses have been put forward. Macroscopically, the brain in established AD shows a variable degree of cortical atrophy with widening of cerebral sulci and compensatory ventricular enlargement. Microscopically, the disease is characterized by amyloid plaques and neurofibrillary tangles (Fig. 4.1). The current criteria for a pathologic diagnosis of AD require the presence of both amyloid plaques and neurofibrillary tangles in excess of that anticipated for age-matched healthy controls. Amyloid plaques consist of a central core of amyloid protein surrounded by astrocytes, microglia, and dystrophic neurites. Neurofibrillary tangles contain paired helical filaments of abnormally phosphorylated tau protein that occupy the cell body and extend into the dendrites. Neuronal loss or atrophy in the nucleus basalis, locus ceruleus, and raphe nuclei of the brainstem leads to deficits in cholinergic, noradrenergic, and serotonergic transmitters, respectively. The deficit in cholinergic neurotransmission and the observation that this correlated strongly with the degree of cognitive impairment led to the “cholinergic hypothesis” of AD and the subsequent development of cholinesterase inhibitors to redress this deficit.

Fig. 4.1

Low power (a) and high power (b) views of hippocampus with neuritic amyloid plaques (P), which consist of a central core of amyloid protein surrounded by astrocytes, microglia, and dystrophic neurites and neurofibrillary tangles (T), which contain paired helical filaments of abnormally phosphorylated tau protein. The current criteria for the histopathological diagnosis of Alzheimer’s disease require the presence of both entities

4.2.5 Amyloid Hypothesis

The amyloid hypothesis remains the best-defined and most studied conceptual framework for AD (Fig. 4.2). Over time, this hypothesis has undergone alterations primarily due to the fact that increased beta amyloid protein (Ab) and plaque formation are no longer considered to be sole triggering factors for deleterious events leading to AD. The exact cellular mechanisms leading to neuronal cell death in AD remain uncertain. The amyloid cascade hypothesis holds that an imbalance between Ab production and clearance plays a critical role in progression of AD. Ab is derived from the much larger transmembrane protein, amyloid precursor protein (APP), by the action of two proteases referred to as beta (b) and gamma (g) secretase. The initial cleavage of APP is mediated by b secretase and then, depending on the exact point of cleavage by g secretase, three principle forms of Ab comprising 38, 40, or 42 amino acid residues, respectively are produced. Most mutations in the APP or presenilin genes alter APP processing resulting in increased levels of Ab. At a certain critical concentration, Ab monomers associate to form neurotoxic oligomers, which then further associate into insoluble fibrils and are deposited as amyloid plaques. The relative amount of Ab 42 formed is important as this longer form of Ab is more prone to aggregate and form oligomers. Ab oligomers could directly inhibit hippocampal long-term potentiation and impair synaptic function in addition to the inflammatory and oxidative stress caused by aggregated and deposited Ab. Much is yet to be learned about the formation and toxicity of these soluble forms of Ab and how they may trigger deleterious changes. The central significance of Ab in the pathogenesis of AD has recently been called into question given negative outcomes from trials of therapeutic agents targeting this pathway. A more current view of the amyloid cascade hypothesis is that other events as well as Ab are important in triggering degenerative processes. The concept of Ab as only one of the factors that causes AD, explains it’s less than perfect correlation with disease severity and it seems increasingly likely that Ab, although necessary, is not by itself, sufficient for AD to occur.

Fig. 4.2

Amyloid cascade hypothesis

4.2.6 Other Proposed Mechanisms

Although amyloid has received much attention with regard to halting the progression of AD, it is not the only target for disease-modifying therapies. Neurofibrillary tangles, which consist of aggregations of hyperphosphorylated tau protein, are another pathologic hallmark of AD. Tau binds to and stabilizes microtubules that are elongated polymers intrinsic to axonal structure and function. When tau is hyperphosphorylated, it aggregates into tangles with resulting destabilization of microtubules and compromised neuronal function. It is unclear whether neurofibrillary tangles are a cause or consequence of AD but their formation may be critical to AD-related cell death. Inflammatory mechanisms have long been known to play an important role in the evolution of AD pathology and many studies have shown a broad variety of inflammatory mediators, including acute phase proteins, cytokines, and chemokines within the vicinity of AD plaques. Neuroinflammation is still considered to be a downstream consequence in the amyloid hypothesis whereby Ab within the CNS brings about activation of microglia, initiating a proinflammatory cascade that results in the release of potentially neurotoxic substances, including cytokines, chemokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, leading to neurodegeneration. It has also been suggested that activation of microglia may lead to phosphorylation of tau and formation of neurofibrillary tangles. However, the exact role of inflammation in the pathology of AD and its mechanisms in terms of the cells involved, which include microglia, astrocytes, and T lymphocytes are still debated.

