A Guide to the Diagnosis and Assessment of Alzheimer's Disease

Section 1
Differentiating Alzheimer's disease from other forms of dementia

• Differentiate dementia from normal aging, depression and delirium and effects of drugs
• Explore the causes of dementia
• Describe the etiology, neuropathology and clinical symptoms of AD
• Briefly review the clinical symptoms of other common dementing disorders

The characteristic clinical feature of dementia is the presence of cognitive decline sufficient to cause functional impairment. Criteria for dementia are defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV) (Table 1). When dementia has been confirmed, the differential diagnosis can begin. The onset of progressive dementia is usually insidious. The first signs are forgetfulness, personality change, changes in the capacity to carry out the ordinary tasks of daily living, and repetitive behavior.

In addition, delusions and paranoid or antisocial behavior may be experienced in more advanced dementia. The exact clinical symptoms vary between patients and the duration of the illness may be long or short, taking from months (e.g. Creutzfeld-Jakob disease) to years (average 9 years in AD). Dementia has diverse etiologies. One challenge is to make a correct differential diagnosis.

• Problems with language (aphasia)
• Inability to performpurposeful actions (apraxia)
• Poor recognition (agnosia)
• Impaired executive functioning

Cognitive deficit:

• Interfering with occupational and/or social functioning
• Representing a decline from a higher level

Aging and cognitive decline

There is a natural age-associated modification in cognition. As a consequence, it can be problematic distinguishing between cognitive impairment associated with normal aging and early dementia. In addition, 'mild cognitive impairment' (MCI) can be experienced. This is characterized by an abnormal level of cognitive impairment, albeit that it does not fulfill dementia criteria as it is insufficient to cause functional decline. It should be noted that MCI is not a feature of normal aging. Some individuals develop MCI but do not develop dementia. However, many patients with MCI do go on to develop dementia.

It is important to distinguish the early stages of dementia from the cognitive changes that can occur with normal aging. During normal aging, the ability to learn and acquire information declines gradually. The ability to recall information remains relatively preserved. This is very different from the early stages of dementia, in particular AD. In AD, there is a progressive decline in learning and the ability to recall information.

Dementia, delirium, depression and drugs

If a patient presents with memory loss, the differential diagnosis should include the '4 Ds'; delirium, depression, drugs, and dementia.

The cognitive impairment that often accompanies delirium and depression can be mistaken for, or can coexist with, dementia. Evidence of delirium or depression should be addressed promptly. Although delirium is common in older adults with acute illnesses, it often goes unrecognized in the clinical setting. Likewise, although depression occurs frequently in older adults, it is under-diagnosed. Some of the factors to distinguish dementia from delirium are detailed in Table 2 below.

It is essential that delirium is discounted as early as possible. The underlying physical disorder, together with decline in cognition, may constitute a medical emergency. Immediate evaluation of the underlying causes and initiation of possible treatment is imperative.

It can be difficult to differentiate between dementia and depression. Depression can manifest as dementia, or the dementia syndrome of depression (depressive pseudodementia) (Table 3). Conversely, dementia can present with depressive symptoms in the early stages of the illness. Depression and dementia, as well as many other illnesses in old age, may coexist. Up to 50% of individuals diagnosed with dementia will have coexisting depressive symptoms at some point in their illness.

Many medications can cause dementia-like states, including over-the-counter products. All medications should be carefully assessed and treatment ceased if appropriate.

• Insidious onset with unknown date
• Slow, gradual, progressive decline
• Generally irreversible
• Disorientation late in illness
• Slight day-to-day variation
• Less prominent physiological changes
• Consciousness clouded only in late stage
• Normal attention span
• Disturbed sleep­wake cycle; day­night variation
• Psychomotor changes late in illness

• Abrupt precise onset with known date
• Acute illness, lasting days or weeks
• Usually reversible
• Disorientation early in illness
• Variable, hour by hour
• Prominent physiological changes
• Fluctuating levels of consciousness
• Short attention span
• Disturbed sleep­wake cycle; hour-to-hour variation
• Marked early psychomotor changes (e.g. agitation)

• Insidious onset
• No psychiatric history
• Conceals disability
• Near-miss answers
• Mood fluctuates day to day
• Stable cognitive deficit
• Tries hard to perform but is unconcerned by losses
• Short-term memory loss
• Memory loss occurs first
• Associated with declining social function

