HEA 3071 Module 6 Alzheimer's Disease Case Study: Amyloid, Tau and the First Disease-Modifying Drugs Example

Plaques, Tangles and a Teacher's Forgotten Names: Alzheimer's Disease in Cherry Hill

Student Name

B.S. in Health Studies, Thomas Edison State University

HEA-3071: Pathophysiology for Health Professionals

Mentor Name

Month Day, Year

Plaques, Tangles and a Teacher's Forgotten Names: Alzheimer's Disease in Cherry Hill

The Patient

Mrs. Feldman is invented for this case. She is 74, a retired high school history teacher who lives with her husband in Cherry Hill. For two years she has forgotten the names of former colleagues, repeated questions within minutes and misplaced her keys and glasses. Last month she got lost driving home from a store she had visited for decades. She still dresses, cooks simple meals and manages her own medicines with a pill box her husband fills. Her score on a brief cognitive test is mildly low, with the greatest difficulty in recalling words after a delay. Her mother had dementia in her eighties.

The Normal Brain and Memory

Memory formation depends on the hippocampus and nearby areas of the medial temporal lobe, which hold new information and connect it to the cerebral cortex for long-term storage. Neurons communicate across synapses using neurotransmitters such as acetylcholine and glutamate. Inside neurons, a protein called tau stabilizes microtubules, the tracks along which materials move within the cell.

The Amyloid Hypothesis

Hardy and Selkoe (2002) set out the amyloid hypothesis. Amyloid precursor protein is cut by enzymes in two ways. In one pathway, beta-secretase and gamma-secretase cut it to release amyloid beta peptides, especially a 42-amino-acid form that tends to clump. Small clumps called oligomers disrupt synapses, and larger deposits form plaques outside neurons. The hypothesis proposed that amyloid accumulation is the starting event, triggering inflammation, oxidative stress and abnormal tau, which leads to neuron death and dementia. Support came from rare families with inherited early-onset Alzheimer's disease, whose mutations all increase amyloid beta production or its tendency to clump. Hardy and Selkoe acknowledged problems, including that plaque amounts correlate poorly with symptoms.

Tau and Neurodegeneration

In Alzheimer's disease, tau becomes abnormally phosphorylated, detaches from microtubules and forms tangles inside neurons. Transport within the cell fails, and neurons die. Tau tangles spread in a predictable pattern, starting in the medial temporal lobe and moving into the cortex, and their spread matches symptoms more closely than amyloid does. The loss of neurons that use acetylcholine contributes to memory problems, which is the basis of older drugs that slow acetylcholine breakdown.

Explaining Her Signs

Mrs. Feldman's trouble recalling recent information and repeating questions reflect early damage to the hippocampus and medial temporal lobe, where tau tangles appear first. Getting lost on a familiar route reflects spread to areas of the parietal cortex involved in spatial orientation. Preserved dressing and cooking show that her disease is at an early stage.

Defining the Disease Biologically

Jack et al. (2018) proposed a research framework that defines Alzheimer's disease by biomarkers rather than symptoms alone. The AT(N) system classifies people by amyloid (A), measured by amyloid PET or cerebrospinal fluid amyloid beta 42; tau (T), measured by tau PET or cerebrospinal fluid phosphorylated tau; and neurodegeneration (N), measured by MRI atrophy, FDG-PET or other markers. A person with abnormal amyloid and tau has Alzheimer's disease biologically, whether or not symptoms are present. The framework was intended for research, but it shaped who could enter drug trials.

An Anti-Amyloid Drug

The Clarity AD trial (van Dyck et al., 2023) tested lecanemab, an antibody that binds amyloid beta clumps. The trial enrolled about 1,800 people with mild cognitive impairment or mild dementia due to Alzheimer's disease and confirmed amyloid. Over 18 months, lecanemab reduced amyloid on PET scans and slowed worsening on the Clinical Dementia Rating, summed across its six boxes, by 0.45 points compared with placebo, about 27 percent less decline. Amyloid-related imaging abnormalities with brain swelling occurred in about 13 percent of the lecanemab group compared with about 2 percent of the placebo group, and microbleeds were also more common; most were without symptoms, but some were serious. The trial supported the amyloid hypothesis while showing that removing amyloid slows but does not stop the disease.

Care for Mrs. Feldman

After an amyloid PET scan was positive, Mrs. Feldman and her husband discussed lecanemab with her neurologist, including the infusions every two weeks, the MRI monitoring for brain swelling and the modest size of the benefit. Genetic testing for the APOE e4 gene, which raises the risk of brain swelling, was offered. She also stopped driving, began a support program for people with early memory loss and completed advance directives while she could express her wishes. Her husband joined a caregiver support group.

Other Contributors

Amyloid and tau are not the whole story. The brain's immune cells, the microglia, normally clear amyloid, but in Alzheimer's disease they become chronically activated and may damage synapses. Small-vessel disease from high blood pressure and diabetes reduces blood flow and often coexists with Alzheimer's changes, so many older adults have mixed dementia. The APOE e4 gene variant, carried by about a quarter of people, raises risk and lowers the age of onset, partly by impairing amyloid clearance. Education, hearing, physical activity and blood pressure control may build resilience. Mrs. Feldman's long career in teaching may have given her cognitive reserve that delayed symptoms despite changes in her brain.

Limits

The trial's benefit was modest, and its meaning for daily life is debated. The research framework was not designed for clinical diagnosis. Mrs. Feldman is invented, and her care illustrates principles.

Conclusion

Mrs. Feldman's forgotten names and repeated questions reflect amyloid plaques and spreading tau tangles in her medial temporal lobe. Hardy and Selkoe's hypothesis explains why amyloid became the main drug target, Jack and colleagues' framework defines the disease by its biology and the Clarity AD trial showed that removing amyloid slows decline modestly at a risk. Care that combines a careful drug decision with planning and family support fits this stage of her disease.

References

Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science, 297(5580), 353-356. https://doi.org/10.1126/science.1072994

Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., Liu, E., Molinuevo, J. L., Montine, T., Phelps, C., Rankin, K. P., Rowe, C. C., Scheltens, P., Siemers, E., Snyder, H. M., . . . Silverberg, N. (2018). NIA-AA research framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & Dementia, 14(4), 535-562. https://doi.org/10.1016/j.jalz.2018.02.018

van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., Froelich, L., Katayama, S., Sabbagh, M., Vellas, B., Watson, D., Dhadda, S., Irizarry, M., Kramer, L. D., & Iwatsubo, T. (2023). Lecanemab in early Alzheimer's disease. New England Journal of Medicine, 388(1), 9-21. https://doi.org/10.1056/NEJMoa2212948