The frequent co-occurrence of cerebrovascular disease with AD and the fact that fewer neuropathologic lesions of AD appear to result in dementia in the presence of comorbid cerebrovascular disease has been well documented (as per the landmark Nun cohort study). In fact, it is now recognized that mixed pathology is the rule rather than the exception and that cerebrovascular disease is clinically under-recognized and under-reported. The vascular hypothesis of AD goes further and proposes that cerebral hypoperfusion and microvascular pathology may be the primary etiological factor in AD. It proposes that AD develops when two biological events converge; advancing age and the presence of vascular risk factors to create a critically attained threshold of cerebral hypoperfusion (CATCH). This leads to dysregulation of endothelial nitric oxide (NO) production, capillary degeneration, and mitochondrial oxidative stress. The resulting crisis leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD.

4.2.7 Clinical Features

The typical clinical presentation of AD is that of insidious progressive impairment of episodic memory representing early involvement of medial temporal lobe structures with the emergence of additional deficits such as aphasia, apraxia, agnosia, and executive deficits as the disease progresses. Findings from longitudinal studies indicate that neuropsychological deficits in multiple cognitive domains are evident several years in advance of a diagnosis of AD. One meta-analysis reported that the largest deficits in preclinical AD exist in the domains of perceptual speed, executive functioning, and episodic memory with smaller deficits in the domains of verbal ability, visuospatial skills, and attention. This is characterized clinically by initial forgetfulness for daily events with progressive involvement of language skills, decision making, judgment, orientation, recognition, and motor skills. Neuropsychiatric symptoms are frequently observed and occur in 60–98 % of patients with dementia. They are a significant source of distress for patients and families and a major determinant of outcomes such as length of hospital stay and nursing home placement. They ordinarily increase with increasing disease severity but are observed early in the disease process and have been documented in 30–75 % of patients with mild cognitive impairment. Apathy, anxiety, depression, and agitation occur most frequently. Delusions are also common and include themes of theft, intruders, imposters, or other ideas of persecution, reference, or infidelity. Visual and auditory hallucinations are the most common perceptual abnormalities although somatic, olfactory, and tactile hallucinations have also been reported. Functional decline starts with the impairment of higher order (instrumental) functions, such as the management of the house-hold affairs or finances before more gross functions relating to basic self-care are affected. Atypical presentations of AD occur in approximately 6–14 % of cases and are more prevalent in those with younger onset disease. Atypical presentations have been divided into a number of variants including a frontal variant, which may present with executive dysfunction or behavioural symptoms and is difficult to distinguish clinically from frontotemporal dementia. There is also a logopenic variant where there is more prominent impairment of language and a posterior variant where deficits in visuospatial function predominate. These presentations remain relatively uncommon, particularly in late onset disease, where the typical clinical course is one of insidious episodic memory decline with progressive involvement of other cognitive skills as outlined above.

4.2.8 Mild Cognitive Impairment

Neurodegeneration is estimated to start 20–30 years before clinical onset. During this pre-clinical phase, the burden of plaque and tangle pathology gradually increases until the threshold for clinical expression is reached. Mild Cognitive Impairment (MCI) is a clinical classification of patients who manifest cognitive deficits in excess of that expected for normal aging but who do not have significant functional impairment.

The initial diagnostic criteria specified the presence of subjective and objective deficits in memory, with the purpose of detecting patients with the earliest clinical signs of Alzheimer’s pathology for recruitment to clinical trials. Patients in these studies were observed to convert to Alzheimer’s disease at a rate of approximately 10–15 % annually. The diagnostic criteria have since been broadened to include patients with deficits in domains other than memory, to reflect the heterogeneity of both progressive and nonprogressive pathologies represented within this classification. Patients with amnestic deficits in addition to deficits in other domains have the greatest risk of progression to Alzheimer’s disease. Significant variation in rates of conversion to Alzheimer’s disease has been observed depending on the diagnostic criteria used and populations investigated. A recent review of longer-term follow-up studies (5 years or more) indicated that the annual conversion rate of 10–15 % only held true in samples monitored over a short observation period and that the conversion rate was highest shortly after presentation with a marked decline in subsequent years. The authors reported an average cumulative conversion rate of 31.4 % over a mean observation period of 6 years in a sample, which included patients derived from both clinic and community populations. Reported variations in conversion to AD likely reflect variations in the underlying aetiology with conversion rates at the higher end of the range anticipated in individuals with MCI due to AD.

4.2.9 Diagnosis and Revised Diagnostic Criteria

Regarding the diagnosis of Alzheimer’s disease there have been two conceptually overlapping but differing revisions of the National Institute of Neurologic and Communicative Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. One developed etc by the International Working Group (IWG) for new Research Criteria for the Diagnosis of Alzheimer’s Disease (AD), the other by the National Institute on Aging – Alzheimer’s Association (NIA-AA) workgroups on diagnostic guidelines for Alzheimer’s disease. Both revisions incorporate biomarkers but differ in how this information is used. Biomarkers are a core requirement in the IWG criteria which are research diagnostic criteria. The NIA-AA revision provides different sets of diagnostic criteria for the different stages of AD, namely the asymptomatic preclinical phase, the symptomatic pre-dementia phase (mild cognitive impairment due to AD), and the dementia phase. The NIA-AA pre-dementia and dementia criteria can be clinically applied even in the absence of biomarkers which are incorporated on a basis of increased or decreased likelihood. Both the NIA-AA criteria and more recently revised IWG criteria (IWG-2) address the issue of atypical presentations of AD which can present as a posterior variant (occipitotemporal or biparietal subtypes), a logopenic (language prominent) variant, or a frontal variant. The IWG-2 criteria outline criteria for diagnosis of typical, atypical and mixed presentations of the disease.

