Alzheimer's Disease Chapter 19 PDF

# Alzheimer's disease ## Introduction Alzheimer's disease is a neurodegenerative disease that causes dementia. Dementia refers to the clinical syndrome (a group of symptoms) that is characterized by progressive cognitive decline severe enough to interfere with the ability to function independently...

# Alzheimer's disease ## Introduction Alzheimer's disease is a neurodegenerative disease that causes dementia. Dementia refers to the clinical syndrome (a group of symptoms) that is characterized by progressive cognitive decline severe enough to interfere with the ability to function independently. Dementia can be caused by multiple diseases. Alzheimer's disease is the most common cause of dementia, accounting for about 70% of all dementia cases. The first and most prominent symptom of Alzheimer's disease is gradually progressive memory loss. However, some cases have an atypical clinical presentation starting with predominant language, visual, executive, or behavioural impairment. As Alzheimer's disease progresses, multiple cognitive domains become affected, leading to increasing interference with activities of daily living. Neuropsychiatric symptoms such as depression, apathy and anxiety are also common. In the final stage of Alzheimer's disease, there is overall cognitive loss, and the person is completely dependent on their environment. Assisted living is then usually needed. ## Diagnostic criteria For the diagnosis of Alzheimer's disease and dementia, it is important to distinguish between the clinical syndrome (dementia) and the aetiologic subtype (the cause of the clinical syndrome). **The diagnostic criteria for dementia are:** * Significant cognitive decline in one or more cognitive domains, based on: * concerns about significant decline compared with previous level of functioning, expressed by the individual or by a reliable informant, or observed by a clinician * substantial impairment in cognitive performance (>2 standard deviations from the normative mean) documented by objective cognitive assessments. * The cognitive impairment is severe enough to interfere with independence in everyday activities (at home or at work). * The cognitive impairment does not (exclusively) occur in the context of a delirium and cannot be explained (better) by another mental disorder. The clinical diagnosis of dementia does not say anything about its cause. The aetiological subtype is defined by the underlying brain pathology. **National Institute on Aging - Alzheimer's Association (NIA-AA) provided international consensus criteria for the clinical diagnosis of dementia due to Alzheimer's disease:** These criteria allow for a step-by-step process to specify whether dementia is likely due to underlying Alzheimer's disease with a high, medium or low probability. The first step is to determine the clinical syndrome (in line with the criteria described on the previous page), followed by determining the level of certainty of Alzheimer's disease as the underlying pathology ('possible' or 'probable'). **The diagnosis of dementia due to Alzheimer's disease is probable if:** * There is an insidious onset and gradually progressive course (over months to years, not hours to days); * The cognitive impairment involves a minimum of two of the following domains: memory, executive functions, language, or visuospatial functions; * There is no evidence of a substantial concomitant cerebrovascular, neurological or psychiatric disease that could explain the cognitive symptoms. The level of certainty can be further increased based on additional evidence including: * evidence of progressive cognitive decline on subsequent evaluations based on information from informants and cognitive testing in the context of either formal neuropsychological evaluation or standardized mental status examinations (documented decline); * evidence of the Alzheimer's disease pathophysiological process obtained through neuroimaging (CT, MRI, or PET scan) or cerebrospinal fluid analysis; * evidence of a causative Alzheimer's disease genetic mutation. ## Case: Alzheimer's disease Mrs Davies, a former midwife, is 79 years old. She is unmarried and visits the memory clinic with a friend. Over the past three years she has noticed a gradual decline in her memory. She frequently misplaces items and forgets appointments. Her friend helps her with cooking every day. Her friend also does her groceries, as Mrs Davies has more difficulty paying at the cash register. Driving is no longer possible. Mrs Davies experiences feelings of sadness because of the changes in her everyday functioning. She had always been an independent woman with a busy midwifery practice. Now she prefers to stay at home and has become more withdrawn. Her score on the MoCA is 24/30. She appears normal at the physical and neurological exam. Neuropsychological testing reveals memory impairment, specifically with delayed recall (Rey Auditory Verbal Learning Test) and learning visual associations (Visual Association Test). In addition, there is impairment in executive functions (increased interference on the Stroop Color and Word Test and decreased cognitive flexibility on the Trail Making Test) and language production (impaired word fluency on profession naming and impaired word finding on the Boston