Alzheimer’s

Introduction

Alzheimer disease (AD) is a neurodegenerative disorder marked by cognitive and behavioral impairment that significantly interferes with social and occupational functioning. It is an incurable disease with a long preclinical period and progressive course. In AD, plaques develop in the hippocampus, a structure deep in the brain that helps to encode memories, and in other areas of the cerebral cortex that are involved in thinking and making decisions. Whether plaques themselves cause AD or whether they are a by-product of the AD process remains unknown. The following image depicts one of the cardinal neuroimaging findings in AD – hippocampal atrophy.

Associated Anatomy

Healthy neurons have an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, binds to the microtubules and stabilizes them.

In AD, tau is changed chemically. It begins to pair with other threads of tau, which become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron’s transport system. The formation of these neurofibrillary tangles (NFTs) may result first in malfunctions in communication between neurons and later in the death of the cells.

In addition to NFTs, the anatomic pathology of AD includes senile plaques (SPs; also known as beta-amyloid plaques) at the microscopic level and cerebrocortical atrophy at the macroscopic level. The hippocampus and medial temporal lobe are the initial sites of tangle deposition and atrophy. This can be seen on brain magnetic resonance imaging early in AD and helps support a clinical diagnosis.

Causes

The cause of AD is unknown. Several investigators now believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia.

The following risk factors for Alzheimer-type dementia have been identified:

• Advancing age
• Family history
• APOE 4 genotype
• Obesity
• Insulin resistance
• Vascular factors
• Dyslipidemia
• Hypertension
• Inflammatory markers
• Down syndrome
• Traumatic brain injury

Midlife hypertension is an established risk factor for late-life dementia, of which AD is the most common type. A brain autopsy study evaluating the link between hypertension and AD found that patients using beta-blockers to control blood pressure had fewer Alzheimer’s-type brain lesions on autopsy compared to patients taking no drug therapy or those taking other medications.

In addition, epidemiologic studies have suggested some possible risk factors such as aluminum and previous depression. Other studies have suggested protective factors (e.g.,education, long-term use of nonsteroidal anti-inflammatory drugs).

Differential Diagnosis

Depression is an important consideration in the differential diagnosis of AD. The clinical manifestations of depression overlap with those of AD. The term pseudodementia refers to the appearence of cognitive dysfunction (dementia) due to depression. In addition, an estimated 30–50% of AD patients have comorbid depression.

Depression in patients with AD appears to differ from depression in cognitively intact elderly patients. Depression in AD more often features motivational disturbances (eg, fatigue, psychomotor slowing, apathy), whereas depression in geriatric patients without cognitive impairment tends to feature mood symptoms (eg, depressed mood, anxiety, suicidality, sleep and appetite disturbances).

Commonly used instruments for assessing depression (eg, Hamilton Scale for Depression, Beck Depression Inventory, Geriatric Depression Scale) were designed for use in other patient populations and may be less reliable in patients with AD. Consequently, the National Institute of Mental Health has developed provisional diagnostic criteria for depression in AD. [74]

Chronic traumatic encephalopathy

Repetitive head trauma has long been recognized as a cause of brain degeneration in boxers (ie, dementia pugilistica). More recently, progressive degenerative brain disease (chronic traumatic encephalopathy [CTE]) has been recognized in athletes with a history of multiple concussions, as well as milder blows to the head that do not cause concussion. Neuropathologically confirmed CTE has been reported in retired professional football and hockey players and other athletes with a history of repeated head injuries.

Pathological hallmarks of CTE, which may not appear until long after the end of active athletic involvement, include the following:

• Tau-positive neurofibrillary tangles (NFTs) in the neocortex, concentrated around penetrating parenchymal vessels
• Neuropil threads
• Neocortical diffuse amyloid plaques, with or without neuritic plaques
• Sparing of the hippocampus
• The distribution of NFTs in CTE differs markedly from that in normal aging and AD, in which there is early involvement of the entorhinal cortex and hippocampus with later involvement of the neocortex in advanced stages.

The symptoms of CTE may include the following:

• Recurrent headaches
• Dizziness
• Mood disorders
• Aggression
• Impaired judgment and impulse control
• Parkinsonian movement disorders
• Progressive dementia

Other disorders:

• Other disorders to consider in the differential diagnosis of AD include the following:
• Age-associated memory impairment
• Alcohol or drug abuse
• Depression
• Vitamin B12 deficiency
• Cerebrovascular disease (and vascular dementia)
• Hearing or visual impairment
• Hypernatremia
• Hypoglycemia
• Hypothyroidism or hyperthyroidism
• Lewy body dementia
• Normal pressure hydrocephalus
• Parkinson’s disease with dementia
• Polypharmacy
• Volume depletion
• Wernicke-Korsakoff Syndrome

Drugs

The mainstay of therapy for patients with AD is the use of centrally acting cholinesterase inhibitors to attempt to compensate for the depletion of acetylcholine (ACh) in the cerebral cortex and hippocampus. A partial N-methyl-D-aspartate (NMDA) antagonist is approved for treatment of moderate and severe AD. Various medications are used for treatment of secondary symptoms of AD, including antidepressants, anti-anxiety agents, and antipsychotic agents.

Cholinesterase Inhibitors

Donepezil (Aricept, Aricept ODT)

Donepezil is indicated for the treatment of dementia of the Alzheimer type. Donepezil has shown efficacy in patients with mild to moderate AD, as well as moderate to severe AD. It selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, and improves the availability of acetylcholine. Donepezil’s long half-life provides a long duration of drug availability for binding at the receptor sites. There is no evidence to suggest that the underlying disease process of dementia is affected by administration of donepezil.

Dosing recommendations for mild to moderate AD are 5-10 mg given once daily. Patients with moderate to severe AD can be given 10 or 23 mg once daily.

Rivastigmine (Exelon, Exelon Patch)

Rivastigmine PO is indicated for the treatment of mild to moderate dementia of the Alzheimer type. Initial dosing recommendations are 1.5 mg PO BID, with a maximum dose of 12 mg/day PO. Rivastigmine is a potent, selective inhibitor of brain AChE and BChE. Rivastigmine is considered a pseudo-irreversible inhibitor of AChE.

While the precise mechanism of rivastigmine’s action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.

The transdermal patch 13.3 mg/24 h is approved for all stages of Alzheimer disease, including severe. Dose titration is needed when initiating.

Galantamine (Razadyne, Razadyne ER)

Galantamine is indicated for the treatment of mild to moderate dementia of the Alzheimer type. It enhances central cholinergic function and likely inhibits AChE. There is no evidence that galantamine alters the course of the underlying dementing process. The dosing recommendation for the immediate-release formulation is 4 mg twice daily. The extended-release formulation is given at a dose of 8 mg once daily. The maintenance dose after dose titration is 16-24 mg/day.

N-Methyl-D-Aspartate Antagonists

Memantine (Namenda, Namenda XR)

Namenda is approved for the treatment of moderate to severe dementia in patients with AD. The initial dose for the immediate-release formulation is 5 mg once daily, and it can be titrated to a maximum dose of 20 mg/day. The initial dose for the extended-release formulation is 7 mg once daily, and it can be titrated to a maximum dose of 28 mg/day.

Nutritional Supplement

Caprylidene (Axona)

Caprylidene is indicated for clinical dietary management of metabolic processes associated with mild to moderate AD. General dosing recommendations include administering 40 g/day (1 packet of caprylidene powder, containing 20 g of medium-chain triglycerides) during breakfast.

Combination products

Memantine/donepezil (Namzaric)

Fixed dose combination capsule containing memantine extended-release and donepezil for patients with moderate-to-severe Alzheimer disease currently stabilized on donepezil 10 mg once daily. Administer once daily in the evening. Memantine is a NMDA receptor antagonist and donepezil is an acetylcholinesterase inhibitor.

Epidemiology

In 2005, Alzheimer Disease International commissioned an international group of experts to reach a consensus on dementia prevalence and estimated incidence in 14 World Health Organization regions, based on epidemiological data acquired over recent years. The results suggested that 24.2 million people lived with dementia at that time, with 4.6 million new cases arising every year. North America and Western Europe have at age 60 the highest prevalence of dementia (6.4 and 5.4% of the population at age 60), followed by Latin America (4.9%) and China and its developing western-Pacific neighbors (4.0%). The annual incidence rates (per 1000) for these countries were estimated at 10.5 for North America, 8.8 for Western Europe, 9.2 for Latin America and 8.0 for China and its developing western-Pacific neighbors, increasing exponentially with age in all countries, especially through the seventh and eighth decades of life.

The prevalence rates for AD also rise exponentially with age, increasing markedly after 65 years. There is almost a 15-fold increase in the prevalence of dementia, predominately Alzheimer disease, between the ages of 60 and 85 years (Evans et al. 1989). Compared with Africa, Asia and Europe, the prevalence of AD appears to be much higher in the US, which may relate to methods of ascertainment. The prevalence may be higher among African-American and Hispanic populations living in the US, but lower for Africans in their homelands, for reasons that remain uncertain.

