Alzheimer’s Disease: An Overview

Last updated: October 7, 2025.

Fall 2025 Alzheimer’s Treatment Updates: The FDA has approved a weekly at‑home injection option for Leqembi after the initial 18‑month IV phase, and new 4‑year data show continued benefit on thinking and daily function with ongoing treatment. Kisunla’s 3‑year data also show growing benefit over time, and its updated titration schedule lowers ARIA risk while maintaining efficacy.

Introduction

Alzheimer’s disease (AD) is a progressive brain disorder and the most common cause of dementia, affecting approximately 7.2 million adults aged 65 and older in the United States as of 2025, a number expected to nearly double by 2050.

Understanding Alzheimer’s Disease

Alzheimer’s disease begins long before symptoms appear, often 10–20 years in advance. The disease primarily affects the brain through:

• Amyloid plaques: Abnormal clumps of protein (amyloid-beta) that build up outside brain cells and disrupt communication between neurons.
  
  
• Tau tangles: Twisted strands of tau protein accumulating inside brain cells, damaging their internal transport system.
  
  
• Neuroinflammation and brain shrinkage (atrophy): Chronic inflammation and oxidative stress eventually cause brain cells to die, leading to widespread brain tissue loss.
  

Early (Prodromal) Symptoms

Early symptoms can be subtle and may include:

Neuropsychiatric Symptoms:

• Depression, anxiety, apathy (lack of motivation)
  
  
• Irritability, sleep disturbances
  
  

Cognitive Symptoms:

• Slight memory lapses (forgetting recent conversations or appointments)
  
  
• Mild trouble finding words, managing finances, or planning daily tasks
  

These early symptoms often prompt initial medical evaluations.

Main Symptoms

As Alzheimer’s disease progresses, symptoms become more noticeable:

• Significant memory loss affecting daily activities
  
  
• Difficulty solving problems, making decisions, or performing familiar tasks
  
  
• Confusion about dates, times, or locations
  
  
• Language difficulties (trouble following conversations or expressing thoughts)
  
  
• Changes in mood and personality (increased anxiety, suspicion, or agitation)

Diagnosing Alzheimer’s Disease

Diagnosis typically involves:

Initial Evaluation:

• Detailed medical history and neurological exam
  
  
• Bedside cognitive screening tests (MoCA or MMSE)
  
  
• Blood tests (vitamin deficiencies, thyroid function)
  
  
• MRI or CT scans to identify brain structure abnormalities
  
  

Standardized Neuropsychological Testing:

• Comprehensive assessments to measure cognitive function, establish a baseline, and track progression over time
  
  

Advanced Diagnostic Tools:

• Amyloid-PET: Visualizes amyloid plaque deposition in the brain, confirming Alzheimer’s pathology. Covered by Medicare as of 2023, making it an accessible confirmatory diagnostic tool for eligible patients.
  
  
• Tau-PET: Currently used mainly in research; should be widely available by 2026.
  
  
• 3T NeuroQuant MRI: Measures brain volume, tracking shrinkage over time. Provides quantitative volumetric analysis of brain structures, allowing objective measurement of atrophy patterns and tracking of disease progression over time.
  
  
• Lumipulse P-tau217/Aβ42 Ratio:
  An FDA-cleared plasma biomarker assay that measures phosphorylated tau-217 and amyloid-β42.
  A positive ratio (≥0.00737) strongly predicts underlying Alzheimer’s pathology with over 95% concordance with amyloid PET.
  
  
• FDG-PET: Measures regional brain glucose metabolism to detect areas of reduced activity, particularly in the posterior cingulate, parietal, and temporal lobes, patterns typical of Alzheimer’s disease.
  
  
• APOE Genetic Testing: Before starting anti-amyloid infusion therapy such as Leqembi or Kisunla, it is important to check the APOE gene type through a simple blood test. People who carry one or two copies of the APOE ε4 gene have a higher chance of developing brain swelling or small areas of bleeding, known as ARIA (Amyloid-Related Imaging Abnormalities).

What’s New for Fall 2025 (Quick Summary)

• Leqembi now has an at‑home weekly injection option (subcutaneous autoinjector) for maintenance after the initial 18‑month IV phase. This can be self‑ or caregiver‑administered at home for many patients.
  
  
• Leqembi long‑term data (up to 48 months) show continued slowing of decline compared with natural history comparators, with many people staying in the early stage longer.
  
  
• Kisunla 36‑month data show growing benefit over time compared with external natural‑history cohorts; earlier start appears better than delayed start.
  
  
• Leqembi MRI monitoring was updated: MRI scans are now recommended before the 3rd, 5th, 7th, and 14th infusions (earlier than before).
  

Treatment and Management

Symptomatic Treatment (Oral Medications):

• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine): Improve symptoms by enhancing neurotransmitter activity.
  
  
• Memantine: Helps manage moderate to severe Alzheimer’s symptoms by regulating glutamate, a neurotransmitter involved in learning and memory.
  
  

Disease-Modifying Therapies (for Mild Cognitive Impairment or Early Alzheimer’s Disease)

Leqembi® (Lecanemab)

• Regulatory Status: Accelerated Approval: January 6, 2023. Traditional (full) Approval: July 6, 2023.
  
  Dosing:
  
  Initial phase (first 18 months): Leqembi is given as an IV infusion every 2 weeks.
  
  Maintenance phase (after 18 months): Patients can continue IV infusions but switch to once every 4 weeks instead of every 2. (FDA approved Jan 2025).
  