Naming Test). The MRI shows substantial global atrophy (GCA score 2) and bilateral hippocampal atrophy (MTA Score 2). White matter abnormalities are within the normal range for her age. Laboratory test results also fall within the normal range. In a multidisciplinary consensus meeting, a diagnosis of dementia is established based on the presence of cognitive impairment in multiple domains and interference with everyday functioning. The neuropsychological profile and clinical presentation are most typical for dementia due to Alzheimer's disease, which is supported by the MRI findings. The diagnosis is discussed with Mrs Davis and her friend. It is proposed to start treatment with a cholinesterase inhibitor to slow down the progression of symptoms. Two weeks after the diagnosis meeting with the doctor, Mrs Davies and her friend return to the neuropsychologist to get advice on how to cope with the cognitive and emotional changes that are associated with dementia. It is suggested to involve a case manager to help Mrs Davies looking for meaningful and enjoyable daily activities. ## Mild cognitive impairment (MCI) The dementia stage is usually preceded by a phase of mild cognitive impairment (MCI). The main difference between MCI and dementia is that the ability to function independently in daily life is still (relatively) intact in MCI. **The criteria for MCI are:** * Modest cognitive decline: * concerns about mild decline compared with previous level of functioning, expressed by the individual or by a reliable informant, or observed by a clinician * modest impairment in cognitive performance (1-2 standard deviations below the mean) documented by objective cognitive assessment. * There is no (overt) interference with independence in everyday activities, although these activities may require more time and effort, accommodation, or compensatory strategies. * The cognitive problems do not (exclusively) occur in the context of a delirium and cannot be explained (better) by another mental disorder. According to the NIA-AA consensus criteria, the syndrome MCI can be attributed to underlying Alzheimer's disease pathology with varying levels of certainty. **The likelihood of MCI due to Alzheimer's disease increases if there is evidence of:** * A cognitive profile that is typical for early Alzheimer's disease, that is: a prominent impairment in episodic memory ('amnestic MCI') with an insidious onset and a progressive course. * A positive biomarker reflecting the Alzheimer's disease pathophysiological process. Amnestic MCI can be considered a prodromal stage of Alzheimer's dementia, but MCI can also be a precursor of other forms of dementia. It is also important to realise that a proportion of people with MCI do not have an underlying neurodegenerative disease at all and thus never develop dementia: some remain stable or even improve over time. The chance of developing dementia within five to ten years after an MCI diagnosis is on average about 50% in a memory clinic population, but this strongly depends on age. Moreover, additional information, for example obtained from a neuropsychological assessment or biomarker evidence, can help to better predict which MCI patients will eventually progress to dementia (Van Maele et al., 2010). In terms of the neuropsychological profile, the amnestic MCI subtype is the most consistent predictor for progression to Alzheimer's dementia. ## Case: MCI Mr Campbell, 67 years old and with a history of Crohn's disease, visits the memory clinic after a referral by his general practitioner. He reports increasing forgetfulness, which is also noticed by his wife. He has a positive family history of Alzheimer's disease (which is also reported by his father and oldest brother). The interview with the patient and informant reveals only minimal interference with his daily activities. Mr Campbell has recently retired and mentions that he had difficulty learning a new computer system in the last year of his work. During that period, he suffered from non-specific physical complaints, such as itching. These physical complaints disappeared since he stopped working. In his daily life, he likes to exercise, such as cycling. He cycles for hours and mentions that he has no difficulty finding his way about familiar streets or outside his own neighbourhood. The score on the MoCA is 26/30; he loses 3 points on the word recall and 1 point on orientation in time. During neuropsychological testing, Mr Campbell seems nervous and insecure. Performance on tests measuring processing speed, attention and concentration falls within the (low) average range. Scores on memory tests are below average (a capricious learning curve and impaired delayed recall on the Rey Auditory Verbal Learning Test; very low score on the Visual Association Test). There are no impairments in other cognitive domains. The MRI shows mild global cerebral atrophy (GCA Score 1) and minimal hippocampal atrophy (MTA Score 1), which could be normal for his age. There are no vascular abnormalities. Laboratory tests just show a slightly increased sedimentation rate, but no further abnormalities. Based on the interview with the patient and informant and the neuropsychological test results, a diagnosis of amnestic MCI is established, possibly as a prodromal stage of Alzheimer's disease. The