Prognosis

The time from diagnosis to death varies from as little as 3 years to as long as 10 or more years. Patients with early-onset AD tend to have a more aggressive, rapid course than those with late-onset AD. The primary cause of death is intercurrent illness, such as pneumonia.

Natural Progression

AD is initially associated with memory impairment that progressively worsens. Over time, patients with AD can also display anxiety, depression, insomnia, agitation, and paranoia. As their disease progresses, patients with AD come to require assistance with basic activities of daily living, including dressing, bathing, and toileting. Eventually, difficulties with walking and swallowing may develop. Feeding may be possible only by gastrointestinal tube, and difficulty swallowing may lead to aspiration pneumonia.

Pathophysiology

A continuum exists between the pathophysiology of normal aging and that of AD. Pathologic hallmarks of AD have been identified; however, these features also occur in the brains of cognitively intact persons. For example, in a study in which neuropathologists were blinded to clinical data, they identified 76% of brains of cognitively intact elderly patients as demonstrating AD.

AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. Certain nerve cells in the brain stop working, lose connections with other nerve cells, and finally die. The destruction and death of these nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease.

The accumulation of SPs primarily precedes the clinical onset of AD. NFTs, loss of neurons, and loss of synapses accompany the progression of cognitive decline.

Considerable attention has been devoted to elucidating the composition of SPs and NFTs to find clues about the molecular pathogenesis and biochemistry of AD. The main constituent of NFTs is the microtubule-associated protein tau. In AD, hyperphosphorylated tau accumulates in the perikarya of large and medium pyramidal neurons. Somewhat surprisingly, mutations of the tau gene result not in AD but in some familial cases of frontotemporal dementia.

Since the time of Alois Alzheimer, SPs have been known to include a starchlike (or amyloid) substance, usually in the center of these lesions. The amyloid substance is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).

One of the most important advances in recent decades has been the chemical characterization of this amyloid protein, the sequencing of its amino acid chain, and the cloning of the gene encoding its precursor protein (on chromosome 21). These advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain, including information about the familial forms of AD.

Alzheimer disease biomarkers may follow a sequential pattern in the brain, according to a study of AD biomarker trajectories. The study included both symptomatic and asymptomatic carriers of autosomal dominant gene mutations linked to AD, including APP, PSEN1, and PSEN2. Researchers did not address tauopathy. Results show that amyloid deposition in the brain occurs first, followed by a decline in glucose metabolism and then structural brain atrophy. The rate of Ab accumulation was significantly higher in mutation carriers compared to noncarriers, and was found to begin more than 2 decades before the expected onset of dementia. In carriers, metabolism began to decrease at a mean of 14.1 years before expected symptom onset, and structural changes in the brain began 4.7 years before expected symptom onset. It is important to note that only about 1% of patients with AD have an autosomal dominant mutation, so results may not be generalizable to sporadic AD.

Although the amyloid cascade hypothesis has gathered the most research financing, other interesting hypotheses have been proposed. Among these are the mitochondrial cascade hypothesis.

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer’s original papers were published. These include the granulovacuolar degeneration of Shimkowicz; the neuropil threads of Braak et al; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

In 2019, researchers identified a new type of dementia that mimics AD but that is caused by another mechanism in the brain. This new classification is limbic-predominant age-related TDP-43 encephalopathy, (LATE). TDP-43 is a protein that helps regulate gene expression in the brain and other tissues, and when it misfolds it causes problems in the brain. According to researchers, misfolded TDP-43 protein is very common in older adults; about 25% of people aged 85 and older have enough misfolded TDP-43 protein to affect their memory and thinking skills.

Possible Complications

Potential complications of Alzheimer’s disease include:

• Abuse by an over-stressed caregiver
• Anosmia
• Bedsores, muscle contractures (loss of ability to move joints because of loss of muscle function), infection (particularly urinary tract infections and pneumonia), and other complications related to immobility during the end stages of AD
• Behavioral and psychotic symptoms of dementia (BPSD) or psychosis
• Chronic brain failure
• Falls and bone fractures
• Harmful or violent behavior toward oneself or others
• Hirano body formation
• Loss of ability to function or care for oneself
• Loss of ability to interact with others
• Malnutrition and dehydration

Possible Treatment

To date, only symptomatic therapies for Alzheimer disease (AD) are available and thus do not act on the evolution of the disease. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and a partial N -methyl-D-aspartate (NMDA) antagonist.

