Alzheimer Disease

DEFINITION
Alzheimer disease (AD) is a neurodegenerative disease and the most common cause of dementia.
AD is thought to account for at least 50% of dementia cases.[1]Dementia is a syndrome characterized by
global cognitive decline that significantly affects daily functioning in the absence of delirium.There is
growing recognition of individuals with cognitive impairment at a severity level insufficient for a diagnosis
of dementia. Two terms have been used to describe these individuals:Cognitive impairment, no dementia
(CIND)Mild cognitive impairment (MCI)Cortical atrophy, amyloid-predominant neuritic plaques, tau-
predominant neurofibrillary tangles, and neuronal death are hallmarks of the pathological diagnosis of AD
confirmed via post-mortem histopathological examination.[2]Cascade view of etiopathogenesis of
AD[3]:Genetic and environmental risk factors interact to increase the production or to decrease the
clearance of a toxic form of a peptide (amyloid beta (abeta) 1-42) derived from turnover of the amyloid
precursor protein (APP), a transmembrane protein present on neurons.If APP is processed through
cleavage by β-secretase preferentially over α-secretase, this leads to the formation of abeta 1-42 that is
prone to dimerization, oligomerization, and deposition in the extracellular space.The deposition abeta 1-
42 accumulates close to the synaptic cleft and is thought to lead over time to synaptic disconnection, the
loss of neurotransmitter systems, and the emergence of symptoms.Cognitive impairment due to AD is
classified under the neurocognitive disorders (NCDs) section of the Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5).[2]
EPIDEMIOLOGY
In the general population, dementia is increasingly recognized as a serious public health concern.In 2011,
an estimated 34 million were living with dementia worldwide.The prevalence is projected to double every
20 years, reaching an estimated worldwide caseload of about 115 million by 2050.Aggregate payments for
health care, long-term care, and hospice for people with AD and other dementias are projected to
increase from $200 billion in 2012 to $1.1 trillion in 2050 in the US alone.[4]Although rates of conversion
vary, transition from MCI to dementia averages 12%-15% per year in community samples.[5]Age is the
primary risk factor for onset of AD and other forms of dementia.[1]
Other risk factors include: traumatic brain injury, reduced reserve capacity of the brain, depression, limited
educational or occupational attainment, brain vascular disease, hyperlipidemia, hypertension,
atherosclerosis, coronary heart disease, atrial fibrillation, smoking, obesity, and diabetes.Familial forms of
AD exist, with onset typically earlier in life (before age 65)[1]:
The inheritance is autosomal dominant and involves mutations in the gene associated with APP on
chromosome 21, as well as presenilin 1 and 2 genes (on chromosomes 14 and 1, respectively).As many as
26 other genes are now thought to contribute to the development of AD:The apolipoprotein E (APOE)
gene ε4allele is a known risk factor for AD and also of cognitive decline earlier in life.Many other genes
have been proposed as risk factors for other forms of dementia, with both familial and polygenic forms of
inheritance.
DIAGNOSIS
Clinical Presentation
AD usually progresses gradually, sometimes with brief plateaus, from mild cognitive impairment to severe
dementia and ultimately death.[6]
Mean duration of survival after dementia onset is 4-5 years at the population level, or 10-12 years in
patients who attend memory clinics.Onset is usually in the eighth and ninth decades.Early-onset forms are
seen as early as the fifth or sixth decades of life.Rapidly progressive or intermittently progressive forms of
AD are less common but definitely occur.Typical course starts with loss of memory fairly early (amnesia),
followed by development of agnosia, apraxia, andaphasiaThese are sometimes remembered as the
four As of ADFollowing with this course, increasing levels of functional impairment often progress to
severe difficulties with mobility and incontinence.Neuropsychiatric symptoms (NPS) (behavioral
disturbances) affect as many as 98% of persons with AD over the course of their illness.The presence of
NPS are associated with faster progression of dementia, added disability for patients, and can be very
frustrating for caregivers.NPS are core features of AD thought to be caused by the same
neurodegenerative process that causes cognitive decline.Examples are: delusions, hallucinations,
agitation/aggression,depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition,
irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating disruption.NPS in patients
with AD by percentage[7]:Depressive phenomena (20-25%)Delusions (25%)Hallucinations (10-
15%)Disinhibition (6-9%)Aberrant motor behavior (15-25%)Apathy (27-40%)Agitation/aggression (20-
25%).