The IWG research criteria differ from previous criteria in that they do not require the presence of significant functional decline to diagnose Alzheimer’s disease given the increasing emphasis on identifying patients in the early clinical or preclinical stages of the disease for recruitment to clinical trials. In contrast, the NIA-AA approach retains the NINCDS-ADRDA two-step approach to the diagnosis of dementia due to AD in which there is initial identification of a dementia syndrome and then the application of criteria based on the clinical features of the AD phenotype. It is important that disorders, which may mimic a dementia syndrome such as delirium or depression, are first excluded. A detailed history of the clinical features and longitudinal course as outlined above should be elicited. This is best obtained from a reliable informant, given the patient’s judgment and insight is frequently impaired. The symptom profile will help distinguish Alzheimer’s disease from other dementia syndromes such as vascular, Lewy body, or frontotemporal dementia. A general neurological and physical examination should be performed to both exclude comorbid medical conditions, which may have an adverse effect on cognitive function and detect other neurological disorders. The neurological examination is ordinarily unremarkable in early AD but focal neurological or atypical features may be an indicator of pathologies such as normal pressure hydrocephalus, neoplasm, Parkinson’s plus syndromes, or motor neuron disease, and should prompt appropriate referral. Motor or sensory abnormalities or disturbance of gait and seizures are uncommon until the later stages of the disease. A mental state examination should detect the presence of mood or anxiety symptoms, which can mimic or complicate cognitive decline. This also provides an opportunity to exclude psychotic symptoms such as delusions or perceptual abnormalities. Neuropsychiatric symptoms must be enquired for as they may not be disclosed by patients or caregivers until they become intolerable or precipitate a crisis. A number of instruments have been designed to quantify the frequency and severity of neuropsychiatric symptoms in patients with AD such as the Neuropsychiatric Inventory (NPI) and Behavioral pathology in Alzheimer’s disease (BEHAVE-AD) rating scale. Function should equally be assessed through the use of structured questionnaires of basic activities of daily living (ADL) such as feeding and toileting and instrumental activities of daily living (IADL) such as shopping, cooking, managing finances, and medication. More complex instrumental functions are typically impaired in the earlier stages. The extent of cognitive testing will be determined by the clinical context and presentation as outlined below.

Regarding biomarkers these include atrophy of medial temporal lobe structures determined through qualitative or quantitative MRI ratings, abnormal concentrations of amyloid beta 42 and total/phospho-tau in cerebrospinal fluid, hypometabolism (typically temporoparietal in AD) on positron emission tomography (FDG PET) and determination of amyloid load using amyloid binding PET ligands such as Pittsburgh compound B (PIB). IWG-2 draws a distinction between Diagnostic (pathophysiological) markers which reflect in-vivo pathology (amyloid beta 42 and total/phospho-tau in csf; amyloid binding PET) and Progression (topographic or downstream) markers which indicate clinical severity (staging marker) and might not be present in the early stages. Their refined criteria for AD require the presence of Diagnostic markers (Table 4.3).

Table 4.3 Summary of NIA-AA and IWG-2 research criteria for probable and typical presentations of AD

Amyloid beta 42 is reduced in the CSF of AD patients (possibly as a result of deposition of the protein in senile plaques) and tau is increased (possibly a reflection of the release of tau in CSF with neuronal loss). The determination of optimal thresholds for detecting incipient AD according to CSF concentrations of amyloid beta 42 and total tau/phospho-tau continues to be refined. Three large multicenter studies (ADNI, DESCRIPTA, SBP) have confirmed that the combination of amyloid beta 42 with either tau or phospho-tau has the highest predictive accuracy for AD.

4.3 Investigations

4.3.1 Cognitive Testing

The extent and the type of cognitive testing to be undertaken will be determined by the clinical context and presentation. The Mini Mental State Examination (MMSE) is one of the best known and simplest bedside cognitive tests to administer. It takes 5–10 min to complete and is a useful measure of global cognitive function. A total score of 23 or less out of a possible perfect score of 30 is considered dementia, but it is important to note that thresholds vary according to age and education. In an educated population, an MMSE cut-off of 26 or below should raise suspicion of dementia, as this is the cut-off utilized in more recent research studies. The MMSE may not be sensitive to very subtle cognitive impairment, but can be useful as a general screening tool or to monitor performance over time. The MMSE declines by approximately 2.8 points per year in patients with Alzheimer’s disease, with a slower decline in the milder stages and faster decline in the moderate to severe stages of the disease. The Montreal Cognitive Assessment (MOCA) is a more recently developed widely used screening test with a similar 30-point format to the MMSE. It includes additional tests of visuospatial and executive function, which make it more sensitive in patients with mild cognitive impairment. Other lengthier tests of global cognitive function include the Addenbrookes Cognitive Examination (ACE-III), Cambridge Cognitive Examination (CAMCOG-R), Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog) and Mattis Dementia Rating Scale (DRS-2). Patients with minor impairments, high levels of educational attainment, or atypical clinical features can perform deceptively well on bedside tests and may require more comprehensive assessment in specialist centers. Measures of free recall, particularly verbal recall, have consistently been shown to be impaired in the earliest clinical stages of Alzheimer’s disease and predict early conversion from mild cognitive impairment. Predictive accuracy may be increased by combining tests of free recall with tests of executive function, processing speed, and semantic fluency.