diagnosis is discussed with Mr Campbell and his wife, and it is suggested to monitor the course and repeat the neuropsychological examination after one year. In a follow-up interview, the neuropsychologist provides a more detailed explanation of his cognitive profile and provides advice on how to deal with the cognitive complaints in his daily life. Mr Campbell is relieved that he does not have dementia. His wife mentions that she can cope with the forgetfulness of her husband. The couple is satisfied with the explanations and has no further request for help at this time. ## Epidemiology It was estimated that 290,000 people were living with dementia in the Netherlands in 2020; and worldwide this was estimated to be over 50 million in that year. Alzheimer's disease accounts for approximately 60 to 70% of all dementia cases. The prevalence of dementia increases rapidly with age: over 8% of all people aged 65 and older have dementia, compared to over 25% of people aged 80 years and older and over 40% of people aged 90 years and older. However, in some cases dementia may also affect people at a younger age. In 2020, there were around 14,000 to 17,000 people with dementia below the age of 65 years in the Netherlands, and around 3.9 million worldwide. This is probably an underestimation of the actual numbers, since dementia is often not well recognised at such a young age, and the diagnostic phase often takes a long time. About one in five people develops dementia. The risk of developing dementia is higher for women (one in three) than men (one in seven). This is partly due to the longer life expectancy of women but may also be explained by sex differences in genetic, biological and socio-economic risk factors for developing dementia. Every year there are more than 30,000 new dementia cases in the Netherlands and nearly ten million new cases worldwide. This means that a dementia diagnosis is established every ten minutes in the Netherlands, and every three seconds worldwide. After having received a dementia diagnosis, a person survives on average seven to ten years. The incidence (the number of new dementia cases per year) has decreased in recent years, which is likely due to better treatment of cardiovascular risk factors (see Paragraph 19.2.5). However, due to the increasing age of the population, it is expected that prevalence (the total number of people with dementia at a given moment) will increase exponentially in the next few decades, with an expected number of half a million cases in the Netherlands and more than 80 million worldwide in 2040. ## Alois Alzheimer’s dementia Alois Alzheimer (1864-1915) was born in Marktbreit, Bavaria. He attended various universities and became a physician in 1887. After starting work in a psychiatric institution in Frankfurt he became interested in neuropathology. Franz Nissl (1860-1919), best known for developing a staining technique to visualise cell bodies, also worked at this institute. Alzheimer and Nissl jointly conducted numerous neuropathological studies, mainly involving the cortex. This resulted in the publication of the six-volume Histologische und Histopatologische Arbeiten über die Grosshiminde between 1908 and 1918. Both Alzheimer and Nissl later worked for Emil Kraepelin in Heidelberg. Kraepelin went to Munich, and Alzheimer followed him in 1903 to carry out research on the effects of epilepsy He observed a distinctive loss of cells in Ammon’s horn (now referred to as the hippocampus), and assumed that this loss was caused by epileptic seizures. In 1906, Alzheimer gave a lecture at a meeting entitled Über eine eigenartige Erkrankung der Hirnrinde (On an Unusual Illness of the Cerebral Cortex), during which he discussed his findings with regard to the case of a female patient, Auguste Deter, whom he had met in 1901 in the hospital in Frankfurt, when she was 51 years old. Alzheimer was in Munich at the time when she died, and asked his superior in Heidelberg whether he could examine the patient’s data, including the findings of the neuropathological research. Alzheimer discovered that the cortex of this patient was unusually thin, and he identified senile plaques, structures that had been described previously. He also observed an anomaly that had not been described before, namely neurofibrillary tangles (fibrous intraneuronal aggregates of protein). Because the patient was relatively young, it was thought that a new syndrome was involved - that is, a type of dementia that occurs at a young age, termed presenile dementia. Kraepelin, the most influential figure in the field of diagnostics and classification in psychiatry at that time, supported this view and introduced the eponym Alzheimer's disease. It was not until around 1980 that it became clear that senile dementia also involved the typical characteristics described by Alzheimer. After its extent had become recognised, Alzheimer’s disease became one of the most prevalent chronic diseases. ## Aetiology and neuropathology **Plaques and tangles** Alois Alzheimer, a German psychiatrist and neuropathologist, was the first to describe the clinical and pathological features of Alzheimer’s disease. The neuropathology of Alzheimer’s disease is characterized by abnormal accumulation and deposition of extracellular plaques of the amyloid-beta protein (senile plaques) and intracellular tangles of the protein tau (neurofibrillary tangles), which lead to degeneration of nerve cells and ultimately brain atrophy (neurodegeneration). Today, the presence of Alzheimer’s disease pathology can still only be confirmed post-mortem by an autopsy-based neuropathology examination. However, recent advances in biomarker research using structural imaging (CT and MRI), molecular imaging (amyloid and tau PET imaging) and cerebrospinal fluid (CSF) now enable the in vivo assessment of the different neuropathological features (amyloid, tau, and neurodegeneration). **Amyloid cascade hypothesis** The cause of Alzheimer's disease is currently not fully understood and still the subject of ongoing debate. The most widely accepted hypothesis explaining the AD pathogenesis is the amyloid cascade hypothesis. This hypothesis postulates that an abnormal accumulation of the amyloid-beta protein is the primary driver of Alzheimer's disease. The amyloid cascade hypothesis is based on research in people with a mutation in the Amyloid Precursor Protein (APP) gene. These individuals show an overproduction of amyloid-beta and eventually all develop Alzheimer’s dementia. APP is a precursor of the amyloid-beta protein, and when the APP is broken down in abnormal proportions, this leads to an overproduction of beta-amyloid. The amyloid cascade hypothesis posits that the accumulation of amyloid-beta plaques triggers the propagation of tau pathology throughout the brain which, in turn, leads to synapse loss followed by neuronal death, cognitive decline and ultimately dementia. Research has shown that amyloid-beta plaques may be present as early as 20 to 30 years before the onset of dementia, and that individuals with amyloid-beta plaques and tau pathology are indeed at higher risk for cognitive decline and progression to Alzheimer’s dementia. On the other hand, it must be noted that the presence of amyloid-beta plaques does not necessarily imply that someone has Alzheimer’s disease or will develop dementia. It appears that about 1 in 3 healthy older people have amyloid pathology in the brain; and it is still unclear if, and when, all of them will develop dementia before the end of their life. Based on the idea that amyloid deposition plays a key role in the development of Alzheimer's disease, clearing amyloid-beta plaques has been the main focus of new therapies that aim to slow or halt the disease process. However, this research has not (yet) provided the results that researchers were hoping for. Although some anti-amyloid drugs were found to be effective in reducing amyloid-beta plaques in the brain, evidence for their clinical efficacy remains inconclusive. A possible explanation for this is that the intervention occurred too late in the disease process, in which amyloid-beta had already caused irreversible brain damage. Another explanation is that amyloid-beta deposition alone is not sufficient to develop the disease, and that multiple pathophysiological processes play a role in the development of Alzheimer's disease. **Vascular hypothesis** The vascular hypothesis postulates that cerebrovascular disease plays an important role in the development of Alzheimer's disease. This hypothesis assumes that vascular risk factors, such as hypertension, high blood pressure, diabetes and obesity, lead to reduced blood flow and oxygen deficiency in the brain. This, in turn, leads to stiffening of the arterial walls but also to a metabolic reaction that causes an overproduction of the amyloid-beta protein and ultimately neurodegeneration. The vascular hypothesis has gained strong support from epidemiological research using large observational cohort studies, showing, for example, that high blood pressure and vascular damage are a predictor of cognitive decline and dementia. Furthermore, studies showed that lifestyle changes that have a positive influence on cardiovascular health, such as increased physical exercise, reduced smoking, and weight loss in case of obesity, reduce the risk of Alzheimer's dementia. **Both hypotheses combined** A growing body of evidence suggests that amyloid pathology and cardiovascular disease risk factors likely interact in the development of Alzheimer’s disease. For example, it appears that amyloid-beta accumulations and cerebrovascular damage often co-occur in later life and may have an additive or even synergistic effect on the degree of neurodegeneration and rate of cognitive decline. In fact, autopsy-based studies in people with Alzheimer’s dementia shows that co-pathology of amyloid, tau and vascular damage is often the rule rather than the exception, and scientists increasingly agree that the amyloid cascade hypothesis and the vascular hypothesis are likely to complement each other instead of being two separate, contradictory hypotheses. ## Risk factors Alzheimer’s disease is a complex disease in which several pathological processes seem to play a role. Further, increasing evidence suggests that multiple risk and protective factors interact with the underlying disease process. **A distinction can be made between modifiable and non-modifiable risk factors.