Alzheimer disease: Clinical sciences

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Introduction0:00–0:43

Alzheimer disease, which is a neurodegenerative condition with slowly progressive cognitive and functional decline, is the most common cause of dementia in the developed world.
Its pathology is characterized by extracellular deposits of amyloid plaques and abnormal intracellular accumulations of tau protein in neurofibrillary tangles.
There’s also a degeneration of cholinergic neurons in the nucleus basalis of Meynert, with a decrease in acetylcholine levels throughout the cortex.
Now, the four main stages of this condition include mild cognitive impairment and mild, moderate, and severe Alzheimer disease.

Focused H&P, consider Alzheimer disease0:43–3:24

Now, if your patient presents with a chief concern suggesting Alzheimer disease, several exams need to be done. First, obtain a focused history and physical exam.
Be sure to perform a standardized screening cognitive exam, along with a depression screen, because many patients with Alzheimer disease or dementia have coexisting depression.
Next, check vitamin B12 and TSH levels to rule out vitamin B12 deficiency and hypothyroidism, which are conditions that can cause cognitive impairment.
Finally, order brain imaging with CT or MRI to ensure no structural processes are causing cognitive impairment. History typically reveals slowly progressive cognitive decline, such as memory loss and difficulty with visuospatial tasks and executing tasks.
In particular, these patients tend to forget specific events, like appointments, important dates such as birthdays, or where they just placed an item, which is known as episodic memory loss.
Also, they have difficulty with performing usual daily activities like self-care. Next, history will be negative for the use of medications or substances that can cause cognitive side effects, such as anticholinergics or excessive alcohol intake; and there will be no other medical conditions that could affect cognition, such as hepatic encephalopathy.
Finally, your patient might be a known carrier of the apolipoprotein e4 allele, which is associated with an increased risk of Alzheimer disease.
Depending on the stage of the disease, your physical exam findings may vary. Early in the disease, the physical exam might be completely normal.
Later, your patient might present with frontal release signs, which are primitive reflexes that are normally present in a newborn and disappear soon after infancy; however, these can reemerge in neurodegenerative conditions that affect the frontal lobe.
For example, your patient could present with a positive palmomental reflex, in which stroking of the palmar muscles at the base of the thumb causes a contraction of the mentalis muscle of the chin.
Another important reflex is the grasp reflex, in which the patient will reflexively grasp an object gently placed in their palms, such as the examiner’s finger.
You might also find rigidity and hyperreflexia. Next, the screening cognitive exam, such as the Mini-Mental State Examination or the Montreal Cognitive Assessment, will be abnormal; while the depression screen may or may not be positive.
Labs will reveal normal vitamin B12 and TSH levels. Finally, brain imaging might show atrophy of the bilateral hippocampi, temporal lobes, or the cortex diffusely.
With these findings, suspect Alzheimer disease. Your next step is to obtain an amyloid PET scan, which detects amyloid deposition in the brain parenchyma.

Suspect Alzheimer disease3:24–4:09

Alternatively, you can order CSF or plasma biomarker assays. These biomarkers include plasma phosphorylated-tau 217, or the ratio of amyloid-beta 42 peptides to amyloid-beta 40 peptides in the CSF.
If the amyloid PET is positive for amyloid deposition or if the biomarker assays are abnormal, diagnose Alzheimer disease.
Keep in mind that these diagnostic methods are not yet readily accessible for many patients, so their use is limited in clinical practice, and the diagnosis of Alzheimer disease currently primarily relies on clinical manifestations.
Once you diagnose Alzheimer disease, use the cognitive testing results to assess the clinical stage of the disease. If your patient is still able to perform daily activities independently despite some difficulties, such as with less efficiency, the patient has mild cognitive impairment.

Mild cognitive impairment4:09–5:52

At this stage, the patient does not yet have dementia, which is the loss of ability to function independently due to cognitive impairment.
Here's a high-yield fact to keep in mind! Mild cognitive impairment is not specific for Alzheimer disease only.
This is also seen in different types of dementia, including vascular dementia and frontotemporal dementia. Finally, don’t forget that in some cases, mild cognitive impairment will not progress to dementia.
Management of mild cognitive impairment includes lifestyle modifications such as exercise, avoiding a sedentary lifestyle, and maintaining a healthy diet.
In individuals who are positive for biomarkers of amyloid-beta, either on PET imaging or in the CSF, consider medical therapy with anti-amyloid-beta monoclonal antibodies, such as lecanemab.
These medications reduce the burden of amyloid-beta plaque and are currently the only disease-modifying medications available for Alzheimer disease.
And here's a high-yield fact! Anti-amyloid-beta monoclonal antibodies can cause brain edema or microhemorrhages, known as amyloid-related imaging abnormalities, or ARIA.
So, once you start your patient on this class of medications, you should closely monitor them using serial brain MRIs. Also, this medication is contraindicated in individuals with an increased risk of intracranial hemorrhage, such as those on blood thinners.

Mild Alzheimer disease5:52–6:55

Now, let’s go back and look at patients with mild Alzheimer disease. In this case, your patient is independent with basic activities of daily living, which are self-care tasks such as eating, toileting, and dressing.
However, they have mild functional impairment in instrumental activities of daily living, which are more advanced tasks that allow them to function in society.
These include using the phone, grocery shopping, taking public transportation, and managing finances. These findings are suggestive of dementia, so you can diagnose the mild stage of Alzheimer disease.
At this stage, available medical therapies include acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine.
Unlike anti-amyloid therapies, acetylcholinesterase inhibitors are not considered disease-modifying drugs but may temporarily improve cognitive symptoms and functional abilities.
Finally, if eligible, your patient could also receive anti-amyloid-beta monoclonal antibodies. Alright, now switching gears and moving on to patients who present with moderate functional impairment, requiring assistance with even basic activities of daily living.

Moderate Alzheimer disease6:55–7:25

In this case, diagnose moderate Alzheimer disease. In this stage, medical therapy includes acetylcholinesterase inhibitors and memantine, which is an N-methyl-D-aspartate, or NMDA, receptor antagonist.
Keep in mind that these patients are not eligible for anti-amyloid-beta monoclonal antibodies. Lastly, if your patient has severe functional impairment and complete dependence on basic activities of daily living, diagnose severe Alzheimer disease.

Severe Alzheimer disease7:25–7:58

In this case, medical therapies include acetylcholinesterase inhibitors and memantine. However, at this point, you should strongly weigh the pros and cons of continuing acetylcholinesterase inhibitors because, in the later stages of Alzheimer's disease, the number of cholinergic neurons is significantly reduced, meaning the therapy is not as effective as during the early stages.
Alright, as a quick recap… If your patient presents with a chief concern suggestive of Alzheimer disease, obtain a focused history and physical examination, and perform a standardized screening cognitive exam and depression screen.

Review7:58–8:47

Also, be sure to obtain vitamin B12 and TSH levels, as well as brain imaging, to rule out conditions that can cause similar manifestations.
Once you suspect Alzheimer disease, your next step is to confirm the diagnosis with an amyloid PET scan, or with CSF and plasma biomarker assays.
Once you confirm the diagnosis, assess the clinical stage of the disease, which includes mild cognitive impairment and mild, moderate, and severe stages of Alzheimer disease.
Depending on the stage, medical therapy options include anti-amyloid-beta monoclonal