Diagnostic Considerations

Depression

Depression is an important consideration in the differential diagnosis of Alzheimer disease (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.^[74]

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).^[74]

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.^[75]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^[76]:

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^[76]:

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

For more information, see the Medscape Reference article Repetitive Head Injury Syndrome.

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

Differential Diagnoses

Workup

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Media Gallery

APP is associated with the cell membrane, the thin barrier that encloses the cell. After it is made, APP sticks through the neuron's membrane, partly inside and partly outside the cell. Image courtesy of NIH.
Enzymes (substances that cause or speed up a chemical reaction) act on the APP and cut it into fragments of protein, one of which is called beta-amyloid. Image courtesy of NIH.
The beta-amyloid fragments begin coming together into clumps outside the cell, then join other molecules and non-nerve cells to form insoluble plaques. Image courtesy of NIH.
Healthy neurons. Image courtesy of NIH.
Image courtesy of NIH.
Preclinical Alzheimer disease. Image courtesy of NIH.
Mild Alzheimer disease. The disease begins to affect the cerebral cortex, memory loss continues, and changes in other cognitive abilities emerge. The clinical diagnosis of AD is usually made during this stage. Image courtesy of NIH.
Severe Alzheimer disease. In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. Patients cannot recognize family and loved ones or communicate in any way. They are completely dependent on others for care. All sense of self seems to vanish. Image courtesy of NIH.
Preclinical Alzheimer disease. Image courtesy of NIH.
Mild-to-moderate Alzheimer disease. Image courtesy of NIH.
Severe Alzheimer disease. Image courtesy of NIH.
Cortical atrophy with hydrocephalus ex vacuo is seen in Alzheimer disease.
Plaques and tangles in Alzheimer disease.
Amyloid angiopathy in Alzheimer disease.
Coronal T1-weighted magnetic resonance imaging (MRI) scan in a patient with moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.

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Author

Shaheen E Lakhan, MD, PhD, MS, MEd, FAAN Clinical Professor of Neurology, Western University of Health Sciences

Shaheen E Lakhan, MD, PhD, MS, MEd, FAAN is a member of the following medical societies: American Academy of Neurology, American Medical Association, International Association for the Study of Pain

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cleveland Clinic; UCLA; MGH; California University of Science and Medicine; Carilion Clinic; Sage Therapeutics; The Learning Corp; Zogenix; Fern Health; Thriveworks; Click Therapeutics; Neurocrine; NeuroSport; SpineThera; Shaheen E. Lakhan, MD.

Chief Editor

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

Additional Contributors

Heather S Anderson, MD Associate Professor, Staff Neurologist, Department of Neurology, University of Kansas Alzheimer's Disease Center

Heather S Anderson, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Acknowledgements

Guy E Brannon, MD Associate Clinical Professor of Psychiatry, Louisiana State University Health Sciences Center; Director, Adult Psychiatry Unit, Chemical Dependency Unit, Clinical Research, Brentwood Behavior Health Company

Guy E Brannon, MD is a member of the following medical societies: American Medical Association, American Medical Writers Association, American Psychiatric Association, American Society of Addiction Medicine, Association of Clinical Research Professionals, Louisiana State Medical Society, and Southern Medical Association

Disclosure: AstraZeneca Grant/research funds Other; Janssen Grant/research funds Other; Pfizer Honoraria Speaking and teaching; Sunovion Honoraria Speaking and teaching; Eli Lilly Grant/research funds Other; Forrest Grant/research funds Other

Linda P Boswell, MD Medical Director of Senior Care Unit, Bossier Medical Center; Private Practice, Shreveport, Louisiana

Linda P Boswell, MD is a member of the following medical societies: American Medical Association, American Psychiatric Association, and Louisiana State Medical Society

Disclosure: Nothing to disclose.

Jody L Haddock, MD Resident Physician, Department of Internal Medicine, University of Tennessee College of Medicine Chattanooga

Disclosure: Nothing to disclose.

Rodrigo O Kuljis, MD Esther Lichtenstein Professor of Psychiatry and Neurology, Director, Division of Cognitive and Behavioral Neurology, Department of Neurology, University of Miami School of Medicine

Rodrigo O Kuljis, MD is a member of the following medical societies: American Academy of Neurology and Society for Neuroscience

Disclosure: Nothing to disclose.

Alan D Schmetzer, MD Professor, Vice-Chair for Education, Assistant Training Director in General Psychiatry and Director of Residency Training in Addiction Psychiatry, Department of Psychiatry, Indiana University School of Medicine

Alan D Schmetzer, MD, is a member of the following medical societies: American Academy of Addiction Psychiatry, American Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives, American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for Convulsive Therapy

Disclosure: Eli Lilly & Co. Grant/research funds Other

Ronald Schneider, MD Chief Medical Officer, Mental Health Outreach Program, Overton Brooks Veterans Affairs Medical Center; Clinical Assistant Professor of Psychiatry, Louisiana State University Health Sciences Center

Ronald Schneider, MD is a member of the following medical societies: American Psychiatric Association and Louisiana Psychiatric Medical Association

Disclosure: Pfizer Honoraria Speaking and teaching; Janssen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment