Advances in the Testing and Treatment of Alzheimer’s Disease - Episode 1

Pathophysiology of Alzheimer’s Disease

Jeffrey L. Cummings, MD, ScD, explains the pathophysiology and common screening tools used to evaluate Alzheimer’s disease.

Jeffrey L. Cummings, MD, ScD: The pathophysiology of Alzheimer’s disease is very complicated. We do know that amyloid is central to the pathophysiology of the disease. Amyloid is present in a number of species. It starts off as a monomer. That’s just 1 molecule. Then it tends to aggregate to become more complicated. First it’s a dimer, which is 2 molecules, then a trimer, 3 molecules, and so on until it becomes an oligomer, with many molecules. And then it begins to become more and more solid as it aggregates more and more. Eventually, it forms the plaque.

In the brain, there are a whole variety of species of amyloid ranging from the very simple to the plaque itself. It’s the plaque that we can see with amyloid imaging, and it’s the monomer, or the most simple species, that we assess with spinal fluid analysis. There are a lot of species of amyloid molecules in between what we can see in the CSF [cerebrospinal fluid] and what we can see on the amyloid PET [positron emission tomography] that we have no measurement for, and they’re very important. That’s something that we need to develop as time goes on.

It appears that after amyloid has been in the brain for some time—usually years—we then begin to see the formation of neurofibrillary tangles. Neurofibrillary tangles tend to be associated with cell death and consequently the appearance of symptoms of Alzheimer’s disease. We have a sequence of biomarkers and a sequence of pathology in the brain that those biomarkers reflect. First comes the amyloid, then the neurofibrillary tangles with cell death, and then the dementia and functional decline. Those are the basics of the pathophysiology of Alzheimer’s disease.

The common screening tools that are used for the evaluation of Alzheimer’s disease are familiar to most clinicians. The most widely used is the Mini-Mental State Examination [MMSE]. It was developed in 1975. It’s quite an old instrument and still remains widely used, although other tools have become more commonly used. For example, the MoCA [Montreal Cognitive Assessment] is also very widely used. Because it’s not subject to the same copyright limitations, it’s becoming somewhat more widely used than the Mini-Mental State Examination. They’re very similar. Each of them has 30 questions. The MoCA has more executive function and more calling on the functions of the frontal lobe, whereas the mini-mental state examination has more memory function. Both are very important tools and very commonly used.

Another tool that you might know about is the Mini-Cog. The Mini-Cog has only 3 memory questions and a clock drawing test. That’s why it’s mini: it’s a very short test. Another test you might hear about is the GPCOG [General Practitioner assessment of Cognition], which was developed in Australia by Henry Brodaty. There’s a caregiver version and a patient version. The patient version is very similar to the Mini-Mental State Examination, only more brief. And then finally, the abbreviated mental test score is less widely used now. It’s an older instrument. It has 1 question on it, for example, “In what year did World War I begin?” An awful lot of people aren’t going to know the answer to that question. It’s gotten old enough now that very few people use it as a screening examination, but there are readily available screening examinations for you to use.

Cognitive decline can be the result of many different types of insults to the brain. Alzheimer’s disease is very common in older individuals, but there are other types of dementia that also have important cognitive impairment as part of their manifestations, including dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and Parkinson’s disease with dementia. As you see a patient with cognitive impairment, you’re going to think about a broad array of neurodegenerative diseases, and you’re also going to think about other possible influences, such as hypothyroidism or B12 deficiency, that can either contribute to the cognitive impairment of a demented individual or in some cases cause the cognitive impairment.

The phenotype of Alzheimer’s disease is mainly memory impairment. That’s why it starts off with mild cognitive impairment that’s mostly a recent memory defect. And then as the disease gets worse, the patient suffers language deficits and visual spatial abnormalities. That comprises a typical example of the progression of Alzheimer’s disease and what the patient would look like when you see them in the office.

This transcript has been edited for clarity.