Surreal illustration representing the complexities of dementia

Unlocking the Mysteries of Dementia: A 100-Year-Old Case Study

Mira Elwood in Health & Wellness July 2025 • 4 min read.

"What can a centenarian's brain tell us about Alzheimer's, hippocampal sclerosis, and other age-related pathologies?"

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. While AD is the most common cause of dementia, diagnosis can be challenging, and other pathologies can contribute to cognitive decline, especially in the very old.

One such pathology is hippocampal sclerosis (HS), marked by neuronal loss and gliosis (scarring) in the hippocampus, a brain region critical for memory. HS has been linked to epilepsy, neurodegenerative diseases like AD, and even normal aging. Distinguishing between AD, HS, and other contributing factors is crucial for understanding and potentially treating dementia.

This article delves into a fascinating case study of a 100-year-old Japanese woman diagnosed with AD. Her autopsy revealed not only AD pathology but also HS, TDP-43 protein accumulation, and alpha-synuclein protein accumulation—a rare combination. By examining this case, we can gain a deeper understanding of the complexities of dementia in the elderly and the interplay of different age-related brain changes.

The Case: A Century of Cognitive Change

Surreal illustration representing the complexities of dementia

The patient, a Japanese woman, began experiencing memory problems at age 84, with disorientation gradually developing. Brain scans revealed significant hippocampal atrophy, but relatively mild frontal lobe atrophy for her age. Interestingly, her behavioral and psychological symptoms of dementia were not prominent throughout the disease course.

She was clinically diagnosed with AD and treated with donepezil. Despite slowly worsening cognitive function, she maintained relative independence for about 10 years. Later in life, she showed behavioral changes such as disrupted sleep and changes in taste preferences, but her condition did not drastically impair the family’s life. By 95, she required assistance and eventually moved to a nursing home.

Key Clinical Observations:

Slowly progressive memory disturbance starting at age 84.
Disorientation and hippocampal atrophy on brain scans.
Relatively mild behavioral and psychological symptoms.
Apolipoprotein E gene analysis showed £3/24 heterozygosity, a genetic factor associated with increased AD risk.

The patient died at 100 years old. An autopsy was performed, which showed not only the typical signs of Alzheimer's but also other issues. The post-mortem examination provided critical insights beyond what clinical observations could reveal.

The Significance: Unraveling the Complexity of Dementia

This case highlights the complex interplay of pathologies that can contribute to dementia in the elderly. While the patient met pathological criteria for AD, the presence of HS, TDP-43, and alpha-synuclein suggests a mixed pathology that may have influenced her disease progression and clinical presentation.

The presence of hippocampal sclerosis (HS) alongside AD is particularly intriguing. HS-aging, the pathology of HS in older individuals, is often misdiagnosed as AD. The patient also had TDP-43 pathology, which has been linked to both AD and HS. The case also showed synuclein protein accumulation, typically related to Parkinson's. In conclusion, the patient was suffering from AD, HS, TDP-43, and synuclein protein.

This case underscores the importance of detailed clinical and pathological examinations in elderly patients with dementia. As age-related pathologies often coexist, a comprehensive approach is needed for accurate diagnosis and a deeper understanding of the disease processes. Future research should focus on the interactions between AD, HS, TDP-43, and other age-related brain changes to develop more targeted therapies for dementia.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1111/neup.12521, Alternate LINK

Title: Autopsied Centenarian Case Of Alzheimer'S Disease Combined With Hippocampal Sclerosis, Tdp‐43, And Α‐Synuclein Pathologies

Subject: Neurology (clinical)

Journal: Neuropathology

Publisher: Wiley

Authors: Yasushi Iwasaki, Akira Deguchi, Keiko Mori, Masumi Ito, Yoshinari Kawai, Akio Akagi, Maya Mimuro, Hiroaki Miyahara, Mari Yoshida

Published: 2018-11-09

Everything You Need To Know

What is Alzheimer's disease, and how is it diagnosed, especially considering other potential contributing factors?

Alzheimer's disease is a neurodegenerative disorder characterized by a decline in cognitive function. The key pathological features of Alzheimer's disease are the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. These structural changes disrupt normal brain function, leading to the symptoms associated with dementia. It's important to note that other factors, such as hippocampal sclerosis and other protein accumulations, can also contribute to cognitive decline, especially in older individuals, making accurate diagnosis challenging.

What is hippocampal sclerosis, and how does it relate to Alzheimer's disease and other age-related cognitive impairments?

Hippocampal sclerosis refers to the neuronal loss and gliosis (scarring) in the hippocampus. The hippocampus is a region of the brain vital for memory. Hippocampal sclerosis has been associated with conditions like epilepsy and neurodegenerative diseases, including Alzheimer's disease, but can also occur as part of normal aging. The relationship between hippocampal sclerosis and Alzheimer's disease is complex, as both can independently contribute to memory impairment and may also interact to worsen cognitive decline.

What are TDP-43 and alpha-synuclein, and what does their presence in the brain of someone diagnosed with Alzheimer's disease suggest?

TDP-43 and alpha-synuclein are proteins that, when misfolded or aggregated, can contribute to neurodegenerative diseases. TDP-43 protein accumulation is commonly found in frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS), while alpha-synuclein protein accumulation is characteristic of Parkinson's disease and Lewy body dementia. The presence of both TDP-43 and alpha-synuclein in the brain of a person diagnosed with Alzheimer's disease suggests a mixed pathology, where multiple neurodegenerative processes are occurring simultaneously, potentially influencing the presentation and progression of dementia.

How does the Apolipoprotein E (APOE) gene affect the risk of developing Alzheimer's disease, and what does it mean to have an £3/£4 heterozygosity?

The Apolipoprotein E (APOE) gene has several variants, with the £4 allele being the most well-known genetic risk factor for Alzheimer's disease. Having an £3/£4 heterozygosity, as seen in the case, means that the individual has one copy of the £3 allele and one copy of the £4 allele. This genetic combination is associated with an increased risk of developing Alzheimer's disease compared to individuals without the £4 allele, but it doesn't guarantee that the person will develop the disease. Other genetic and environmental factors also play a significant role.

What does the co-occurrence of Alzheimer's disease, hippocampal sclerosis, TDP-43, and alpha-synuclein protein accumulation reveal about dementia in the elderly, and what are the implications for treatment?

The case revealed a combination of Alzheimer's disease pathology, hippocampal sclerosis, TDP-43 protein accumulation, and alpha-synuclein protein accumulation. This suggests that dementia in the elderly can arise from a complex interplay of multiple age-related brain changes, rather than a single cause. This mixed pathology can influence how the disease manifests and progresses, making it essential to consider all contributing factors for accurate diagnosis and potential treatment strategies. It also implies that treatments targeting only one pathology, like amyloid plaques in Alzheimer's disease, might not be fully effective in individuals with mixed pathologies.