Secondary symptoms of AD (eg, depression, agitation, aggression, hallucinations, delusions, sleep disorders) can be problematic. Behavioral symptoms in particular are common and can exacerbate cognitive and functional impairment. The following classes of psychotropic medications have been used to treat these secondary symptoms:

• Antidepressants
• Anxiolytics
• Antiparkinsonian agents
• Beta-blockers
• Antiepileptic drugs (for their effects on behavior)
• Neuroleptics

Most studies of psychotropic drugs for AD have demonstrated no or limited efficacy. However, many issues make interpretation of data from these studies difficult.

Current pharmacologic research in AD focuses principally on the development of disease-modifying drugs that can slow or reverse the progression of AD. Targets of these investigational agents have included beta-amyloid production, aggregation, and clearance, as well as tau phosphorylation and assembly. To date, none of these drugs has demonstrated efficacy in phase III trials.However, a 2018 phase II study showed promising results for an antiamyloid agent in patients with early-stage AD. The study included 856 patients with early AD (mild cognitive impairment due to AD or mild AD dementia) and amyloid pathology confirmed by positron-emission tomography (PET) or cerebral spinal fluid (CSF) tracer. The agent, BAN2401, was found to significantly reduce brain amyloid at high doses. The study also showed a dose-dependent, statistically significant, and clinically meaningful slower decline in cognition and function with the highest dose compared to placebo.

Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD.

Hospitalization should be considered for any unstable medical condition that may complicate the patient’s treatment. If the patient becomes a danger to him/herself or others, short-term hospitalization may be indicated to facilitate ruling out infectious and metabolic processes and adjusting psychotropic medications. The most common reason for admission to a long-term care facility is the need for 24-hour supervision that cannot be given at home and/or caregiver stress/burnout.

Primary Prevention

No specific, well-validated measures to delay or prevent the onset of AD exist. This is due to contradictory results of global studies, as well as a paucity of proven causal relationships between risk factors and the development or progression of the disease.

Modifiable factors such as diet, cardiovascular risks, pharmaceutical products, or intellectual activities have all been evaluated with epidemiological studies to see if they increase a population’s risk of developing AD.

The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may reduce the risk and course of Alzheimer’s disease.

There is evidence that frequent and moderate consumption of alcohol (beer, wine or distilled spirits) reduces the risk of the disease, but it is still considered premature to make dietary recommendations on this basis.

Vitamins E, B, and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease, but may have important secondary effects in conjunction with other therapies.

Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD, statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease. However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.

Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia, and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.

Lifestyle Factors

A nutritious diet, physical activity, social engagement, and mentally stimulating pursuits can all help people stay healthy. New research suggests the possibility that these factors also might help to reduce the risk of cognitive decline and Alzheimer’s disease.

Scientists are investigating associations between cognitive decline and vascular and metabolic conditions such as heart disease, stroke, high blood pressure, diabetes, and obesity. Understanding these relationships and testing them in clinical trials will help us understand whether reducing risk factors for these diseases may help with Alzheimer’s as well.

Intellectual activities such as playing chess, completing crossword puzzles, or engaging in regular social interaction may also delay the onset or reduce the severity of Alzheimer’s disease. Bilingualism also appears to be correlated to a later onset of Alzheimer’s disease.

Secondary Prevention

The secondary prevention of Alzheimer’s disease is similar to its primary prevention.

Risk factors

The most potent risk factors for the development of Alzheimer’s disease (AD) are age and genetic mutations. Females are more prone to development of Alzheimer’s disease. Inhabitants of Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea are more predisposed to the development of Alzheimer’s disease. Stroke increases the risk of Alzheimer’s dementia.

The following risk factors may lead to the development of Alzheimer’s dementia (AD):

• Increasing age
• Genetic mutations
• Gender (females > males)
• Early-life negative events and physical attributes
• Literacy and education (low literacy and education increases the chances of developing AD)
• Geographical location (Central African Republic, East Africa, Southern Africa, Malaysia, Australia, and Papua New Guinea, APOE4 is a risk factor for AD among women but not men in Venezuela)
• Stroke
• Vascular disease
• Diet (fruits, vegetables, and fibre decrease risk; Tofu, cycad fruit, salivary phytooestrogens e.g. genistein and daidizein are associated with increased risk)

Signs or Symptoms

Memory loss is the key symptom of Alzheimer’s disease. An early sign of the disease is usually difficulty remembering recent events or conversations. As the disease progresses, memory impairments worsen and other symptoms develop.

