ALZHEIMER’S

DISEASE

Clinical Management
of Patients With
Alzheimer’s Disease
The central theme is supportive care aimed at improving quality of life.
By Riddhi Patira, MD and Sanjeev Vaishnavi, MD, PhD

It is estimated that 5.3 mil- ment, a retrospective timeline of memory loss often is
lion people in the US have obtained. The clinician must consider whether symptoms
Alzheimer’s disease (AD) and are sudden in onset, which would be uncommon for AD,
that a new individual is diag- or if they are slowly progressive symptoms that were sud-
nosed with the disease every denly noted.
70 seconds.1 This devastating
disease is reaching epidemic proportions, and there are no
effective therapies to prevent onset or stop disease pro- TABLE 1. NIA-ALZHEIMER’S ASSOCIATION
gression. This article covers current guidelines on clinical DIAGNOSTIC CRITERIA
management of patients with AD and clinical use of imag-
ing biomarkers in light of new technological advances. Dementia due to ADa Memory, thinking, and behavioral
symptoms that impair a person’s
Definition and Diagnostic Criteria ability to function in daily life.
AD is the most common form of dementia, comprising
60% to 70% of all cases. It is a clinical diagnosis of progres-
MCI due to ADa Mild changes in memory and think-
sive cognitive and functional decline. The diagnostic guide-
ing abilities, enough to be noticed
lines for AD were revised in 2011 as the NIA-Alzheimer’s
and measured, but not impairment
Association criteria (Table 1).2
that compromises everyday activities
and functioning.
Clinical Evaluation
Clinical evaluation of patients with memory loss requires
Preclinical ADb Measurable changes in biomarkers
an effective history, often provided by a collateral infor-
(such as brain imaging and spinal
mant. There are numerous objective scales used to char-
fluid biomarkers) before symptoms
acterize the level of cognitive impairment, including the
are visible.
Clinical Dementia Rating (CDR) and Dementia Severity
Rating Scale (DSRS), which are limited by time available for a
assessment. Regardless of objective functional rating scales, The first two definitions are recommended for use in clinical
the goal of the clinical history is to obtain the following practice, and a functional assessment of the patient is required
key information: to make this diagnosis.
b
This diagnosis is intended for use in research only.
History
Symptom onset. Although initial memory loss symptoms Abbreviations: AD, Alzheimer’s disease; MCI, mild cognitive
are often missed or attributed to typical aging, when impairment.
symptoms progress to cause significant functional impair-

