<p>Alzheimer’s disease (AD) is increasingly recognized as a neurologically diverse condition with symptoms and progression patterns that can vary widely across individuals. Differences in the regions of the brain that are affected by AD can shape how the disease presents and evolves. Understanding this heterogeneity is essential for improving diagnosis, personalizing treatment, and guiding future research.</p>

In the 100-plus years since the discovery of AD, we have come to appreciate that for every 100 people with AD, we can get 100 different presentations. Often, the predominant presentation of AD echoes its pathophysiology. First, you get the initial deposition of amyloid-β protein plaques and subsequent tau tangles primarily in the entorhinal cortex, including the hippocampus. Not surprisingly, then, damage to the hippocampus leads to impairments in short-term memory and learning. Thus, an amnestic presentation becomes the foundation for most of the initial cases that we see.

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This is variable, however, because we often see patients who present not only with memory impairment but also with mood or behavioral symptoms, or nonamnestic symptoms involving language, executive function, or visuospatial skills. These heterogeneous presentations reflect underlying amyloid and tau deposition and neurodegeneration, along with disproportionate damage to posterior cortical regions or to frontal and temporal lobes. Even when we can detect and visualize the pathology of AD, there is not always a clear correlation with the type and severity of clinical symptoms. The rate of progression also varies greatly, and we still do not understand why some people progress rapidly while others remain stable for long periods.

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It is also common for people to have the pathology and clinical symptoms of AD while also having evidence of other neurocognitive disorders. For example, you can have Parkinson’s disease or Lewy body dementia along with amyloid and tau deposition in the brain, or you can have behavioral or language symptoms consistent with frontotemporal dementia along with aspects of AD.

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These different pathological findings and clinical pictures help us to appreciate the heterogeneity of AD and the challenges in terms of diagnosis, prognosis, and what we tell patients. It is important for us to get to know the person with the disease and that we discuss the unique features of their condition with them and their care partners. Otherwise, we have an incomplete picture of the patient’s overall condition, which can lend itself to incomplete or even inappropriate approaches to treatment.

One of the things that can increase your risk of developing AD is the presence of unmanaged psychiatric conditions in midlife. Untreated depression is an example of this. There are also some data suggesting that unmanaged anxiety disorders and associated high levels of stress may increase your risk for AD.

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AD itself can damage multiple areas of the brain, many of which are of critical importance in terms of emotions and behavior. So, we may see clinical symptoms of behavioral and emotional disruptions that may be due to AD pathology. In preclinical AD, we may begin to see anxiety and depressive features, some irritability, and the beginning of apathy, all of which tend to become more prominent and tend to progress when a patient develops mild cognitive impairment and subsequent dementia. Apathy is probably the most common neuropsychiatric symptom of AD, but it is often overlooked because it is somewhat easy to ignore.

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This not only highlights the heterogeneity of symptoms throughout the different stages of AD but also brings attention to the fact that we need to address mental health issues throughout the life span because they increase your risk of developing multiple conditions, including the dementias, later in life. If you follow a patient from the beginning of their disease to the end, most will have developed a meaningful degree of often highly distressing neuropsychiatric symptoms at some stage during their illness. In fact, neuropsychiatric symptoms are one of the leading reasons for caregiver or care partner burnout and patient admissions to higher levels of care.

One single data point is typically not sufficient to confirm a diagnosis of AD. There are some hallmark symptoms that we see with AD, the most common one being amnestic-predominant changes, with other cognitive domains being affected over time. If you see those symptoms and if you have cerebrospinal fluid or positron emission tomography (PET) biomarker evidence to confirm the presence of amyloid plaques and/or tau tangles, this can help support the idea that AD may be the driver of a patient’s clinical picture.

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There is good reason to think that the regions and networks of the brain that are involved in AD are correlated with the symptoms that we see. For example, if a case of posterior cortical atrophy is due to AD, I expect to see signs of neurodegeneration, either atrophy on a magnetic resonance imaging scan or hypometabolism on a glucose PET scan, especially affecting the back parts of the brain. I expect to see evidence of amyloid plaques. Likely, I would also see tau tangles in the same posterior parts of the brain. Those pieces of evidence can help you pair the clinical picture with the diagnosis, and mapping those 2 together really helps augment our patient counseling.

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However, these tests are not perfectly correlated with symptoms. There may be times when you see a lot of hippocampal atrophy on a magnetic resonance imaging scan, and the patient presents with a memory problem. They may actually not have AD as the driver of their memory issue and may have another condition instead. Some patients can have profoundly abnormal glucose PET scans indicating widespread neurodegeneration in an AD pattern, but, from a clinical standpoint, they have mild symptoms. This may point to something explaining the disconnect, such as a patient possibly having other factors helping them cope with the changes that are seen on a brain scan, allowing them to continue to function well clinically.

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Clinical symptoms and AD testing do not always correlate perfectly with each other. However, by using tools such as biomarkers, including imaging, tests, and other assessments, we can get a sense of neurodegeneration and topography of change, which can help provide a more comprehensive assessment of a patient.