** * Non-modifiable risk factors for Alzheimer's disease include older age, female sex, and genetic predisposition. However, genetic predisposition does not necessarily mean that Alzheimer's disease is always inheritable. Only in rare cases, there is an autosomal dominant inherited form caused by a mutation in the APP, presenilin-1 (PS-1) or presenilin-2 (PS-2) gene. This form, also referred to as familial Alzheimer’s disease, almost certainly leads to Alzheimer’s disease. However, it only explains a small proportion (< 1%) of all cases. Thus, in most cases Alzheimer’s disease is not inherited, and is referred to as sporadic Alzheimer’s disease. Some genetic risk factors are thought to play a role in the development of sporadic Alzheimer’s disease, of which the apolipoprotein E (APOE) genotype is the most strongly confirmed genetic risk factor so far. The presence of an APOE E4 allele is associated with an increased risk of developing Alzheimer’s, while the APOE E2 allele seems to have a protective effect. However, carrying the APOE E4 form of the gene does not mean that a person will definitely develop the disease, and some people with no APOE E4 allele may also develop Alzheimer’s. Therefore, determining one’s APOE genotype has no role (yet) in the clinical diagnosis of Alzheimer’s disease. * Modifiable risk factors are factors that can be addressed through lifestyle changes, such as exercise, diet, and mental activity. In 2017, a report by an international research group revealed nine important risk factors over the lifespan that are associated with the development of dementia in general (not only due to Alzheimer’s disease): lower educational level, high blood pressure, hearing loss, smoking, obesity, depression, little physical activity, diabetes, and a small social network. Excessive alcohol consumption, brain injury and air pollution were added to this list of potentially modifiable risk factors in 2020. Together, these 12 modifiable risk factors account for around 40% of worldwide dementias, which consequently could theoretically be delayed or even prevented. ## Clinical and cognitive profile ### Clinical course The clinical course of Alzheimer’s disease can be described as a continuum of gradually progressive cognitive decline, starting with subtle cognitive changes, followed by increasingly persistent cognitive decline, functional impairment, and ultimately the dementia syndrome. The most reported cognitive complaints that patients initially present with are difficulty remembering recent events, forgetting appointments and word-finding problems. In rare cases, patients present with other symptoms and memory problems are less prominent. Due to the insidious onset of the disease, cognitive complaints have usually been present for a while when the patient visits the general practitioner, memory clinic or other institution for a diagnostic workup. A thorough clinical interview with the patient as well as an informant is thus of crucial importance to obtain proper insight into the onset and course of symptoms. The interview with the informant is of particular importance when dementia is suspected, because in that stage of the disease a patient may have lack of insight and might be unable to recognize changes in their own functioning. The clinical course of Alzheimer’s disease can be divided into the following stages: mild cognitive impairment (MCI), mild dementia, moderate dementia, and severe dementia. The Clinical Dementia Rating (CDR®) scale is an instrument that is often used to assess the clinical stage of Alzheimer’s disease. The CDR is a semi-structured interview with the patient and informant, in which cognitive and functional performance is rated in six domains (Memory, Orientation, Problem-solving ability, Social activities, Home and hobbies, Personal care). The ratings based on interview data and clinical judgement for each domain are summarized in the table: | Impairment | None | Questionable | |---|---|---| | Memory | No memory loss or slight inconsistent forgetfulness | Consistent slight forgetfulness; partial recollection of events; 'benign' forgetfulness | | Orientation | Fully oriented | Fully oriented except for slight difficulty with time relationships | | Judgement and problemsolving | Solves everyday problems, and handles business and financial affairs well; judgement good in relation to past performance | Slight impairment in solving problems, similarities, and differences | | Community affairs | Independent function at usual level in job, shopping, volunteer and social groups | Slight impairment in these activities | | Home and hobbies | Life at home, hobbies, and intellectual interests well maintained | Life at home, hobbies, and intellectual interests slightly impaired | | Personal care | Fully capable of self-care | Fully capable of self-care | **Mild** - Moderate memory loss; more marked for recent events; defect interferes with everyday activities - Moderate difficulty with time relationships; oriented for place at examination; may have geographical disorientation elsewhere - Moderate difficulty in handling problems, similarities, and differences; social judgement usually maintained **Moderate** - Severe memory loss; only highly learned material retained; new material rapidly lost - Severe difficulty with time relationships; usually disoriented to time, often to place - Severely impaired in handling problems, similarities, and differences; social