4.3.2 Blood Tests

The bloods tests, which are routinely ordered as part of a cognitive screen include full blood count, B12/folate, renal/liver/bone profile, and thyroid function tests. This may be supplemented by screening for vascular risk factors with a fasting lipid profile and fasting glucose. Syphilis serology may be requested but is not routinely screened in many centers depending on the risk profile of the patient. Nonspecific markers of inflammation, such as ESR or CRP may be helpful where infective or inflammatory diseases are suspected.

4.3.3 Neuroimaging

Structural neuroimaging should be used in the evaluation of every patient suspected of dementia. Non-contrast CT can be used to identify surgically treatable lesions and vascular disease. MRI (with a protocol, including T1, T2, or FLAIR sequences, and susceptibility weighted sequences) can increase sensitivity for subcortical vascular contributions to cognitive decline and exclude other intracranial pathology or identify regional atrophy. Atrophic changes in medial temporal lobe structures such as the entorhinal cortex and hippocampus, as well as in parietal cortices may be seen on neuroimaging, which may become more marked and generalized as the disease advances (Fig. 4.3). However, volumetric changes may be minimal or absent in the very early stages of Alzheimer’s disease. Functional neuroimaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT) may usefully augment structural imaging where uncertainty exists regarding the clinical features and presentation. A reduction in blood flow or glucose hypometabolism in temporoparietal areas is most commonly described in AD. The use of amyloid PET scans has been largely confined to research settings to date although with increasing availability and standardization of methods this may play a greater role over time.

Fig. 4.3

Alzheimer’s disease. Coronal T2-weighted fast spin echo (FSE) sequence. Note the pattern of generalized atrophy with preferential involvement of the medial temporal lobes (hippocampi) bilaterally (arrows). There is little or no white matter disease indicating a reasonably pure form of plaque and tangle disease

4.3.4 Other Investigations

Electroencephalography (EEG) may be a useful adjunct and should be included in the diagnostic workup of patients suspected of having Creutzfeldt–Jakob disease or transient epileptic amnesia. CSF analysis is mandatory when inflammatory disease, vasculitis, or demyelination is suspected. The use of CSF biomarkers such as amyloid beta 42, total tau and phospho-tau has been largely confined to clinical research settings to date with considerable variability in results between laboratories. However, with improved standardization of methods and publication of consensus criteria, CSF biomarkers are likely to play a greater role, and are increasingly recommended in young onset and atypical presentations.

4.4 Management

4.4.1 Cognitive Symptoms

Acetylcholinesterase inhibitors are currently the mainstay of pharmacological therapy for Alzheimer’s disease. The acetylcholinesterase inhibitors in use are donepezil, galantamine, and rivastigmine, which act to increase cholinergic neurotransmission through inhibition of the enzyme, acetylcholinesterase. The three compounds have certain unique pharmacological properties although no difference in efficacy between the three medications has been consistently demonstrated. Prescriber choice is ordinarily determined by side effect profile and individual familiarity (Table 4.4). Donepezil and galantamine are selective acetylcholinesterase inhibitors while rivastigmine inhibits acetylcholinesterase and butyrylcholinesterase with similar affinity. Galantamine also allosterically modulates presynaptic nicotinic receptors. The efficacy of these medications has been studied in over 30 randomized double-blind clinical trials and they have been shown to have a treatment effect on average of 2.5–3.5 points on the Alzheimer’s disease assessment scale, cognitive subscale (ADAS-Cog, range 0–70) over 6 months compared with patients receiving placebo. There is some variability between studies but approximately twice as many patients who receive a cholinesterase inhibitor have a 4-point difference on the ADAS-Cog (25–50 % vs. 15–25 %) and approximately three times as many patients who receive a cholinesterase inhibitor have a 7-point difference (12–20 % vs. 2–6 %) on the ADAS-Cog compared to those taking placebo. A 7-point difference is equivalent to slowing the symptoms by approximately 1 year and more patients have less decline rather than a measurable improvement in symptoms. It is important to discuss this point with patients and their families who may anticipate improvement rather than a reduction in the rate of decline.

Table 4.4 Summary characteristics of the cholinesterase inhibitors

A Cochrane review concluded that donepezil, rivastigmine, and galantamine are efficacious in mild-to-moderate Alzheimer’s disease and that treatment benefits included small improvements on measures of activities of daily living and behavior in addition to cognitive measures. There is nothing to suggest that the effects are less for patients with severe dementia although there fewer studies in this regard. More recently, a study which randomized patients with moderate to severe AD who had been stable on donepezil to either continue or discontinue the treatment found a functional and cognitive advantage for those who continued donepezil.