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Domains of cognitive impairment. While AD is typically of anticholinergic drugs, all of which can cause memory
thought of as an amnestic disorder with predominantly impairments and should be assessed directly whenever
short-term memory difficulties, there are many variants of possible. The American Academy of Neurology (AAN) rec-
AD including posterior cortical atrophy (PCA), in which ommends including screening for depression, vitamin B12
patients present with primary visuospatial difficulties; logo- deficiency, and hypothyroidism in the routine evaluation
penic variant primary progressive aphasia (lvPPA), in which of dementia and allowing specific risk factors to guide any
patients present with anomia and word-finding difficulties; additional testing.4 Lumbar puncture is not recommended
and frontal variant AD, in which patients present with for routine evaluation of dementia unless being used to
behavioral changes resembling frontotemporal dementia rule out other disorders of the central nervous system.4
(FTD); and others. Prompts for obtaining information that
will help differentiate these include: Cognitive Testing
• Does the patient repeat himself in conversation fre- Screening tools. The primary goal of a cognitive assess-
quently? Is he remembering appointments and taking ment is to determine if the patient’s subjective memory
medications as directed? complaints have objective correlates. In clinical practice,
• Does the patient have difficulties with getting lost? Is this often is done via a brief cognitive screening examina-
she driving, and if so, is she using GPS or other assis- tion; in memory centers, this includes a more compre-
tive devices? hensive 20 to 30 minutes of psychometric testing. Among
• Does the patient have frequent word finding dif- available brief screens, the Mini-Mental Status Examination
ficulties or lapses in communication? Does he have (MMSE) is the most commonly utilized, although it is lim-
difficulties understanding spoken or written words? ited by time and cost. The Montreal Cognitive Assessment
Does he have difficulties putting words together into (MoCA) is well validated in numerous languages and
sentences? scaled to educational level, which provides some added
• Does the patient have difficulties with her vision? Is benefit, especially because it has higher sensitivity for mild
she bumping into objects at home or falling often? cognitive impairment (MCI).5 The AAN supports the use
Functional impairment. To assess functional impair- of screening tests to identify individuals with MCI who are
ments, the following prompts are helpful. at risk of developing dementia.6 The American Association
• Driving: Is the patient driving? Does he get lost? Are of Family Practice and the American Geriatrics Society rec-
you concerned about his ability to drive? (often a ommend very brief screens (eg, the Mini-Cog—a combina-
sensitive marker for patients who need further driving tion of three-word recall and drawing a clock) for initial
evaluation). screening, followed by MMSE or MoCA if the Mini-Cog
• Management of household chores: Is she able to cook result is positive.7 A summary of brief standardized screen-
for herself, clean, or pay bills, and to what extent is ing instruments and measures of accuracy is available in
that different from usual for her? the US Preventive Services Task Force (USPSTF) guidelines.
• Finances: Are you concerned about his ability to Although these guidelines support the use of screen-
manage finances? Is he paying late fees or missing ing tools in clinical practice, the clinical benefit remains
payments? Has a bank or financial advisor raised any unclear.8 The Alzheimer’s Association suggests that assess-
concerns about management of finances? ment of cognition be required as part of an annual well-
• Personal Care: Is she independent in her activities of ness visit for Medicare beneficiaries as part of the Patient
daily living? Does she have difficulties or need remind- Protection and Affordable Care Act of 2010.9
ers or help to do tasks such as bathing, brushing her Follow-up cognitive testing. Screening tools give limited,
teeth, or toileting? although useful, information about clinical symptoms, but
are not comprehensive assessment of cognitive function. If
Differential Diagnosis a patient has a typical amnestic syndrome with short-term
While there may be significant overlap in clinical symp- memory difficulties and no other domains are affected, the
toms and pathologies, especially in much older adults,3 brief screening tests may be adequate to diagnose AD. If
making a clinical diagnosis of AD dementia includes rul- there are atypical features, then further follow-up cogni-
ing out or establishing a lower likelihood of an alternate tive testing may be warranted. For example, if there are
diagnosis. Patients who have a significant discrepancies difficulties with language, the Boston Naming Test (BNT)
between functional abilities and objective cognitive may be helpful. If there are visuospatial difficulties, the
measures may have other disorders (eg, mood disorders, Rey-Osterrieth Complex Figure (ROCF) test may be useful.
schizophrenia, other psychiatric disorders, sleep distur- Difficulties with executive function may be further charac-
bances, or substance abuse) or be experiencing side effects terized with the Trail Making A and B (oral or written) test.