• Less insidious onset
• History of depression
• Highlights disabilities
• 'Don't know' answers
• Diurnal variation in mood
• Fluctuating cognitive deficit
• Tries less hard and gets distressed by losses
• Short- and long-term memory loss
• Depressed mood coincides with memory loss
• Associated with anxiety

Many different disease states can produce the clinical syndrome of dementia. These can be divided into two groups:

• Reversible
• Irreversible

Reversible dementia syndrome

The term reversible or potentially/ partially reversible is used to define a cognitive disorder in which normal or nearly normal function may be restored. The potential to reverse or delay deterioration emphasizes the importance of an early diagnosis of a reversible dementia. The most common causes of reversible dementia are depression, delirium, and drug toxicity. Other causes include normal pressure hydrocephalus, neoplasms, metabolic disorders, trauma, medications and infections.

Irreversible dementia syndrome

The most common causes of irreversible dementia include:

• Alzheimer's disease
• Vascular dementia

These account for at least 70­80% of all cases.

Less common, and more difficult to recognize clinically, are:

• Dementia of Lewy body type
• Pick's disease (dementia of the frontal lobe-type [DFT])

Alzheimer's disease

Diagnosing Alzheimer's disease

Previously, the definite diagnosis of AD was based purely on neuro-pathological findings. Reliably diagnosing the disease during the lifetime of the patient, without a brain biopsy, was considered impossible. Opinions have changed. The implementation of existing skills, the development of new diagnostic techniques, coupled with a greater appreciation of the disease, now makes the clinical diagnosis of AD a realistic possibility during the lifetime of the patient.

AD is no longer considered to be a diagnosis of exclusion. AD has a relatively consistent onset, clinical presentation and course which makes it one of the most characteristic of mental disease processes. Although it is still necessary to eliminate the possibility of other dementia syndromes, the clinical symptoms of AD are clearly defined and can be evaluated using a variety of assessment techniques.

Although the prospect of developing a cure is unlikely in the foreseeable future, new symptomatic treatments are becoming available. This further supports the value of early recognition of AD.

Many approaches are currently being investigated in the search for symptomatic therapies. These include the development of cholinergic agonists, in particular muscarinic and nicotinic agonists, and the use of neurotropic factors. Cholinesterase (ChE) inhibitors are the first agents approved for use in clinical practice.

In addition, the escalating number of people with AD in society demands greater efforts to reduce or delay the effects of the disease. This, coupled with the demand that this will place on limited healthcare resources, emphasizes the need for early diagnosis and intervention.

The process of making a diagnosis provides an opportunity to address other important issues. It will determine how well patients and caregivers are coping. Providing families with an understanding of what to expect can reduce the levels of stress and anxiety, making it easier to cope. Caregiver support programs also ease the burden and play an important role in the management of AD.

AD prognosis

AD is a progressive neurodegenerative disease, characterized by an insidious onset and a gradual decline in cognition and functional ability (Figure 2). It is the most common cause of dementia (Figure 3). Establishing the diagnosis of AD makes it easier to help both the patient and the caregiver. Although there is currently no cure, slowing the symptomatic decline of the patient and maintaining the level of functional ability would present clear advantages to patients, caregivers and physicians. With this in mind, however, treatment expectations should be realistic. This will reduce frustration both for the patient and for the caregiver.

There are multiple risk factors for AD. Almost certainly a variety of factors, both genetic and environmental, can contribute concurrently to the development of the AD syndrome. However, a number of specific risk factors have been associated with its onset (Table 4 below).

• Age
• Family history of AD
• Gender
• Head trauma
• Down's syndrome
• Educational level

Age is a risk factor for AD. The prevalence of AD doubles every five years after the age of 60.

Family history

A family history of AD is a consistent risk factor, and represents around a fourfold increase in the risk of developing the disease. It is thought that as many as 33% of all cases of AD may be familial.

A link has been established between the frequency of a specific allele, apolipoprotein E4 (ApoE4), and the occurrence of AD. The presence of the ApoE4 allele increases the probability that the patient with dementia has AD. The absence of the ApoE4 allele makes this less likely. Although there is a strong link between ApoE4 and AD, not everyone who carries the allele develops AD. Conversely, not all AD patients carry the allele. So despite the fact that ApoE4 is a risk factor for AD in some patients, it is not suitable for routine use as a diagnostic marker for AD.