Overall, these medications are well tolerated and adverse effects such as nausea, vomiting, or diarrhea are most frequently reported. This can ordinarily be avoided by starting at a low dose, which is then titrated upward. Coadministration with food also delays absorption and can reduce gastrointestinal side effects. Rivastigmine is available as a daily patch, which has a more favorable gastrointestinal side effect profile than oral rivastigmine. Other important possible adverse effects to consider include cholinergically mediated exacerbation of chronic obstructive pulmonary disease, peptic ulcers, or atrioventricular conduction abnormalities. Both donepezil and galantamine are metabolized by the cytochrome P450 enzymes, CYP2D6 and CYP3A4, and can thus interact with drugs that inhibit these enzymes. Rivastigmine has less potential for interaction given that it is metabolized at the site of action and does not have a hepatic metabolism.

A beneficial response to a cholinesterase inhibitor may be determined by the clinician’s global assessment of cognitive, functional, and behavioral symptoms taking into account the report of the primary caregiver. Observation for up to 6 months may be necessary to assess for potential benefit. Brief tests of cognitive function may be relatively insensitive to the cognitive effects of acetylcholinesterase inhibitors. Medication should be discontinued if it is poorly tolerated or if deterioration continues at the pretreatment rate. There is some evidence that patients who either do not tolerate or respond to one cholinesterase inhibitor may benefit from another. It is important to note that acetylcholinesterase inhibitors are a symptomatic treatment and do not alter the underlying neurodegenerative process which is progressive.

Acetylcholinesterase inhibitors have been used in a number of interventional studies to see if they can delay transition to Alzheimer’s dementia in patients with mild cognitive impairment. There is currently little compelling evidence to recommend their use in such patients given that the majority of studies to date have failed to meet their primary efficacy objectives. One group reported delayed progression to Alzheimer’s disease over 12 months but not over 3 years, while another noted a small beneficial effect on cognition, which did not translate into improved function. Various explanations for these largely negative findings have been proposed, including the heterogeneity of patients under study, the possibility that there is simply less cholinergic dysfunction in patients with mild cognitive impairment, or that current outcome measures are insufficiently sensitive to changes in patients with mild disease.

Memantine is a noncompetitive NMDA receptor antagonist, which is believed to protect neurons from glutamate-mediated excitotoxicity, which may occur in Alzheimer’s disease. Memantine has been shown to have a small beneficial effect on measures of cognition, function, and behavior in moderate-to-severe Alzheimer’s disease with a barely detectable clinical effect in patients with milder disease. Memantine is generally well tolerated with few adverse events. There is conflicting evidence regarding whether the addition of memantine to donepezil in patients with moderate-to-severe disease may yield additional symptomatic benefit. Despite the theoretically neuroprotective properties of memantine, it is felt that current drug trials are too short to assess if the drug has any disease-modifying effects.

4.4.2 Neuropsychiatric Symptoms (See Also Chap. 12)

Neuropsychiatric symptoms (NPS) occur in approximately 80 % of individuals with dementia during the course of the disease. Neuropsychiatric symptoms (NPS) are distressing for the patient, lead to increased caregiver stress and are associated with greater likelihood of institutional care and increased costs. Non-pharmacological interventions are ordinarily first line and should be exhausted before pharmacological approaches are considered. The type of neuropsychiatric symptoms together with their frequency, diurnal pattern, and identifiable triggers or reinforcers should be documented. A number of instruments have been designed to quantify the frequency and severity of NPS including the neuropsychiatric inventory, the behavioural pathology in AD scale and Cohen-Mansfield agitation inventory among others. Accurate documentation of frequency, severity and relevant triggers will help in the formulation of a tailored and targeted treatment approach. A person-centred care approach which aims to understand the reasons for the behavior from the patient’s perspective are central to any intervention. First, consider unmet medical needs, such as pain, delirium, or a recent change in medication. Environmental and psychosocial factors, which increase the likelihood of behavioral disturbance, include overcrowding, lack of privacy, noise, or poor communication between carers and patients. Orientation through the use of a memory book, family photographs, and a calendar around the patient’s bed can help decrease agitation. Motor disturbances may alternately be an expression of discomfort, fear, paranoia, or simply boredom. Education for carers regarding the behavioral management of such symptoms is helpful and should be considered as part of an initial treatment approach.

Pharmacological treatments are only helpful for specific symptoms and their use should be targeted (discussed in more detail in Chap. 12). There is some evidence to support the use of antidepressant medication for the treatment of depression in Alzheimer’s disease although there have also been a number of negative studies and symptoms may sometimes resolve with other supportive measures. When an antidepressant is chosen, SSRIs are generally favored and medications such as older tricyclic agents are generally avoided. Benzodiazepines should generally be avoided except for short term or occasional use for anxiety symptoms and should be limited to shorter acting agents. Cholinesterase inhibitors have not been associated with notable improvement of NPS and there are conflicting findings regarding memantine with a number of negative studies. There is some emerging evidence that certain SSRIs such as citalopram may reduce agitation in AD and further studies in this area are required.