50 PRACTICAL NEUROLOGY JUNE 2018

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TABLE 2. OTHER CAUSES OF DEMENTIA TO RULE symptoms, it may be useful to obtain a PET scan with or
OUT ON PHYSICAL EXAMINATION without amyloid tracer ligands.4 It must be noted, how-
ever, that although markers of amyloid pathology in the
Signs and symptoms Possible cause of dementia brain and CSF are available and approved by the Food and
Drug Administration (FDA) for commercial use, none is
Cogwheel rigidity and Lewy body dementia, vascular currently covered by Medicare or private insurers. Another
parkinsonism parkinsonism current limitation of these and other biomarkers (eg, tau
Eye movement abnormalities Progressive supranuclear palsy imaging) is that standardized values for positive levels that
translate into reliable predictors of developing AD demen-
Dysarthria or dysphagia Frontotemporal dementia, tia have yet to be established (see Disclosing Amyloid Status
amyotropic lateral sclerosis, or to a Person Without Cognitive Impairments p. 30).
tauopathies
Treatment
Frontal release signs Frontotemporal dementia
Treatment of Cognitive Symptoms
Myoclonus and hyperreflexia Creutzfeld-Jakob disease Symptomatic treatments are not recommend for
patients with MCI.6 For patients with AD dementia these
Neglect Stroke, PCA, AD variants drugs have been shown to provide small but significant
Weakness or focal Stroke, corticobasal syndrome
improvement in some domains of cognition, at least
neurologic signs
temporarily, and are FDA-approved. It is useful to advise
patients that the goal of symptomatic treatment is not to
Abbreviations: AD, Alzheimer’s disease; PCA, posterior cortical improve symptoms, but rather to help stabilize symptoms
atrophy. of functional decline, which is where these drugs have been
shown to have greatest impact. The therapies available are
Physical Examination cholinesterase inhibitors (ie, donepezil, rivastigmine, and
A comprehensive physical evaluation includes a detailed galantamine) and an NMDA-receptor antagonist, meman-
neurological examination with tests for other causes of tine. Traditionally, cholinesterase inhibitors have been
dementia. Often the physical examination for patients used as first-line medication, and memantine is used as an
with AD dementia is grossly normal, except for decreased adjunct for moderate-to-severe dementia.
ankle reflexes. If there are focal neurological abnormalities, Trials of complementary, alternative, and traditional
further assessment and approach to the clinical diagnosis medicines including vitamin E, selegiline, and antioxidants
changes significantly and other causes must be ruled out require further studies.11 Trials exploring gingko,12 estro-
(Table 2). gen,13 and anti-inflammatories14 have shown no significant
benefit, and these compounds are not recommended.
Imaging Studies and Biomarkers Although high-intensity statin did not have any significant
The diagnosis of AD dementia is made clinically as benefit in cognitive measures, it had no major side effects
described. Although imaging biomarkers are increasingly over 72 weeks of use.15
being used to support a diagnosis or to make a diagnosis
for the purpose of research, we do not have sufficient data Treatment of Psychiatric and Behavioral Symptoms
to use biomarkers alone to diagnose AD outside of the Behavioral symptoms are common in patients with AD,
research setting. interfere with caregiving, could lead to significant caregiver
Brain MRI without contrast is appropriate to rule out burden, and are a frequent reason for institutionalization.
structural lesions,4 including vascular disease, cortical or The informant should be educated about such symp-
subcortical infarctions, subdural hemorrhage, and tumors. toms and offered support. Graded assistance and positive
Brain MRI, especially 3T MRI with thin coronal slices, can reinforcement are recommended to increase functional
also provide markers of hippocampal volume and cortical independence11 and may help with apathy. Mild irritabil-
atrophy. Both may provide further prognostic informa- ity and frustration is common in early stages and can be
tion about the likelihood of progression to AD dementia. treated with selective serotonin reuptake inhibitors (SSRIs).
Hippocampal atrophy has the highest predictive value for Sertraline is generally preferred because it has a milder side
progression of MCI to dementia.10 In cases where the brain effect profile and can be titrated to higher doses as needed
MRI findings are negative or inconclusive for neurodegen- and as tolerated. Depression can be treated by antidepres-
eration and there is a clinical suspicion of FTD, especially sants including SSRIs.11 In later stages of AD, behavioral
in patients less than age 65 with behavioral or language symptoms can become more prominent (eg, agitation,