Other risk factors

Gender appears to be a risk factor, women being at greater risk of developing AD than men. The higher prevalence of AD among women is probably due to a longer life expectancy. Repeated head trauma also increases the risk of developing AD. The presence of vascular disease is a potential risk factor. All individuals with Down's syndrome develop the characteristic neuropathological features of AD by the age of 40, although many do not demonstrate the clinical symptoms of dementia.

Neuropathology of AD

The most characteristic neuropathological features (Table 5) are amyloid (senile) plaques and neurofibrillary tangles (NFTs) (Figure 4). Amyloid protein is believed to play an important role in the pathogenesis of AD and may be critical for the formation of the amyloid or senile plaques in the brain. These plaques seem to reflect damage in the surrounding nerve endings. This damage to the neurons causes impaired neurotransmission and results in the cognitive deficits observed with AD.

Although NFTs are also a characteristic finding in the brain they are not specific to AD and are found in several other degenerative dementing disorders. NFTs contain paired helical filaments (PHFs) which are composed of abnormal microtubule-associated proteins (tau protein). In AD, abnormal phosphorylation of the tau protein results in aggregation of PHFs to form the NFTs. The definite diagnosis of AD relies on the presence of sufficient numbers of both amyloid plaques and NFTs at autopsy or via biopsy.

• Neurofibrillary tangles
• Senile (amyloid) plaques
• Neuronal loss
• Cortical and central atrophy

Many areas of cognition are compromised in AD. In the early stages, in particular, memory, language and frequently visuospatial abilities are affected.

Memory

Memory is a complex function and, in simple terms, is made up of a temporary store (short-term or primary memory) and a permanent store (long-term memory) (Figure 5 Below). Short-term memory describes the ability to learn and briefly retain information. This area of memory is generally not substantially affected by age. Long-term memory, particularly retrieval, the ability to learn information and retain it for longer periods, however, begins to decline at the age of 50 as part of the normal aging process. In AD, short-term memory is affected, first causing difficulties in learning and recalling new information. Patients may fail to remember a recent conversation or a telephone number long enough to repeat it. Remote (biographical) memory is usually not affected until late into the disease.

The initial, characteristic cognitive feature of AD is progressive loss of memory. This decline in memory often triggers the patient or family member to seek help from a physician.

Two important aspects of memory retrieval are affected: recall (e.g. remembering a street or person's name) and recognition (e.g. recognizing a street or person's name). The ability to remember general information, such as the names of capital cities or the president/premier, is also affected. Remembering how to perform tasks, procedural memory, is not altered in the early stages of AD. As the disease progresses, short-term memory is dramatically compromised, and long-term memory also fades.

Language impairment (aphasia) is a common feature of AD. Difficulty in finding words in spontaneous speech and the ability to name objects are affected first. Although the ability to construct sentences is initially retained, they become less complex. Patients may experience great difficulty in remembering and using appropriate words. As the disease progresses, word pronunciation also deteriorates.

Visuospatial deficits

Although decline in visuospatial awareness is part of normal aging, it may be exacerbated in AD. Patients with AD may experience difficulty driving the car, finding their way in the home or may put clothing on back-to-front. Visuospatial awareness can be tested by asking the patient to copy/draw and recognize two- and three-dimensional figures and objects.

Functional impairment

Functional ability is usually separated into two categories: self-maintenance skills or Activities of Daily Living (ADLs), and the more complex higher-order skills, Instrumental Activities of Daily Living (IADLs). Decline in functional ability is linked to cognitive decline and can be correlated to a decline in MMSE (Table 6). Changes in functional ability are often the first indication that a dementing illness is present. Functional decline in AD causes considerable concern for both the sufferer and caregivers. IADLs are usually affected first, with ADLs affected later in the disease.

Deterioration in social and occupational activities is a characteristic clinical feature of AD. Initially in AD, the inability to carry out normal IADL tasks is diminished. Patients have problems driving the car, paying bills or functioning at work. As the disease progresses, more basic ADL tasks, the basic living skills, are affected. The ability to perform tasks; personal care, bathing, eating, etc, becomes restricted (Table 6 Below).

Changes in behavior are common in AD and include mood swings, aggression, agitation and disinhibition. These changes are distressing both for the patient and family and are often difficult to come to terms with.