At first, a person with Alzheimer’s disease may be aware of having difficulty with remembering things and organizing thoughts. A family member or friend may be more likely to notice how the symptoms worsen.

Brain changes associated with Alzheimer’s disease lead to growing trouble with:

Memory

Everyone has occasional memory lapses. It’s normal to lose track of where you put your keys or forget the name of an acquaintance. But the memory loss associated with Alzheimer’s disease persists and worsens, affecting the ability to function at work or at home.

People with Alzheimer’s may:

• Repeat statements and questions over and over
• Forget conversations, appointments or events, and not remember them later
• Routinely misplace possessions, often putting them in illogical locations
• Get lost in familiar places
• Eventually forget the names of family members and everyday objects
• Have trouble finding the right words to identify objects, express thoughts or take part in conversations

Thinking and reasoning

Alzheimer’s disease causes difficulty concentrating and thinking, especially about abstract concepts such as numbers.

Multitasking is especially difficult, and it may be challenging to manage finances, balance checkbooks and pay bills on time. These difficulties may progress to an inability to recognize and deal with numbers.

Making judgments and decisions

The ability to make reasonable decisions and judgments in everyday situations will decline. For example, a person may make poor or uncharacteristic choices in social interactions or wear clothes that are inappropriate for the weather. It may be more difficult to respond effectively to everyday problems, such as food burning on the stove or unexpected driving situations.

Planning and performing familiar tasks

Once-routine activities that require sequential steps, such as planning and cooking a meal or playing a favorite game, become a struggle as the disease progresses. Eventually, people with advanced Alzheimer’s may forget how to perform basic tasks such as dressing and bathing.

Changes in personality and behavior

Brain changes that occur in Alzheimer’s disease can affect moods and behaviors. Problems may include the following:

• Depression
• Apathy
• Social withdrawal
• Mood swings
• Distrust in others
• Irritability and aggressiveness
• Changes in sleeping habits
• Wandering
• Loss of inhibitions
• Delusions, such as believing something has been stolen

Preserved skills

Many important skills are preserved for longer periods even while symptoms worsen. Preserved skills may include reading or listening to books, telling stories and reminiscing, singing, listening to music, dancing, drawing, or doing crafts.

These skills may be preserved longer because they are controlled by parts of the brain affected later in the course of the disease.

Stage

If left untreated, Alzheimer’s disease (AD) may progress through three stages:

• (i) Preclinical stage:
  • The preclinical phase of AD represents asymptomatic individuals with serological evidence of AD associated pathological changes and individuals exhibiting minor cognitive decline, but who do not yet meet the clinical criteria for mild cognitive impairment
• (II) Mild cognitive impairment (MCI) :
  • MCI denotes the period during which there is observable evidence of cognitive impairment, often also reported by an informant; however, the impairment is not enough to limit daily activities
• (III) Alzheimer’s disease dementia:
  • The transition or prodromal stage between normal ageing and dementia or mild cognitive impairment (MCI) is a heterogeneous entity.
  • Advanced dementia may display the following features:
    • Becoming unaware of the time and place
    • Difficulty recognizing relatives and friends
    • Increased need for assisted self-care
    • Difficulty walking
    • Behavioural changes that may escalate and include aggression

Studies

Active Not Recruiting

Number of studies: 94

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Completed

Number of studies: 1, 130

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Enrolling by Invitation

Number of studies: 39

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Not Yet Recruiting

Number of studies: 102

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Recruiting

Number of studies: 432

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Results Available

Number of studies: 281

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Results Not available

Number of studies: 1, 902

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Suspended

Number of studies: 4

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Terminated

Number of studies: 164

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Withdrawn

Number of studies: 32

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Typical Test

Alzheimer disease (AD) is a clinical diagnosis. However, ancillary imaging studies (eg, computed tomography [CT]; magnetic resonance imaging [MRI]; single-photon emission CT [SPECT]; or positron emission tomography [PET]) and laboratory tests may be used. These tests help exclude other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B12] deficiency, syphilis, thyroid disease).