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1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the
physical aggression, paranoia, hallucinations, wandering). 2010 census. Neurology. 2013;80(19):1778-1783.
Nonpharmacological approaches that modify the behav- 2. Jack CR, Albert M, Knopman DS, et al. Introduction to revised criteria for the diagnosis of Alzheimer’s disease: National
ior or environment should be attempted.17,18 If these Institute on Aging and the Alzheimer Association Workgroups. Alzheimers Dement. 2011;7(3):257-262.
3. Schneider JA, Arvanitakis Z, Bang W, et al. Mixed brain pathologies account for most dementia cases in community-
interventions do not control these symptoms well enough dwelling older persons. Neurology. 2007;69(24):2197-2204.
to prevent risks to patient or caregivers, it is reasonable 4. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review)
to use pharmacological therapies.11 Based on systematic Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1143-1153.
5. Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild
reviews, it is suggested that a trial of cholinesterase inhibi- cognitive impairment. J Am Geriatr. 2005;53:695-699.
tors and memantine be used before atypical antipsychot- 6. Petersen RC, Lopez O, Armstrong MJ, et al. Practice guideline update summary: mild cognitive impairment: report of
ics.16-18 Because of the risk of extrapyramidal side effects, the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.
Neurology. 2018;90(3):126-135.
metabolic issues, and a black box warning of higher asso- 7. AGS Clinical Practice Committee. Guidelines abstracted from the American Academy of Neurology’s Dementia Guidelines
ciation with mortality than placebo, use of antipsychotics for Early Detection, Diagnosis, and Management of Dementia. J Am Geriatr. 2003;51(6):869-873.
is off-label in AD and most appropriate for intermittent 8. Lin JS, O’Connor E, Rossom R, et al. Screening for cognitive impairment in older adults: an evidence update for the U.S.
Preventive Services Task Force. Evidence Synthesis No. 107. AHRQ Publication No. 14-05198-EF-1. Rockville, MD: Agency
dosing. Benzodiazepines should be avoided and reserved for Healthcare Research and Quality; 2013.
only for occasional use as last resort.18 9. Cordell CB, Borson S, Boustani M, et al. Alzheimers Association recommendations for operationalizing the detection
of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting. Alzheimers Dement.
2013;9(2):141-150.
Supportive Care and Promoting Healthy Aging 10. Jack CR, Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impair-
Healthy aging can be promoted by addressing modifi- ment. Neurology. 1999;52(7):1397-1403.
able risk factors.19 The functional impairment of AD can 11. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia (an evidence-based review) Report
of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1154-1166.
significantly effect medical comorbidities and vice versa. 12. Vellas B, Coley N, Ousset PJ, et al. GuidAge Study Group. Long-term use of standardised ginkgo biloba extract for the
Proper geriatric care aimed at managing medical comor- prevention of Alzheimer’s disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurology. 2012;11(10):851-859.
bidities in the context of AD is essential. Nutrition should 13. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer
disease: a randomized controlled trial. Alzheimer’s Disease Cooperative Study. JAMA. 2000;283(8):1007-1015.
be addressed, although there is limited evidence that 14. Jaturapatporn D, Isaac MG, McCleery J, et al. Aspirin, steroidal and nonsteroidal anti-inflammatory drugs for the treat-
supplements, appetite stimulants, or assisted feeding are ment of Alzheimer’s disease. Cochrane Database Syst Rev. 2012;2:CD006378.
helpful in late-stage AD. Rehabilitation including cognitive 15. Feldman HH, Doody RS, Kivipelto M, et al. LEADe Investigators. Randomized controlled trial of atorvastatin in mild to
moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956-964.
rehabilitation, speech therapy, and physical therapy may 16. Gauthier S, Molinuevo JL. Benefits of combined cholinesterase inhibitor and memantine treatment in moderate-severe
be tried and can be helpful in early stages but is limited as Alzheimer’s disease. Alzheimers Dement. 2013;9(3):326-331.
AD progresses. Behavior modification, scheduled toilet- 17. G Livingston, K Johnston, C Katona, et al. Systematic review of psychological approaches to the management of
neuropsychiatric symptoms of dementia. Am J Psychiatry. 2005;162:1996-2021.
ing, and prompted voiding are recommended to reduce 18. Sink KM, Holden KF, Yaffe K. Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the
urinary incontinence.11 A checklist of minimal critical evidence. JAMA. 2005;293(5):596-608.
interventions for supportive care and caregiver education 19. Baumgart M, Snyder HM, Carrillo MC, et al. Summary of the evidence on modifiable risk factors for cognitive decline
and dementia: A population-based perspective. Alzheimers Dement. 2015;11(6):718-726
is available from the American Association for Geriatric 20. Lyketsos CG, Colenda CC, Beck C, et al. Task Force of American Association for Geriatric Psychiatry. Position statement
Psychiatry and provides guidance on safety issues like driv- of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from
ing, lack of supervision, environmental hazards, wandering, Alzheimer disease. Am J Geriatr Psychiatry. 2006;14(7):561-572.

falls, lack of daily structured activities, and loss of decision-

making capacity prompting a proactive assignment of
proxy decision makers.20 Early advanced care planning Riddhi Patira, MD
can prevent futile treatment and unnecessary hospitaliza- Clinical Fellow
tions that can exacerbate delirium in patients with AD. Penn Memory Center
The goals of care are guided by quality of life and patients’
University of Pennsylvania
caregivers’ preferences because of the limitations of a prog-
Philadelphia, PA
nostic model to estimate survival times.

Conclusions Sanjeev Vaishnavi, MD, PhD

Current practice guidelines for clinical management of Assistant Professor of Clinical Neurology
AD have been developed to tackle this complex disease and Director, Cognitive and Behavioral Neurology
standardize its care. With the ongoing research efforts aimed Fellowship Program
at development and validation of biomarkers along with Penn Memory Center
investigation of disease-modifying drug therapies, we await Perelman School of Medicine
incorporation of these into the clinical practice. Until then, University of Pennsylvania
the central theme of disease management is supportive care Philadelphia, PA
aimed at improving quality of life as per patients’ and care-
givers’ preferences. n

52 PRACTICAL NEUROLOGY JUNE 2018