At the onset of the illness, family members may report changes in personality. Patients exhibit increased irritability, a lack of enthusiasm, unhappiness, unreasonable behavior, a loss of sensitivity. Many sufferers become agitated or wander.

Symptoms of depression and anxiety as well as psychiatric phenomena such as delusions or hallucinations may often be present. Symptoms of depression and anxiety may initially accompany AD. Depression may be difficult to distinguish from apathetic states related to AD. Paranoid delusions are common, leading to, for example, accusations of theft or a fear of unknown intruders.

Diagnostic criteria for AD

A number of criteria-based approaches to the diagnosis of AD have been developed. The three most commonly used are:

• International Classification of Diseases, 10th revision (ICD-10)
• Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV)
• National Institute of Neurological and Communicative Disorders and Stroke ­ Alzheimer's Disease and Related Disorders Association workgroup (NINCDS-ADRDA)

Each of these classifications specifies particular criteria that must be satisfied in order to
confirm a diagnosis of AD. The NINCDS-ADRDA criteria take a slightly different approach to the ICD-10 and DSM IV classification systems. The NINCDS-ADRDA approach (Appendix 1):

• Defines the diagnosis of AD as 'possible', 'probable', or 'definite'
• Allows a diagnosis of probable or possible AD during the lifetime of the patient

The clinical features of AD are summarized in Table 7 below.

Difficulties in one or more of the following:

• Language (aphasia)
• Purposeful action (apraxia)
• Recognition (agnosia)
• Executive function

Progressive decline in cognition

No gait difficulties in the early stages

Other dementias that occur less frequently include vascular dementia, Lewy body disease and Pick's disease. These dementias can be more difficult to diagnose and patients suspected of suffering from these forms of dementia should be sent for specialist referral.

Vascular dementia

Vascular dementia (VaD) is the second most common cause of dementia, after AD. The prevalence of VaD, although variable between populations, accounts for 10­20% of all cases of dementia.

VaD is a syndrome that produces behavioral impairment as a result of cerebrovascular disease in the brain (Table 8). Recently it has been recognized that vascular dementia is caused not only by discrete infarcts but also by a number of other cerebrovascular conditions, such as hypertension, and subarachnoid hemorrhage. Cerebral infarcts resulting from hypertension are the major and most preventable risk factor for vascular dementia.

There is great variation in how many, how large and where the vascular lesions need to appear in order to initiate dementia. The following cerebrovascular lesions may be associated with VaD syndromes; multi-infarct, strategically-located single-infarct dementia, smaller infarcts, small-vessel disease, and hemorrhagic dementia.

• Classically, abrupt decline in cognitive function
• Step-wise rather than smooth progression
• Focal neurologic signs, such as gait abnormalities
• History of stroke
• Presence of vascular disease and stroke risk factors

Lewy body disease

Lewy body disease is a common dementia characterized by the presence of Lewy bodies in brain regions at autopsy (Table 9). Whether Lewy body disease is a type of AD or a separate condition is still unclear. The disease is characterized by a progressive yet fluctuating decline in cognitive function and attention disorder. The fluctuation in attention, alertness and episodes of confusion may occur on a day-to-day basis.

• Fluctuating and progressive decline in cognitive function
• Episodes of delirium are common
• Parkinsonian features are common
• Optical hallucinations and paranoid delusions
• Loss or clouding of consciousness
• Mild extrapyramidal features (e.g. gait difficulty, flexed posture)
• Long duration of clinical symptoms
• Intolerance to neuroleptics

Pick's disease is characterized by a decline in mental functioning and changes in behavior associated with dysfunction of the frontal and temporal lobes (Table 10). There is a prominent loss of memory and language ability. It appears to be both inherited and sporadic. Distinct pathological features include extensive atrophy of the frontal and temporal lobes. The disease is relentlessly progressive and usually extends for 2­7 years.

• Insidious onset and slow progression
• Early and severe changes in personality, euphoria, emotional blunting, disinhibition and apathy or restlessness
• Decline in mental function
• Severe frontal lobe atrophy

• Has a relatively consistent onset, clinical presentation and course, which makes it one of the most characteristic mental disease processes
• AD needs to be distinguished from delirium, depression, side effects of drugs and other causes of dementia
• Symptomatic therapies establish the need for early diagnosis of AD
• Symptomatic therapies should be judged on realistic improvements