The best-studied pharmacologic agents for NPS are antipsychotic medications and there is evidence to support the use of risperidone, olanzapine and aripiprazole for agitation and aggression in AD. However, antipsychotic medications have been associated with increased risk of cerebrovascular events, mortality and cognitive decline limiting their use to circumstances where alternate approaches have been ineffective and there is severe distress or risk. It is important to obtain informed consent where possible, discuss the risks/benefits with the next of kin and document the relevant considerations before starting such a medication. Medication should be reviewed regularly and discontinued if the risks outweigh the benefits. It is known that a proportion of patients may have antipsychotic medication safely discontinued after 3 months while those with more severe symptoms at baseline may require ongoing treatment.

4.4.3 Supporting Caregivers and Legal Considerations

The physical and emotional health of the primary caregiver is critical to optimal care of the patient with Alzheimer’s disease. Caregivers have increased rates of psychological and physical morbidity, which in turn predict early transfer to long-term care and escalation of costs. One of the most widely used tools to assess the demands of caregiving on the care-giver is the Zarit burden inventory, which is a 22-item, self-administered questionnaire. Multimodal and multidisciplinary interventions tailored to the needs of individual caregivers have been shown to achieve improved outcomes for patients and carers and can delay time to institutional care. Legal issues should also be addressed with patients and carers such as advance directives and power of attorney as appropriate. Voluntary organizations such as the Alzheimer’s association (www.Alz.org) and the Alzheimer’s society (www.alzheimer.org.uk) have an important role to play and can provide patients and their families with useful information regarding Alzheimer’s disease and the availability of daycare and respite services locally.

4.4.4 Lifestyle Issues, Cognitive Stimulation, and Alternate Therapies

In recent years, there has been an increasing amount of epidemiological evidence, which links low educational level, vascular risk factors, and decreased social activation with increased risk of Alzheimer’s disease. These findings, coupled with an increased under-standing of neural plasticity, have stimulated interest in the area of lifestyle interventions to improve cognitive function.

Several observational studies have documented decreased risk of cognitive decline and dementia in adults who exercise more and are more physically active. However, interventional studies in individuals with AD or individuals at risk of AD are less frequent and further studies are required. One interventional study, which randomized 170 participants with memory complaints (60 % of whom had mild cognitive impairment) to either a 24 week home-based program of physical activity or to education and usual care reported a 1.3 point difference on the ADAS-Cog in favor of the intervention. Exercise has also been shown to benefit the physical functioning of patients with AD and has been associated with fewer falls during the course of a 1-year intervention.

The utility of cognitive training techniques and whether gains on neuropsychological test scores translate into everyday functional improvement continues to be explored. A recent systematic review of cognitive training and rehabilitation in patients with mild to moderate AD concluded that cognitive training was not associated with positive or negative outcomes but that the overall quality of the trials was low to moderate. Further research is warranted in clearly defined at-risk populations to determine whether cognitive training may prevent or delay incident dementia.

Vascular risk factors such as hypertension, hypercholesterolemia, obesity, diabetes, and smoking in midlife and later years have been associated with increased risk of AD (as discussed in more detail above). It is already known that comorbid cerebrovascular disease facilitates the clinical expression of Alzheimer’s pathology, but there is now increasing knowledge regarding converging and shared pathogenic mechanisms. There is mixed evidence regarding the treatment of hypertension for prevention of dementia, and interventional studies of statins have had negative results on cognitive outcomes to date. There remain compelling cardiovascular and cerebrovascular indications for the detection and treatment of vascular risk factors, which should ordinarily be addressed in the course of cognitive screening.

Patients sometimes enquire about the benefit of alternative therapies such as Gingko biloba or vitamin E. Recent systematic reviews have concluded that there is no consistent evidence to recommend their use in patients with AD or to prevent progression from MCI to AD. One systematic review of interventional studies using omega-3 fatty acids reported improvement in specific cognitive domains for participants with Cognitive Impairment No Dementia (CIND) but not in healthy subjects or those with AD.

4.5 Recent Advances

4.5.1 Disease-Modifying Therapies

In addition to ongoing research in cognitive and lifestyle interventions to delay or prevent the onset of Alzheimer’s dementia (as outlined above), there are currently a large number of clinical trials underway in the area of potentially disease-modifying pharmacological therapies. Given the projected expansion in Alzheimer’s disease worldwide, the public health implications of an intervention, which would delay disease onset by even a modest interval, would be highly significant. Disease-modifying therapies would differ from existing symptomatic therapies in that they should delay disease progression through impacting upon underlying pathophysiological processes with resultant long-lasting changes in disability. Accurate characterization of the underlying pathophysiology of Alzheimer’s disease, as outlined above, has suggested a number of targets for potential disease-modifying treatments. Therapeutic agents under investigation may be broadly considered under the headings of anti-amyloid, tau related, neuroprotective, and neurorestorative therapies (Table 4.5).

Table 4.5 Summary of disease-modifying agents and approaches to Alzheimer’s disease

4.5.2 Anti-amyloid Therapies

Anti-amyloid agents generally act upon the production, aggregation, or clearance of the Ab peptide. These therapies target different parts of the amyloid cascade and include agents that reduce amyloid production through inhibition or modulation of γ and β secretases, agents, which prevent the oligomerization and fibrillization of Ab and immunotherapeutic agents, which facilitate clearance of Ab. The central significance of amyloid in the pathogenesis of AD has recently been called into question given negative outcomes from trials of a number of agents targeting this pathway. Tarenflurbil, an agent that modulates g secretase activity, failed to achieve significance on its primary endpoints in a phase III trial and another agent, Tramiprosate, which binds soluble Ab(beta), thus preventing amyloid deposition, was also negative. Epidemiological studies which linked cholesterol-lowering statin medication with reduced risk of AD and laboratory data indicating a possible mechanism through which statins might reduce production of Ab(beta) triggered further investigation of statins for AD. However, randomized controlled trials of statins for AD have been negative to date. There has also been interest in antihypertensive agents such as calcium channel blockers and those acting on the angiotensin system. Nilvadipine is a calcium channel blocker which has been shown to enhance Ab clearance and restore cortical perfusion in mouse models of AD. There have been promising findings from early clinical studies in patients with AD and a large phase III study of this agent is currently underway.

Immunotherapy forms another potential strategy in anti-amyloid therapy,. A number of hypotheses have been proposed to explain how immunotherapy may result in Ab(beta) clearance. It has been proposed that microglial activation with endocytosis and phagocytosis of Ab(beta) plaques facilitates clearance while alternately, it has been proposed that circulating antibodies may draw soluble Ab(beta) across the blood-brain barrier, thus preventing detrimental binding within the CNS. Research into this area began in earnest when it was found that it was possible to prevent or reverse Ab(beta) accumulation in the brain of an animal model by active immunization with Ab(beta)42. A phase II trial utilizing this method demonstrated effective removal of Ab(beta) plaques but was stopped prematurely because 6 % of patients developed meningoencephalitis. The specificity of Ab(beta) antibodies has since been investigated and active immunization therapies targeting different regions of Ab(beta)42 are under investigation. It was similarly found that passive immunization by peripheral infusion of Ab(beta) antibodies facilitated Ab(beta) clearance in animal models while other investigators utilizing intravenous immunoglobulin containing naturally derived human antibodies against Ab(beta) also presented promising results.

More recently, the results of two Phase III trials utilizing humanized monoclonal antibodies, bapineuzumab and solanezumab, in patients with mild to moderate AD were published. Both antibodies failed to demonstrate positive results on their primary cognitive and functional outcomes measures. The authors concluded that the initiation of anti-amyloid treatment after dementia develops may be too late to affect the clinical course of the disease. The point at which anti-amyloid therapy should be commenced is a critical consideration and studies in samples with earlier stages of the disease are now underway.

4.5.3 Tau-Related Therapies

The formation of neurofibrillary tangles is dependent upon hyperphosphorylation of tau and tau phosphorylation is regulated by a balance between multiple kinases and phosphatases. Glycogen synthase kinase 3 (GSK-3b(beta)) is a key tau kinase, and medications, which are known to inhibit GSK 3b(beta), such as lithium, have shown positive effects in animal studies. Valproic acid has similarly been reported to inhibit GSK 3b(beta). The need to expand therapies for AD beyond amyloid-based approaches means that kinase inhibitor therapeutics now forms an expanding area of research with ongoing exploration of new and existing compounds, which target GSK 3b(beta) and other kinases implicated in the hyperphosphorylation of tau.

4.5.4 Neuroprotective Therapies

These therapies target the neurotoxic effects of Ab through numerous secondary pathways. These include oxidation, inflammation, and demyelination. Astrocyte activation has been hypothesized to play a role in AD pathogenesis and astrocyte-modulating compounds in patients with AD are under investigation. The receptor for advanced glycation end-products (RAGE) is a ubiquitous cell surface receptor, which has been postulated to mediate many of the toxic and neuroinflammatory effects of Ab(beta) and may have potential as a therapeutic target. AMPA type glutamate receptors are believed to mediate most fast synaptic neurotransmission in the brain and positive modulation of these receptors may potentially enhance cognition. An antihistamine (dimebon) with postulated mitochondrial stabilizing properties was tested in a trial in patients with mild-to-moderate Alzheimer’s disease and demonstrated significant efficacy on cognitive, functional, and neuropsychiatric outcome measures, although these findings were not replicated in phase III studies which were subsequently discontinued.

4.5.5 Neurorestorative Therapies

These approaches consist of nerve growth factor (NGF) and neurotrophin therapies, stem cell approaches, and transplantation that may assist in cell survival or replacement and regeneration. NGF, like other neurotrophins, promotes cell survival by signaling through specific tyrosine kinase receptors to effectively block apoptosis from occurring in either a developing or damaged neuron. The impermeability of the blood–brain barrier to exogenous NGF and other neurotrophins is a significant challenge for the development of potential therapeutic agents in AD and strategies to circumvent this difficulty are being researched.