  
• New option: FDA also approved a weekly under-the-skin injection using the LEQEMBI IQLIK autoinjector (360 mg once weekly). With proper training, many patients or caregivers can give these at home, reducing infusion-center visits.
  
  
  • Updated guidance: obtain MRIs before the 3rd, 5th, 7th, and 14th infusions; most ARIA events occur in the first 6 months of the IV initiation phase.
    
    
• Efficacy: In clinical studies, Leqembi slowed the progression of Alzheimer’s disease by about 27% over 18 months. This was linked to about a 31% lower risk of moving to the next stage of the disease. Based on long-term modeling, this may translate to roughly one extra year of preserved memory and daily function over four years. These results are based on large research studies comparing people who received Leqembi to those who did not. They show average trends across groups, not exact outcomes for any one person.
  
  New long‑term data: With continuous treatment to 4 years, Leqembi showed a 1.75‑point smaller decline vs the ADNI natural‑history cohort and 2.17‑point vs the BioFINDER cohort. In a low‑tau subgroup (earlier disease), many patients improved or had no decline on clinical scales over 4 years. These findings support staying on therapy to preserve independence longer.
  
  
• ARIA Risk:
  
  
  • ARIA-E: ~13%, ARIA-H: ~17%, Combined ARIA-E/H: ~21%.
    
    
  • The main risk is ARIA (brain swelling or small bleeds). ARIA risk is highest early and is greater in APOE‑ε4 carriers.
    
    
  • In studies of the weekly SQ maintenance dose, the overall safety profile was similar to IV maintenance, with fewer systemic infusion reactions and expected mild local injection‑site reactions for some people.
    

Kisunla™ (Donanemab)

• Regulatory Status: July 2, 2024: Kisunla (Donanemab) received full FDA approval.
  
  
• Dosing: Monthly IV infusions with a titration schedule. Treatment can be stopped once amyloid on PET falls to a low/negative level per label.
  
  
  • Baseline MRI, then before the 2nd, 3rd, 4th, and 7th infusions.
    
    
• Efficacy: In clinical studies, Kisunla slowed memory and thinking decline by about 29% after 18 months, and by up to 36% in people treated at the earliest stage of Alzheimer’s disease. After 18 months, this translated to an average delay in decline of about 5–7 months. By 3 years, the estimated delay reached about 9 months. Kisunla also reduced the chance of progressing to the next stage of the disease by about 37%.
  
  New 36‑month data from the TRAILBLAZER‑ALZ 2 long‑term extension show a growing benefit over time. Compared with a matched ADNI natural‑history cohort, the CDR‑SB difference increased from –0.6 at 18 months to –1.2 at 36 months. Earlier initiation outperformed delayed start in time‑to‑progression analyses.
  
  
• ARIA Risk:
  
  • Combined ARIA-E/H: ~37%; symptomatic ARIA occurs in ~6% of patients.
    
    
  • ARIA risk exists and is higher in APOE‑ε4 carriers.

Modified Titration (TRAILBLAZER-ALZ 6 Protocol)

• Updated titration to lower ARIA risk: A modified dosing schedule (TRAILBLAZER‑ALZ 6) reduced ARIA‑E (about 13.7% vs 23.7% at 24 weeks) without compromising efficacy; the FDA updated the label in July 2025 to reflect a revised titration approach.
  
  

What these results mean in plain terms: Both medicines work by removing amyloid from the brain. Their long‑term data now show that benefits accumulate with time, especially when started earlier in the disease. The new at‑home injection option for Leqembi’s maintenance phase can make ongoing treatment easier for many families.

Risks and Monitoring

• ARIA (amyloid‑related imaging abnormalities) can include brain swelling or small brain bleeds. It is usually asymptomatic but can be serious; careful MRI monitoring is required, particularly early in treatment.
  
  
• Genetics (APOE‑ε4): carriers have a higher ARIA risk.
  

Emerging Treatments

• Leqembi SQ as a starting dose: now approved for maintenance only; the company has initiated a rolling FDA submission to evaluate a subcutaneous starting‑dose autoinjector.
  
  
• TRAILBLAZER‑ALZ 3 (Kisunla for prevention): testing whether treatment in cognitively normal adults with elevated amyloid and early tau can delay or prevent symptoms.
  
  
• AHEAD 3‑45 (Leqembi for prevention): testing lecanemab in cognitively unimpaired adults with intermediate to elevated amyloid to slow or prevent progression.

Supportive Care and Lifestyle

Supportive strategies complement medical treatments:

• Structured cognitive exercises and occupational therapy
  
• Regular physical activity, a Mediterranean‑style diet, and adequate sleep
  
• Education and support for caregivers to manage behavior and maintain safety

Conditions Similar to Alzheimer’s

Conditions that may resemble or co-exist with Alzheimer’s include:

• Depression (“pseudodementia”): can mimic memory loss but often improves with treatment.
  
• TDP‑43/LATE: a different protein process that can look like Alzheimer’s in older adults and can co‑exist with Alzheimer’s pathology.

Conclusion

Early, precise diagnosis paired with long‑term disease‑modifying treatment and practical supports offers real hope for preserving independence. At Los Altos Neurology, we provide personalized evaluation, advanced diagnostic testing, and access to the latest therapies, including Leqembi IV and SQ maintenance and Kisunla. We help families decide if these options are right for them and coordinate safe monitoring.