judgement usually impaired **Severe** - Severe memory loss; only fragments remain - Oriented to person only - Unable to make judgement or solve problems - Unable to function independently at these activities although may still be engaged in some; appears normal to casual inspection - Appears well enough to be taken to functions outside home - No pretence of independent function outside home - Mild but definite impairment of function at home; more difficult chores abandoned; more complicated hobbies and interests abandoned - Only simple chores preserved; very restricted interests, poorly maintained - Appears too ill to be taken to functions outside a family home - No significant function in the home - Needs prompting - Requires assistance in dressing, hygiene, keeping of personal effects - Requires much help with personal care; frequent incontinence ### Cognitive profile Neuropsychological assessment is important for establishing a syndrome diagnosis as it can reliably distinguish between normal cognition, MCI and dementia. An extensive neuropsychological assessment is especially valuable in the prodromal and early stages of dementia. Sometimes only a brief cognitive screener, such as the Montreal Cognitive Assessment (MOCA), is administered to determine the syndrome diagnosis. A low score on such a screening test can provide sufficient confirmation when there are clear signs and symptoms of advanced dementia. However, this is insufficient for the clinical diagnosis in an early phase of the disease, and a more extensive neuropsychological assessment is advised as it provides more thorough information about the cognitive profile and can thereby better differentiate between cognitive impairment due to Alzheimer’s disease versus other types of dementia. The cognitive profile of dementia due to Alzheimer’s disease is typically characterized by prominent episodic memory deficits accompanied by a decline in semantic memory, language, working memory and executive functions, followed by visuoconstructive and praxis deficits in more advanced stages of the disease. Whereas the exact neuropsychological profile as well as the rate of decline per cognitive domain varies greatly per individual. There is a global trajectory of cognitive decline that distinguishes Alzheimer’s disease from other types of dementia. This typical neuropsychological profile of Alzheimer’s disease is discussed in the next paragraphs, separately by clinical stage and corresponding global CDR score (Table 19.1). **Amnestic MCI as predementia stage (CDR 0.5)** Episodic memory deficits are typically the first signs of cognitive impairment due to Alzheimer's disease, mostly manifesting as impaired learning and retrieving of recently learned information (anterograde amnesia). This is due to deficits in memory consolidation caused by neuronal loss of the hippocampus. Another commonly reported complaint in the MCI stages is word-finding problems, but these are difficult to establish with the currently available naming tests. The cognitive problems in the MCI stage should not lead to substantial functional impairment, but performing certain complex activities of daily living can be more challenging, such as working or managing finances (Jekel et al., 2015). **Mild dementia (CDR 1)** In this stage, problems in other cognitive functions start to emerge, including language production, orientation in time and place (when outside one’s own familiar environment), and planning an performing activities. Language problems mainly concern a gradual decline in semantic knowledge and relationships, due to the increasing atrophy in the medial temporal lobe. A characteristic example of initial language changes in Alzheimer’s disease is that category fluency is relatively more affected than letter fluency. The reduced orientation in time and place at this stage is often related to episodic memory deficits: patients often forget the exact date or month. Regarding executive functioning, problems with planning and organising complex actions are most profound, caused by deficits in mental flexibility and divided attention. Cognitive problems lead to clear limitations in daily life, especially in more complex activities of daily living, also referred to as instrumental activities of daily living (IADL). IADL are activities that require multiple higher-order cognitive processes, such as driving, cooking, and shopping. In this stage of dementia, people have more difficulty in performing IADL activities than previously or are no longer performing them independently. **Moderate dementia (CDR 2)** In this stage of dementia, even more extensive cognitive impairments occur. Episodic memory deficits are now also evident for information of the more distant past, orientation in time and place deteriorates, and impairments in word-finding and visuoconstruction, as well as apraxia, may be present. The person becomes increasingly dependent on others in daily life, and even the more basic activities of daily living, such as brushing one’s teeth or dressing, become more difficult. **Severe dementia (CDR 3)** In the final stage of dementia there is severe cognitive loss, and the person is completely dependent on their environment. Sometimes it is possible to continue living at home but taking care of a relative with severe