Tests and Procedures
In establishing a diagnosis of dementia, obtaining a history from the patient as well as
family/friends/caregivers is a must.History-taking must be systematic and provides the vast majority of
information that supports an eventual diagnosis.The evaluation should include physical and neurological
exams, as well as some objective measure of cognition:A brief bedside measure of cognition is adequate
in most cases.For example, Mini-Mental State Examination (MMSE)[8] or Montreal Cognitive Assessment
(MoCA)If impairments are more subtle or diagnosis is unclear, referral for neuropsychological testing may
be indicated.Certain blood tests, as well as brain imaging, are typically obtained as part of a cognitive
evaluation[1]:Thyroid studies, liver tests, metabolic panel, complete blood count, vitamin B12, and folate
levels are recommended.Additional tests, such as a heavy metal screen, syphilis serology, toxicology, EKG,
and chest x-ray should be considered.Structural brain imaging, such as head CT or brain MRI, are usually
obtained:These may show volume reduction in the hippocampus bilaterally followed by temporal and
parietal lobes, and eventually the frontal lobes.In some cases, positron emission tomography (PET) and
single-photon emission computed tomography (SPECT) are used.PET for glucose metabolism shows
decreased metabolism in the bilateral parietal and temporal association cortex in the majority of AD
patients.[1]Other forms of PET scanning using amyloid ligands (e.g., florbetapir) have been approved by
the FDA for the diagnosis of AD.Biomarkers, such as cerebrospinal fluid tau and amyloid-β levels, are used
in research but rarely in clinical practice.Genetic testing is used in research but rarely in clinical
practice.Some advocate for EEG testing, with the observed change in dementia being a slowing of
background activity.[1]
Differential Diagnosis
Mild cognitive impairmentDementia due to Lewy Body disease (e.g.,Parkinson or Parkinson
’plus’)Dementia due to frontotemporaldegenerationDementia due to cerebrovascular diseaseOther
neurocognitive disordersMajor depressive disorder (especially late life depression)DeliriumThyroid
disorders
TREATMENT
General
The American Association of Geriatric Psychiatry (AAGP) provided a position statement in 2006 regarding
principles of care for patients with dementia resulting from AD[9]. A minimal checklist was created for
issues that needed to be addressed:Safety matters, especially with regard to driving, living alone,
medication administration, environmental hazards, wandering, and fallsDay-to-day living should be
structured to maximize patients’ remaining abilities and function.General medical health should be closely
monitored.Advanced care planning, including advance directives, should be carried out.
Pharmacotherapy
There are no specific disease-modifying treatments for AD.Management of vascular brain disease and its
risk factors is part of the care for patients with AD:For patients with proven, significant brain vascular
disease and AD, low-dose aspirin therapy, or if appropriate other forms of anticoagulation, should be
seriously considered as a treatment that might prevent worsening of dementia.HMG-CoA reductase
inhibitors ("statins") are not indicated to treat AD other than to reduce plasma cholesterol
levels.Management of blood pressure (in the 130-150 systolic range), blood glucose, or other active
comorbidities may delay AD progression.Use of NSAIDs and estrogen have been shown in several studies
to not affect AD progression.Studies support the use of high-dose Vitamin E (2,000 IUs/day) to slow
progression, but use is controversial in part because of concerns of cardiac risk.The cholinesterase
inhibitors were introduced in 1997 and are first-line pharmacotherapy agents for AD. Treatment effects
are modest at best:These drugs work by inhibiting the breakdown of acetylcholine by blocking
acetylcholinesterase in the brain (primarily).Acetylcholine is a neurotransmitter important in
memory.Examples include: donepezil (Aricept®), galantamine (Razadyne®), and rivastigmine
(Exelon®).All are FDA-approved for mild-to-moderate AD.Donepezil carries an FDA indication for severe
AD.Rivastigmine carries an FDA indication for Parkinson diseasedementia.A Cochrane review from
2006[10]showed that there are notable improvements in cognitive function when these medications are
used in mild-to-moderate AD.There was also improvement in activities of daily living and behavior with
their use, though treatment effects were small.Most common reported side effects are nausea, vomiting,
and diarrhea.A less common, but potentially more serious side effect is bradycardia.Cholinesterase
inhibitors increase the risk of hospitalization for bradycardia, syncope, pacemaker placement, and hip
fracture[11][12].
Therefore, caution is advised when prescribing cholinesterase inhibitors in patients with preexisting
bradycardia, cardiovascular disease, or concurrently taking other medications which may lower heart
rate.Memantine (Namenda®), a low-affinity antagonist to glutamate NMDA receptors, may prevent
excitatory neurotoxicity in dementiaMemantine is FDA-approved for moderate-to-severe AD. Treatment
effects, again, are modest at best.A Cochrane review from 2006[13]showed a small beneficial effect of
memantine in moderate-to-severe AD in terms of cognition and behavior, supported by clinical
impression of changeIn mild-to-moderate AD there was a marginal benefit on cognition, no effect on
behavior, and little detection of improvement clinicallyPatients taking memantine were slightly less likely
to develop agitationMemantine tends to be well-toleratedCholinesterase inhibitors and memantine are
often combined. However, there is limited clinical trial evidence to support this combination.A recent
systematic review suggests a small cognitive, but not functional, benefit from combination therapy[14].A
one-year clinical trial reported no significant benefit from the combination of donepezil plus memantine
versus donepezil alone in patients with moderate-to-severe AD[15].Because aggression,
agitation,depression, and psychosis occur in the majority of people with dementia, the efficacy and safety
of neurolepticmedications is of utmost importance.All neuroleptics carry an FDA black box warning for
"Increased Mortality in Elderly Patients with Dementia-Related Psychosis."The risk of first-generation
antipsychotics is greater than that of second-generation antipsychotics[16].Due to associated risks and
comparable efficacy to the antidepressant citalopram, the use of antipsychotics as first-line therapy is not
recommended unless there are compelling reasons.Antidepressants have also been studied for the
treatment of agitation and psychosis in dementia.A Cochrane review from 2011[17]showed that SSRIs lead
to a reduction in symptoms of agitation compared to placebo and are well-tolerated. However, this review
noted that further study is needed.A recent study confirmed the efficacy of citalopram 30mg for the
treatment of agitation but also revealed the risk of QT prolongation at this dose[18].
Citalopram dosed at 20-30mg daily should be considered as a first-line treatment option for agitation in
AD.
Psychotherapy
Given the lack of disease-modifying treatments for AD, the most effective treatments are environmental
or behavioral.The same holds true for the NPS of AD.It is important to provide proper support to the
family and other informal caregivers of patients with dementia.Areas to address are: educating caregivers,
teaching problem-solving skills, accessing resources, long-range planning, emotional support, and respite.