Alzheimer’s Disease¶
Chapter 442 | Part 13: Neurologic Disorders
KEY CLINICAL POINTS¶
- Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60–70% of all dementia cases with ~55 million global patients.
- Amyloid-beta (A β ) plaques and neurofibrillary tangles (NFTs) are hallmark pathologic features, with APOE ε 4 allele being the strongest genetic risk factor.
- Early diagnosis relies on biomarkers (amyloid PET, CSF A β 42/p-Tau, and plasma A β 42/p-Tau) and clinical staging, with emerging therapies targeting amyloid and tau pathology.
1. DEFINITION & OVERVIEW¶
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral changes. It is the most common cause of dementia, contributing to 60–70% of all dementia cases. Pathologically, it is defined by amyloid-beta (A β ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. The disease typically presents with insidious memory loss progressing to severe dementia.
Amyloid-Related Imaging Abnormalities (ARIAs)¶
| Severity | Criteria |
|---|---|
| Mild ARIA-E | FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm |
| Mild ARIA-H | £4 new incident microhemorrhages or 1 new focal area of superficial siderosis |
| Moderate ARIA-E | FLAIR hyperintensity 5–10 cm in single greatest dimension or >1 site of involvement (<10 cm each) |
| Moderate ARIA-H | 5–9 new incident microhemorrhages or 12 focal areas of superficial siderosis |
| Severe ARIA-E | FLAIR hyperintensity >10 cm with gyral swelling and sulcal effacement |
| Severe ARIA-H | ‡10 microhemorrhages, >2 focal areas of superficial siderosis, or ‡1 macrohemorrhage (‡10 cm) |
1.1 Clinical Staging¶
AD progresses through three stages: mild (early-stage), moderate (middle-stage), and severe (late-stage). Early stages involve memory impairment and executive dysfunction, while late stages feature loss of autonomy, severe cognitive decline, and behavioral disturbances.
1.2 Biomarkers¶
Amyloid PET, CSF A β 42/p-Tau, and plasma A β 42/p-Tau are used to detect AD pathology. Amyloid PET confirms A β plaques, while CSF biomarkers reflect amyloid and tau pathology. Plasma assays are emerging as scalable diagnostic tools.
2. EPIDEMIOLOGY¶
AD affects ~10% of people over age 65 in the U.S., with prevalence increasing with age: 3% at 65–74, 17% at 75–84, and 32% at ≥ 85. Risk factors include age, family history, APOE ε 4 allele, head trauma, low education, and vascular disease. APOE ε 4 carriers have 3–15x higher risk, with ε 4/ ε 4 homozygotes at 10–15x risk. Preclinical AD may precede symptoms by 20+ years.
2.1 Demographics¶
Women are more commonly affected than men, likely due to longer lifespan and higher APOE ε 4 prevalence. Early-onset AD (before 65) accounts for 1–2% of cases, often with autosomal dominant inheritance.
2.2 Risk Factors¶
Age, APOE ε 4, head trauma, low education, vascular disease, diabetes, and lifestyle factors (e.g., sleep disorders, obesity) increase risk. Protective factors include higher education, physical activity, and cognitive engagement.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
AD is caused by accumulation of A β plaques and NFTs. Genetic factors include APOE ε 4, APP, PSEN1, and PSEN2 mutations. Pathogenesis involves amyloid deposition, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction. A β oligomers are toxic, while tau aggregates disrupt microtubules and neuronal function.
3.1 Genetic Factors¶
APOE ε 4 is the strongest genetic risk factor. Autosomal dominant mutations in APP, PSEN1, and PSEN2 cause early-onset familial AD (FAD), with PSEN1 mutations most common (40–70% of FAD cases).
3.2 Molecular Mechanisms¶
A β aggregation leads to synaptic dysfunction and neuroinflammation. Tau hyperphosphorylation forms NFTs, disrupting axonal transport. Amyloid angiopathy (CAA) increases hemorrhagic risk. Vascular pathology and comorbidities (e.g., diabetes) exacerbate disease progression.
4. CLINICAL FEATURES¶
Early symptoms include memory loss and executive dysfunction. Middle stages feature language impairment, visuospatial deficits, and behavioral changes. Late stages involve severe cognitive decline, loss of autonomy, and physical disability. Non-memory symptoms (e.g., word-finding difficulty, visuospatial deficits) may precede memory loss in ~20% of cases.
