Overview

Alzheimer disease (AD) is an acquired disorder of cognitive and behavioral impairment that markedly interferes with social and occupational functioning. It is an incurable disease with a long 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 used in thinking and making decisions. Whether plaques themselves cause AD or whether they are a by-product of the AD process is still unknown. See the image below.

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.

Signs and symptoms

Preclinical Alzheimer disease

A patient with preclinical AD may appear completely normal on physical examination and mental status testing. Specific regions of the brain (eg, entorhinal cortex, hippocampus) probably begin to be affected 10-20 years before any visible symptoms appear.

Mild Alzheimer disease

Signs of mild AD can include the following:

• Memory loss

• Confusion about the location of familiar places

• Taking longer to accomplish normal, daily tasks

• Trouble handling money and paying bills

• Compromised judgment, often leading to bad decisions

• Loss of spontaneity and sense of initiative

• Mood and personality changes; increased anxiety

Moderate Alzheimer disease

The symptoms of this stage can include the following:

• Increasing memory loss and confusion

• Shortened attention span

• Problems recognizing friends and family members

• Difficulty with language; problems with reading, writing, working with numbers

• Difficulty organizing thoughts and thinking logically

• Inability to learn new things or to cope with new or unexpected situations

• Restlessness, agitation, anxiety, tearfulness, wandering, especially in the late afternoon or at night

• Repetitive statements or movement; occasional muscle twitches

• Hallucinations, delusions, suspiciousness or paranoia, irritability

• Loss of impulse control: Shown through behavior such as undressing at inappropriate times or places or vulgar language

• Perceptual-motor problems: Such as trouble getting out of a chair or setting the table

Severe Alzheimer disease

Patients with severe AD cannot recognize family or loved ones and cannot communicate in any way. They are completely dependent on others for care, and all sense of self seems to vanish.

Other symptoms of severe AD can include the following:

• Weight loss

• Seizures, skin infections, difficulty swallowing

• Groaning, moaning, or grunting

• Increased sleeping

• Lack of bladder and bowel control

In end-stage AD, patients may be in bed much or all of the time. Death is often the result of other illnesses, frequently aspiration pneumonia.

Diagnosis

Means of diagnosing AD include the following:

• Clinical examination: The clinical diagnosis of AD is usually made during the mild stage of the disease, using the above-listed signs

• Lumbar puncture: levels of tau and phosphorylated tau in the cerebrospinal fluid are often elevated in AD, whereas amyloid levels are usually low; at present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings

• Imaging studies: Imaging studies (eg, computed tomography [CT]; magnetic resonance imaging [MRI]; and, in selected cases, 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) and rule out potentially treatable causes of progressive cognitive decline, such as chronic subdural hematoma or normal-pressure hydrocephalus

Essential update: Brain protein may be biomarker for Alzheimer's up to ten years before diagnosis

In a cross-sectional study of 48 AD patients without diabetes, 20 cognitively normal diabetic patients, 16 patients with frontotemporal dementia, and 84 cognitively normal controls, researchers found that dysfunctionally phosphorylated insulin receptor substrate-1 (IRS-1), a neuronal protein, is detectable in blood using exosome-based technology and may be able to predict AD up to 10 years before the appearance of symptoms.

Compared with all other groups, patients with AD had several-fold higher p-Ser312-IRS-1 and Ser312/p-panY ratios and lower p-panY-IRS-1. In a longitudinal analysis of 22 of the AD patients who provided blood samples 1 to 10 years before diagnosis, preclinical and clinical levels of all three proteins were indistinguishable, while preclinical levels differed significantly from those of control s (P < .001).