4.5.6 Novel Biomarkers

Diagnosis of Alzheimer’s disease in its earliest clinical stages can be difficult and biological markers of underlying Alzheimer’s pathology have become an increasingly important component of early diagnostic evaluation. This not only improves diagnostic accuracy but assists with prognosis and evaluation of response to potential disease-modifying therapies, which are likely to be of greatest benefit if used before the onset of significant functional impairment. Novel neurochemical, structural, and functional neuroimaging methodologies increasingly augment standard neuropsychological investigations and clinical evaluations as outlined above. These include cerebrospinal fluid levels (CSF) of amyloid beta 42, total tau, and hyperphosphorylated tau, which have displayed good accuracy in identifying incipient AD among subjects with MCI. Methods of CSF analyses continue to be refined and there have been increased efforts to overcome variability between centers with recent publication of consensus criteria to facilitate standardization of CSF biomarker testing. A variety of potential plasma biomarkers for incipient AD have been identified including plasma amyloid beta 42 or plasma amyloid beta 42/40 ratio and additional proteins identified through the use of proteomic methodologies. To date, no single plasma biomarker of Alzheimer’s pathology has displayed sufficient sensitivity or specificity although combining biomarkers from different metabolic pathways may increase diagnostic accuracy and further studies of this approach are underway.

4.5.7 Neuroimaging Biomarkers

Recent advances in neuroimaging techniques have greatly enhanced clinical research in early Alzheimer’s disease. In particular, PET tracers, which can bind to amyloid-beta, now allow the detection of amyloid pathology in vivo. The majority of studies published to date have utilized 11C-Pittsburgh Compound B (PiB), but a number of 11-F tracers with a much longer half-life, have also been developed. The vast majority of patients with a clinical diagnosis of AD have evidence of amyloid on PET imaging studies and antemortem amyloid PET imaging correlates well with findings at autopsy. A consistent finding across studies is that approximately 30 % of cognitively normal older individuals have evidence of amyloid pathology, consistent with the hypothesis that the pathophysiological process of AD may begin years, if not decades prior to the diagnosis of clinical dementia. Early detection of amyloid burden in individuals at risk of cognitive decline and AD has facilitated investigation of anti-amyloid therapies in individuals who are presymptomatic or in the very early stages of disease. It is also possible to track the activity and efficacy of novel therapeutic agents upon amyloid burden with serial imaging. However, PET tracers remain largely a research tool as there are still methodological variations between centres and not all individuals with amyloid pathology necessarily progress to AD. Novel tracers have also emerged to allow in vivo assessment of tau pathology in patients with AD opening new possibilities for the measurement and assessment of novel therapeutic agents targeting this other key pathologic hallmark of AD.

Novel methods for structural MRI continue to evolve, including measures of cortical thickness and tensor morphometry. These techniques have demonstrated evidence of subtle atrophy in MCI and very mild AD. Other neuroimaging techniques which are also under active investigation, include functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose (FDG) PET. FDG PET measures glucose metabolism and decreased FDG uptake is an indicator of impaired synaptic function. In patients with AD there is typically decreased uptake in the lateral temporoparietal or posterior cingulate-precuneus areas with similar changes in patients with early disease. fMRI has consistently shown abnormal hippocampal function during memory encoding in patients with mild AD. fMRI studies have also examined functional connectivity, and have demonstrated disruptions in the default network in patients with AD. Similar disruptions in functional connectivity have been reported in MCI and even in amyloid-positive normal older individuals, suggesting that alterations in this network may be an early sensitive marker of brain dysfunction.

4.5.8 Future Directions

The AD field continues to evolve toward earlier diagnosis, in the hope that earlier intervention with potential disease-modifying therapies will be more efficacious. There have been recent changes to refine diagnostic criteria and incorporate greater use of biomarkers so that older individuals with memory impairment and evidence of amyloid pathology or atrophy should be considered to have very mild AD. Clinical trials of amyloid-lowering agents in these individuals with very early disease and even in the preclinical stages of disease are currently ongoing.

New research criteria have described the category of “preclinical” AD, which encompasses individuals with evidence of amyloid pathology on PET imaging or CSF markers, but who have no clinical symptoms or only very subtle cognitive decline. Several recent studies have demonstrated that clinically normal older individuals with high amyloid burden demonstrate functional and structural brain alterations similar to those observed in MCI and AD. Furthermore, these studies suggest that amyloid-positive older individuals may already have subtle memory impairment, particularly evident when level of cognitive reserve or baseline intellectual capacity is taken into account. However, further longitudinal study is required to determine if the presence of amyloid in cognitively normal individuals is both necessary and sufficient to reliably predict progression to the clinical dementia of AD. An international effort to acquire longitudinal biomarkers in presymptomatic carriers of autosomal dominant mutations (the Dominantly Inherited Alzheimer Network—DIAN study) is also developing methods to track disease progression in the preclinical stages of AD. These studies are critical to moving the field toward a different treatment paradigm. Similar to cardiovascular disease and cancer, the optimal treatment for AD may be at these very early stages, perhaps prior to the emergence of any clinical impairment.