dementia can be burdensome. Caregivers may want to use support services, such as a care home. Patients have more difficulty communicating in this stage, due to loss of speech and perseverations or intrusions in language. Orientation to time, place and person is impaired, which often leads to confusion and disturbed behaviour. Basic motor functions, such as chewing and swallowing, become affected and incontinence problems also occur due to the severe brain pathology. Eventually, dementia will (usually in an indirect way) lead to death by complication such as pneumonia infection, not eating or drinking, or other comorbidities. ### Brain changes Structural neuroimaging based on CT or MR is currently still the most commonly used biomarker in clinical practice for the diagnosis of Alzheimer’s disease and other forms of dementia. It is used primarily to rule out another neurological disorder, and second to identify positive signs for the aetiological cause of dementia. Alzheimer’s disease is characterized by a typical pattern of grey matter volume loss, starting in the medio-temporal lobe followed by more posterior and frontal cortical regions and eventually global cortical atrophy. When Alzheimer’s disease is suspected, the structure and volume of the hippocampus are inspected first. The rate of atrophy in the hippocampal areas can be visually assessed using the Scheltens scale, also known as the medio-temporal atrophy (MTA) scale. The MTA score is calculated using a T1-weighted coronal section and based on the 1) width of choroid fissure; 2) the width of the temporal horn; and 3) the height of the hippocampus (see Table 19.2 and Figure 19.3). The age-adjusted MTA score has high sensitivity and specificity for Alzheimer’s disease and is a good predictor for progression to Alzheimer’s dementia in older adults with MCI. | Score | Width of choroid fissure | Width of temporal horn | Height of hippocampus | Age-related cut-off values | |---|---|---|---|---| | 0 | Normal | Normal | Normal | Normal regardless of age | | 1 | ↑ | Normal | Normal | Normal for age > 65 | | 2 | ↑↑ | ↑ | ↓ | Normal for age > 70 | | 3 | ↑↑↑ | ↑↑ | ↓↓ | Normal for age > 80 | | 4 | ↑↑↑ | ↑↑↑ | ↓↓↓ | Abnormal regardless of age | ↑ = increased, ↓ = decreased An electroencephalogram (EEG) is used to detect abnormal brain changes by measuring its electrical activity. The most characteristic abnormality of an EEG consistent with Alzheimer’s disease is an overall slowing of the dominant rhythm (alpha activity), manifested by a reduction in peak frequency. It is important to note that the significance of the EEG in the diagnosis of Alzheimer’s disease is limited. An abnormal EEG can support the diagnosis of Alzheimer’s disease, but a normal EEG does not necessarily rule out the disease. However, a normal EEG would strongly argue against other forms of dementia, such as dementia with Lewy bodies; and therefore can be of added value to differentiate between Alzheimer’s disease and other dementias. Positron emission tomography (PET) with 18F-fluoro-2-Deoxy-D-glucose (FDG) provides an alternative way to measure functional abnormalities in the brain. FDG-PET measures reductions in the cerebral metabolic rate for glucose, which is a measure of neuronal activity. Studies using FDG-PET showed that abnormalities in glucose metabolism, especially in the temporo-parietal regions, can be detected in the early stages of Alzheimer's disease and are a predictor of disease progression. A more recent advancement is the use of PET to visualise amyloid-beta and tau deposition in the brain, enabling the in vivo detection of Alzheimer’s disease pathology. Studies have consistently shown that an abnormal amyloid PET scan correlates well with having cerebral amyloid pathology at post-mortem examination. However, an abnormal amyloid PET scan can also occur in older people without dementia. Additionally, in individuals with dementia, the amount of amyloid deposition does not strongly correlate with disease severity. Current diagnostic guidelines do not recommend amyloid PET scan as a routine examination, but it may be considered in individual cases, for example in younger adults (< 65 years) with the goal to differentiate between Alzheimer’s disease or another form of dementia. Research into the use and diagnostic value of tau PET scans is ongoing and tau PET is currently still used only for research purposes. Information about the presence of amyloid-beta and tau pathology can also be obtained using a lumbar puncture. Here, a small part of the cerebrospinal fluid is collected to determine the concentration of amyloid-beta, tau and phosphorylated tau (P-tau). A decreased concentration of amyloid-beta and an increased concentration of tau and P-tau is a typical cerebrospinal fluid (CSF) profile for Alzheimer’s disease. The advantage of CSF diagnostics is that it is quicker, more easily available, and at lower costs than an amyloid PET scan. A disadvantage is that the concentration in the CSF does not provide any information about the localisation of pathology. When Alzheimer’s disease is suspected, CSF biomarkers may have value in increasing the certainty of the diagnosis or excluding the diagnosis. However, as with amyloid PET scans, the diagnostic value of CSF biomarkers for Alzheimer’s appears to decrease