Blood Studies

Laboratory tests can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B12) level and a thyroid function screening test. Additional investigations are left up to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following:

• Abnormalities in complete blood cell count and cobalamin (vitamin B12) levels require further workup to rule out hematologic disease
• Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease
• Abnormalities in thyroid-stimulating hormone (TSH) levels require further workup to rule out thyroid disease
• Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis
• Abnormalities in HIV serology and/or PCR require further workup to rule out HIV/AIDS
• Abnormalities in paraneoplastic antibodies require further workup to rule out autoimmune encephalitis
• Abnormalities in CSF proteins tau, P-tau, and 14-3-3 require further workup to rule out Creutzfeldt-Jakob disease

There is a possible link between vitamin D deficiency and cognitive impairment. However, vitamin D deficiency has not been identified as a reversible cause of dementia.

Brain MRI or CT Scanning

American Academy of Neurology (AAN) recommendations indicate that structural neuroimaging with either a noncontrast computed tomography (CT) scan or magnetic resonance image (MRI) is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor).

Imaging studies are particularly important for ruling out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus. In patients with AD, brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic of AD.

In clinical research studies, atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD.

A study by Chen et al suggests that resting state functional MRI can help classify patients with AD, patients with amnestic mild cognitive impairment (MCI), and cognitively healthy patients.  Default mode network (DMN) imaging appears to distinguish AD, MCI, and controls well, and it may complement positron emission tomography (PET) scanning or prove to be more sensitive.

A study by McMillan et al suggests that MRI may provide a reasonably accurate, noninvasive surrogate for cerebrospinal fluid (CSF) biomarkers, reducing the need for lumbar puncture in discriminating AD from frontotemporal lobar degeneration (FTLD). The investigators derived a structural brain pattern from MRI that predicts the ratio of total tau to β-amyloid in CSF, to discriminate AD from FTLD. In this way, they were able to differentiate between the 2 dementia types 75% of the time.

Other investigators have suggested that MRI plus biomarkers may be key to finding early AD. In a cross-sectional, longitudinal cohort study of 207 older adults with normal cognition, investigators found a correlation between decay in the DMN, as observed on resting-state functional connectivity MRI (rs-fcMRI), and levels of 2 CSF biomarkers of early AD. This suggests that rs-fcMRI may be an effective noninvasive means of detecting early asymptomatic AD.

In the study, Ances and colleagues reported that decreases in DMN integrity had an independent association with reductions in CSF amyloid beta 42 and increases in CSF phosphorylated tau181. Moreover, the posterior cingulate cortex and the medial temporal lobe, 2 regions that are frequently impacted by AD, were found to have the most prominent decreases in functional connectivity.

SPECT or PET scanning

Brain scanning with SPECT or PET is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases or when a form of frontotemporal dementia is a more likely diagnosis.

Electroencephalography

Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis. Periodic high-amplitude sharp waves can eventually be detected in most cases of Creutzfeldt-Jakob disease.

EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia, and an EEG would be valuable for evaluating such a possibility.

Lumbar Puncture

Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus or central nervous system infection (eg, neurosyphilis, neuroborreliosis, cryptococcosis).

CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80%—and more often 90%—can be achieved.

At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity.

Genotyping

Genotyping for apolipoprotein E (APOE) alleles is a research tool that has been helpful in determining the risk of AD in populations, but until recently it was of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. Numerous consensus statements have recommended against using APOE genotyping for predicting AD risk.

Investigators from the Copenhagen General Population Study and the Copenhagen City Heart Study have reported that plasma levels of APOE epsilon 4 (APOE ε4) are associated with the risk of dementia, independent of the APOE genotype. The risk of Alzheimer disease increased with decreasing levels of APOE levels, with a highly significant 3-fold increased risk for the lowest tertile of APOE levels relative to the highest tertile—an association that remained even after adjusting for the APOE genotype. The APOE genotypes with highest risks of Alzheimer disease were ε43 and ε44, whereas those with the lowest risks were ε22, ε32, ε42, and ε33.

Concern has previously been expressed that in asymptomatic individuals, genetic testing that identifies increased risk may trigger an untoward psychological response. However, in a trial of the effect of disclosing APOE genotyping results to 162 asymptomatic adults who had a parent with AD, Green et al found that follow-up testing over the course of a year showed no significant differences with disclosure versus nondisclosure on time-averaged measures of anxiety, depression, or test-related distress. Test-related distress was reduced in those who learned that they did not carry the APOE E4) allele. Persons who had high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure.

Reference:

https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptoms-causes/syc-20350447
https://emedicine.medscape.com/article/1134817-overview
https://www.wikidoc.org/index.php/Alzheimer%27s_disease_risk_factors
https://clinicaltrials.gov