4.1 Cognitive Decline¶
Memory impairment progresses to deficits in executive function, language, and visuospatial skills. ~20% present with non-memory complaints (e.g., word-finding, navigation difficulty).
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish AD from vascular dementia, Lewy body dementia (LBD), frontotemporal dementia (FTD), normal pressure hydrocephalus (NPH), and depression. Key differentiators include pattern of cognitive decline, presence of parkinsonism, and response to treatment. ARIA and imaging findings help differentiate from other dementias.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic workup includes MRI (cortical atrophy), CSF biomarkers (A β 42, p-Tau, t-Tau), and amyloid PET. Biomarker-positive AD is defined by amyloid PET or CSF evidence of A β and tau pathology. Clinical diagnosis is confirmed at autopsy in ~70–80% of cases.
6.1 Biomarker Criteria¶
Amyloid PET confirms A β plaques. CSF A β 42/p-Tau ratio <0.09 and t-Tau/A β 42 >0.8 indicate AD. Plasma A β 42/p-Tau assays are emerging as scalable tools. Biomarker-negative cases may have preclinical AD or non-AD etiologies.
6.2 Imaging¶
MRI shows posterior cortical atrophy in AD vs. frontal atrophy in FTD. Amyloid PET reveals neocortical A β deposition. FDG-PET shows hypometabolism in temporal/parietal regions.
7. MANAGEMENT & TREATMENT¶
Multidomain management includes cholinesterase inhibitors (donepezil, rivastigmine, galantamine), memantine, and antiamyloid antibodies (lecanemab, donanemab). Non-pharmacologic strategies include lifestyle modifications, caregiver support, and cognitive stimulation.
Amyloid-Related Imaging Abnormalities (ARIAs)¶
| Severity | Criteria |
|---|---|
| Mild ARIA-E | FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm |
| Mild ARIA-H | £4 new incident microhemorrhages or 1 new focal area of superficial siderosis |
| Moderate ARIA-E | FLAIR hyperintensity 5–10 cm in single greatest dimension or >1 site of involvement (<10 cm each) |
| Moderate ARIA-H | 5–9 new incident microhemorrhages or 12 focal areas of superficial siderosis |
| Severe ARIA-E | FLAIR hyperintensity >10 cm with gyral swelling and sulcal effacement |
| Severe ARIA-H | ‡10 microhemorrhages, >2 focal areas of superficial siderosis, or ‡1 macrohemorrhage (‡10 cm) |
7.1 Pharmacologic Therapies¶
Cholinesterase inhibitors improve cognition in mild-to-moderate AD. Memantine is used in moderate-to-severe stages. Antiamyloid antibodies (lecanemab, donanemab) reduce amyloid burden and slow cognitive decline, with ARIA (amyloid-related imaging abnormalities) as a known side effect.
7.2 Non-Pharmacologic Interventions¶
Lifestyle modifications (exercise, diet, cognitive engagement), caregiver education, and environmental safety measures are critical. Respite care and support groups improve quality of life.
8. PROGNOSIS & COMPLICATIONS¶
Median survival is 8–10 years post-diagnosis, with 1–25-year variability. Complications include infections, malnutrition, aspiration pneumonia, and secondary complications from immobility. ARIA (amyloid-related imaging abnormalities) may cause microhemorrhages or edema.
9. SPECIAL CONSIDERATIONS¶
AD in younger patients may present with atypical features (e.g., behavioral changes). APOE ε 4 homozygotes have higher ARIA risk. Management in elderly patients must consider comorbidities and medication interactions. Anticoagulants and thrombolytics increase ARIA risk.
9.1 Pregnancy & Pediatrics¶
AD is rare in younger patients, but early-onset cases may have autosomal dominant mutations. Management in pregnancy focuses on non-pharmacologic strategies and monitoring for ARIA.
9.2 Elderly Patients¶
Elderly patients require careful evaluation for comorbidities (e.g., vascular disease, diabetes) and medication interactions. APOE ε 4 carriers face higher ARIA risk with antiamyloid therapies.
10. KEY POINTS & CLINICAL PEARLS¶
- AD is the most common dementia cause, with APOE ε 4 as the strongest genetic risk factor.
- Biomarkers (amyloid PET, CSF, plasma) enable early diagnosis and treatment monitoring.
- Antiamyloid therapies (lecanemab, donanemab) reduce amyloid burden but carry ARIA risks.
- Multidomain management with cholinesterase inhibitors, memantine, and lifestyle modifications is essential.
- Distinguish AD from other dementias using clinical features, imaging, and biomarkers.