with age. Neuropsychological assessment and structural imaging are therefore still the main methods of diagnostic investigation when Alzheimer’s is suspected, especially in older adults with MCI or dementia. ### Atypical variants of Alzheimer’s disease The previous paragraph describes the ‘typical’ form of Alzheimer’s disease, characterized by prominent memory impairment and a pattern of atrophy distribution starting in the medio-temporal lobe. However, in some rare cases, the clinical presentation and disease course can be atypical. These atypical variants of Alzheimer’s disease have the same underlying pathology (amyloid plaques and tau tangles), but brain changes start in different cortical regions and consequently lead to different cognitive symptoms in the initial stage of the disease. **Posterior cortical atrophy (PCA)** Posterior cortical atrophy (PCA) is characterized by prominent deficits in visuospatial functions. Individuals with PCA initially have impaired visuoconstruction and visuoperception (visual agnosia), while their memory remains relatively intact. The pattern of neurodegeneration usually starts in the parietal and occipital lobe and then spreads to the occipitotemporal lobe as well. Compared with the typical variant of Alzheimer’s disease, the medio-temporal lobe is spared for a relatively long time. **Logopenic variant primary progressive aphasia (lvPPA)** This variant of Alzheimer’s disease starts with predominant language and communication deficits and is also called the language variant of Alzheimer’s disease. The initial cognitive symptoms include word-finding deficits and impaired repeating of sentences. During the course of the disease, language comprehension, executive functions and verbal memory become affected as well. In the early stages, atrophy distribution is asymmetrical and most pronounced in the left temporal lobe. ## Case: logopenic variant primary progressive aphasia (lvPPA) A 69-year-old man visits the memory clinic for a second opinion because of language problems that have existed for four years. He reports increasing word-finding problems and has more difficulty speaking. The patient says that others increasingly fill in his sentences when he is not able to find the right word. Before placing a phone call, he writes down the keywords that he wants to talk about. He pronounces words incorrectly, for example by reversing the syllables, or uses the wrong words. When asked, the patient has also noticed more forgetfulness. He may forget small things, but these problems are not as noticeable and prominent as the language problems. His wife adds that her husband sometimes does not complete his sentences, as if he no longer knows what he wanted to say. The neurological examination is normal. Performance on the MoCA is impaired with a score of 19/30. The MRI scan shows symmetrical parietal atrophy, and to a lesser extent also asymmetrical atrophy of the frontal and temporal lobes which is more pronounced in the left hemisphere. During neuropsychological testing, speech is predominantly fluent, but word-finding problems and phonematic errors are notable. There is no clear agrammatism, although sentences are sometimes not completed. Comprehension is normal. Naming, repeating sentences and phonology are impaired. Scores on focused attention tasks are also abnormal. Performance on tests tapping into executive functions, memory, visuospa-tial functions and social cognition still falls within the normal range. Based on the clinical interview with the patient and informant, the behavioral observations, imaging and neuropsychological profile, the patient meets the core and supporting criteria for lvPPA. ### The behavioural/dysexecutive variant The behavioural/dysexecutive variant of Alzheimer’s disease presents with behavioural changes and impairments in executive function and social cognition as predominant symptoms. The type of behavioural changes can vary by individual and range from disinhibition to apathy. Cortical atrophy is initially most pronounced in the frontal lobe regions. As a result, the clinical presentation is consistent with the behavioural variant of frontotemporal dementia (see Chapter 20), but PET and CSF biomarkers reveal underlying Alzheimer’s pathophysiology. ### Early-onset Alzheimer’s disease The previously discussed atypical variants of Alzheimer’s disease all have in common that the initial symptoms usually appear at a younger age (i.e., before the age of 65). However, sometimes the typical form of Alzheimer’s disease (memory impairment as the most prominent symptom) also begins at a younger age. Early-onset Alzheimer’s disease (sometimes also called young-onset Alzheimer’s disease, and previously known as presenile dementia) can be a diagnostic challenge given the potential atypical clinical presentation. In addition, the symptoms are often initially associated with other causes that are more common at a younger age, such as a burnout or depression. As a consequence, it can take a relatively long time before a young person is referred to a memory clinic for a dementia screening. The period from noticing the first symptoms to the diagnosis of dementia lasts on average more than four years in individuals at a younger age. During the diagnostic workup, it is important to pay attention to ‘