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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

For Alzheimer's disease, early identification has been a long-sought goal. Not only does it allow individuals to make decisions about their future, but it enables them to start on disease-modifying medications to slow progression and opens up the potential for effective research.

However, no single test alone can define Alzheimer's disease. Clinical assessment of symptoms must work together with objective testing to help rule out alternative diagnoses.

The diagnostic process starts with taking a thorough medical history, which will include any cognitive, functional, and behavioral changes as obtained from a close family member or other person who knows the patient well, medications the person is taking, and any family history of Alzheimer's disease or other dementias.

Health issues like depression, untreated sleep apnea, delirium, certain medication side effects or vitamin deficiencies, thyroid problems, and excessive alcohol consumption can all have symptoms that mimic Alzheimer's disease. If present, these conditions may require further assessment (including blood tests) and treatment.

Other potential causes of Alzheimer's-like symptoms, such as stroke, Parkinson's disease, brain tumors, and buildup of fluid in the brain need to be ruled out -- typically with brain imaging with magnetic resonance imaging (MRI) or computed tomography (CT).

A neurologic exam should check reflexes, coordination, muscle tone and strength, eye movement, speech, and the senses.

Cognitive, functional, and behavioral tests to evaluate changes in behavior, memory, thinking, and simple problem-solving abilities impacted by Alzheimer's disease include the following:

• Ascertain Dementia 8

• Functional Activities Questionnaire

• Mini-Cog

• Mini-Mental State Exam

• Montreal Cognitive Assessment

• Neuropsychiatric Inventory Questionnaire

Digital cognitive testing tools cleared for use in Alzheimer's include the Automated Neuropsychological Assessment Metrics, Cambridge Neuropsychological Test Automated Battery, CognICA, Cognigram, and Cognivue. The Cognision headset measures electrical activity in the brain responsible for cognitive function.

While many cases can be diagnosed without further testing, National Institute on Aging Alzheimer's Disease Centers data showed sensitivity of clinical diagnosis ranging from 70.9% to 87.3% and specificity from 44.3% to 70.8%, as compared with the reference standard of pathological diagnosis at autopsy.

An noted that "objective neurobehavioral tests are helpful in documenting the type and severity of cognitive impairment but are not by themselves diagnostic."

For cases with significant uncertainty as to the etiology of the cognitive impairment after those tests, a brain scan with positron emission tomography (PET) using a fluorodeoxyglucose (FDG) tracer can point to which areas of the brain are in metabolic deficit to help distinguish between different types of degenerative brain disease. PET scans that detect the buildup of beta-amyloid and tau in the brain have also been developed and are used in some memory clinics.

If diagnostic uncertainty persists, biomarkers can improve diagnostic accuracy. Lumbar puncture can show factors predictive of Alzheimer's disease in the cerebrospinal fluid (CSF). These include buildup of tau and beta-amyloid proteins and high levels of neurofilament light (NfL), a marker of axonal injury.

The Alzheimer's Association workgroup recommended advanced CSF biomarker testing for complex and atypical cases where the differential diagnosis list can be long. Settings where the group considered these biomarkers appropriate include the following:

• Subjective cognitive decline not confirmed on objective testing in patients considered to be at increased risk for Alzheimer's disease

• Mild cognitive impairment that is persistent, progressing, and unexplained

• Symptoms that suggest possible Alzheimer's disease

• Mild cognitive impairment or dementia with onset before age 65

• Meeting core clinical criteria for probable Alzheimer's disease with onset after age 65

• Patients whose dominant symptom is a change in behavior (such as paranoid delusions, unexplained delirium, combative symptoms, and depression) and where Alzheimer's diagnosis is being considered

A variety of other blood biomarkers -- such as pTau 217, pTau 181, AB42, AB40, glial fibrillary acidic protein, growth differentiation factor-15, and latent-transforming growth factor beta-binding protein 2 -- are also being explored for patients who already have clinical symptoms of Alzheimer's, but the biomarkers are not yet recommended for routine clinical use.

In the recent COAST study of nearly 1,300 Han Chinese adults ages 45-65, temporal trajectories showed that CSF biomarkers deviated by up to 18 years before Alzheimer's diagnosis between people who were subsequently diagnosed with sporadic Alzheimer's disease and people who remained cognitively normal. The difference was seen at 18 years prior to diagnosis for amyloid-beta 42 levels, 14 years for the ratio of CSF amyloid-beta 42 to amyloid-beta 40, 11 years for phosphorylated tau 181, 10 years for total tau, and 9 years for CSF NfL as compared with 8 years for hippocampal atrophy on MRI and 6 years for cognitive decline on Clinical Dementia Rating-Sum of Boxes assessments.

As discussed in the first installment of this series, a revised disease staging system and new biologically based criteria that define the disease as a process detectable by abnormal biomarkers when patients do not yet have cognitive symptoms has also been published. However, testing cognitively unimpaired individuals outside of research studies is still not recommended.

Formal clinical practice guidelines around treatment and testing in this setting are expected from the Alzheimer's Association in the near future.

Direct-to-consumer APOE gene tests can be misleading and are by the Alzheimer's Association for use outside of a research or clinical setting.

Read previous installments in this series:

Part 1: Defining Alzheimer's Disease

Part 2: The Complex Pathogenesis and Genetics of Alzheimer's Disease

Up next: A noteworthy case report