Development of Alzheimer’s Disease Hypothesis

Case Scenario

A 76-year -old man is brought to the primary care office by his wife with concerns about his worsening memory. He is a retired lawyer who has recently been getting lost in the neighborhood where he has lived for 35 years. He was recently found wandering and has often been brought home by neighbors. When asked about this, he becomes angry and defensive and states that he was just trying to go to the store and get some bread.

His wife expressed concerns about his ability to make decisions as she came home two days ago to find that he allowed an unknown individual into the home to convince him to buy a home security system which they already have. He has also had trouble dressing himself and balancing his checkbook. At this point, she is considering hiring a day-time caregiver help him with dressing, meals and general supervision why she is at work.

Past Medical History: Gastroesophageal reflux (treated with diet); is negative for hypertension, hyperlipidemia, stroke or head injury or depression

Allergies: No known allergies

Medications: None

Family History

• Father deceased at age 78 of decline related to Alzheimer’s disease
• Mother deceased at age 80 of natural causes 
• No siblings

Social History

• Denies smoking
• Denies alcohol or recreational drug use 
• Retired lawyer
• Hobby: Golf at least twice a week

Review of Systems

• Constitutional: Denies fatigue or insomnia
• HEENT: Denies nasal congestion, rhinorrhea or sore throat.  
• Chest: Denies dyspnea or coughing
• Heart: Denies chest pain, chest pressure or palpitations.
• Lymph: Denies lymph node swelling.
• Musculoskeletal: denies falls or loss of balance; denies joint point or swelling

General Physical Exam  

• Constitutional: Alert, angry but cooperative
• Vital Signs: BP-128/72, T-98.6 F, P-76, RR-20
• Wt. 178 lbs., Ht. 6’0″, BMI 24.1

HEENT

• Head normocephalic; Pupils equal and reactive to light bilaterally; EOM’s intact

Neck/Lymph Nodes

• No abnormalities noted  

Lungs 

• Bilateral breath sounds clear throughout lung fields.

Heart 

• S1 and S2 regular rate and rhythm, no rubs or murmurs. 

Integumentary System 

• Warm, dry and intact. Nail beds pink without clubbing.  

Neurological

• Deep tendon reflexes (DTRs): 2/2; muscle tone and strength 5/5; no gait abnormalities; sensation intact bilaterally; no aphasia

Diagnostics

• Mini-Mental State Examination (MMSE): Baseline score 12 out of 30 (moderate dementia)
• MRI: hippocampal atrophy
• Based on the clinical presentation and diagnostic findings, the patient is diagnosed with Alzheimer’s type dementia.

Discussion Questions

1. Compare and contrast the pathophysiology between Alzheimer’s disease and frontotemporal dementia.
2. Identify the clinical findings from the case that supports a diagnosis of Alzheimer’s disease.  
3. Explain one hypothesis that explains the development of Alzheimer’s disease
4. Discuss the patient’s likely stage of Alzheimer’s disease.

1. Pathophysiology of Alzheimer’s disease vs. Frontotemporal dementia:
   • Alzheimer’s Disease (AD):
     • Pathological hallmarks include the accumulation of beta-amyloid plaques outside neurons and tau protein tangles inside neurons.
     • Neurodegeneration primarily affects the hippocampus and cortex, leading to memory loss and cognitive decline.
     • It is characterized by widespread brain atrophy, particularly in the temporal and parietal lobes.
     • Typically presents with memory impairment as an early symptom, followed by progressive cognitive decline.
     • Genetics play a role, with mutations in genes such as APP, PSEN1, and PSEN2 being implicated in familial cases.
   • Frontotemporal Dementia (FTD):
     • Pathological features include abnormal protein aggregates such as tau, TDP-43, or FUS, leading to neuronal dysfunction and death.
     • Predominant atrophy occurs in the frontal and/or temporal lobes, affecting behavior, personality, and language.
     • Early symptoms often involve changes in behavior, personality, or language rather than memory impairment.
     • Subtypes include behavioral variant FTD, primary progressive aphasia, and semantic dementia.
     • Genetics also play a significant role, with mutations in genes such as MAPT, GRN, and C9orf72 being associated with familial cases.
2. Clinical findings supporting a diagnosis of Alzheimer’s disease:
   • Progressive memory impairment, as evidenced by getting lost in familiar surroundings and difficulty with recent events.
   • Impaired decision-making, demonstrated by allowing unknown individuals into the home and making unnecessary purchases.
   • Difficulties with activities of daily living such as dressing oneself and managing finances.
   • Cognitive decline confirmed by a low MMSE score (12 out of 30) indicating moderate dementia.
   • Neuroimaging findings of hippocampal atrophy on MRI, consistent with Alzheimer’s disease pathology.
3. Hypothesis explaining the development of Alzheimer’s disease:
   • One hypothesis is the amyloid cascade hypothesis, which posits that the accumulation of beta-amyloid plaques is the initial trigger in the pathogenesis of Alzheimer’s disease.
   • According to this hypothesis, abnormal processing and accumulation of amyloid precursor protein (APP) lead to the formation of insoluble beta-amyloid plaques.
   • These plaques are toxic to neurons, leading to neuronal dysfunction, inflammation, and ultimately neuronal death.
   • Tau protein pathology, including the formation of neurofibrillary tangles, is thought to exacerbate neuronal damage and cognitive decline.
   • This hypothesis suggests that targeting beta-amyloid accumulation and tau pathology could be potential therapeutic strategies for Alzheimer’s disease.
4. Likely stage of Alzheimer’s disease:
   • The patient’s MMSE score of 12 out of 30 indicates moderate dementia.
   • Clinical symptoms such as getting lost, impaired decision-making, and difficulties with activities of daily living suggest moderate-stage Alzheimer’s disease.
   • Neuroimaging findings of hippocampal atrophy further support the diagnosis and stage of Alzheimer’s disease.
   • The patient may benefit from interventions and support services tailored to individuals with moderate Alzheimer’s disease, including caregiver assistance and pharmacological treatments aimed at managing symptoms and slowing disease progression.