Alzheimer's Disease

Overview

• Harrison's Principles of Internal Medicine, 22e

Historical Background

• Bradley and Daroff's Neurology in Clinical Practice

Pathology

1. Amyloid (Neuritic) Plaques

• Extracellular deposits composed primarily of amyloid-beta (Aβ) peptides, derived from amyloid precursor protein (APP) via proteolytic cleavage
• Aβ deposition follows a sequential pattern: cortex → hippocampus → basal ganglia → thalamus → basal forebrain → brainstem/cerebellum
• Plaques are heterogeneous lesions containing Aβ, tau, and cellular components

2. Neurofibrillary Tangles (NFTs)

• Intraneuronal accumulations of hyperphosphorylated tau protein filaments
• Earliest tau pathology (Braak staging) appears in the locus coeruleus as early as the 3rd or 4th decade, before involving limbic areas or amyloid plaques
• Tau pathology spreads in a prion-like transsynaptic manner through anatomically connected regions

Macroscopic Changes

• Diffuse brain atrophy with reduced brain weight at autopsy
• Preferentially affected: multimodal association areas, hippocampi, cingulate gyrus, locus coeruleus
• Relatively spared: primary motor/somatosensory/auditory/visual cortices, substantia nigra

Genetics

• Bradley and Daroff's Neurology in Clinical Practice; Thompson & Thompson Genetics and Genomics in Medicine

Clinical Manifestations

Typical Presentation (Amnestic AD)

• Insidious onset of episodic memory impairment
• Progresses to deficits in executive function, language, and visuospatial abilities
• Brain atrophy begins in medial temporal lobes, spreads to inferior temporal, parietal, and frontal cortices
• Depression, social withdrawal, and anxiety may precede cognitive symptoms

Atypical Variants (~20% of cases)

• Posterior cortical atrophy: visual processing dysfunction is the initial complaint
• Logopenic aphasia: word-finding difficulty and difficulty with repetition
• Corticobasal syndrome: asymmetric akinetic-rigid-dystonic features
• Frontal variant: prominent dysexecutive or behavioral changes

Disease Stages

• Harrison's Principles of Internal Medicine, 22e

Biomarkers & Diagnosis

• A - β-Amyloid deposition (amyloid PET positivity or low CSF Aβ42)
• T - Pathological tau (tau PET positivity or elevated phospho-tau in CSF/plasma)
• (N) - Neurodegeneration (brain atrophy on MRI, FDG-PET hypometabolism, elevated CSF total tau)

Treatment

1. Neurotransmitter-Based (Symptomatic) Therapies

• Cholinesterase inhibitors: GI symptoms (nausea, diarrhea, cramps), vivid dreams, bradycardia, muscle cramps
• Memantine: constipation, dizziness, headache, somnolence
• Harrison's Principles of Internal Medicine, 22e

2. Disease-Modifying Therapies (Anti-Amyloid Monoclonal Antibodies)

• Harrison's Principles of Internal Medicine, 22e; Lancet Treatment Review 2025

3. Non-Pharmacological & Supportive Care

• Caregiver education and structured support networks
• Mediterranean diet: A 2025 meta-analysis (Fekete et al., Geroscience 2025, PMID 39797935) confirms a reduced risk of cognitive impairment and AD with Mediterranean diet adherence
• Physical activity and cognitive stimulation
• Management of behavioral and psychological symptoms (agitation, depression, psychosis) with targeted pharmacotherapy when needed
• Advance care planning and legal/financial arrangements early in the disease course

Differential Diagnosis (Key Mimics)

• Lewy body dementia - visual hallucinations, parkinsonism, fluctuating cognition
• Frontotemporal dementia (FTD) - prominent behavioral/personality changes or language syndrome
• Vascular dementia - stepwise progression, focal deficits, vascular risk factors
• LATE (Limbic-predominant Age-related TDP-43 Encephalopathy) - recently characterized; can closely mimic AD clinically (Wolk et al., Alzheimers Dement 2025, PMID 39807681)
• Normal pressure hydrocephalus - triad of dementia, gait apraxia, urinary incontinence
• Hypothyroidism, vitamin B12 deficiency - reversible causes

Key Recent Evidence (2025-2026)

Cushing Syndrome - Physiology & Pathophysiology

1. Normal HPA Axis Physiology (The Foundation)

The Axis - Step by Step

Hypothalamus
    │ CRH (Corticotropin-Releasing Hormone)
    ↓
Anterior Pituitary (corticotrope cells)
    │ ACTH (Adrenocorticotropic Hormone) via POMC cleavage
    ↓
Adrenal Cortex (Zona Fasciculata)
    │ Cortisol (~20 mg/day)
    ↓
Target tissues + Negative feedback ──→ back to Hypothalamus & Pituitary

• CRH from the hypothalamus is the most important driver of ACTH release. Vasopressin (ADH) and oxytocin also stimulate it
• ACTH (cleaved from POMC) stimulates cortisol AND adrenal androgen production, and is also trophic - it maintains adrenocortical cell viability. Without ACTH, all but mineralocorticoid-producing cells undergo apoptosis
• Cortisol binds receptors in the hypothalamus and pituitary to suppress CRH and ACTH (negative feedback loop)
• Circadian rhythm: CRH secretion is under control of the suprachiasmatic nucleus. Cortisol peaks in the early morning and reaches a nadir around 11 PM. Loss of this diurnal rhythm is a hallmark of Cushing syndrome
• Stress (physiological or psychological) is the most powerful modulator of HPA axis activity
• Campbell Walsh Wein Urology; Medical Physiology

2. Normal Cortisol - Physiological Actions

3. Definition of Cushing Syndrome

• Cushing's disease specifically refers to the subset caused by a pituitary corticotrope adenoma (ACTH-secreting)
• First described by Harvey Cushing in 1912
• Incidence of endogenous Cushing syndrome: ~1.8-3.2 per million per year (rare)
• Iatrogenic (exogenous glucocorticoid therapy) is by far the most common cause overall (~1% of the population uses chronic glucocorticoids)
• Harrison's Principles of Internal Medicine 22e

4. Classification by Cause

ACTH-Dependent (~80-85% of endogenous cases)

ACTH-Independent (~10-15% of endogenous cases)

Iatrogenic (Exogenous)

• Administration of glucocorticoids for anti-inflammatory/immunosuppressive purposes
• HPA axis is suppressed by exogenous glucocorticoids; abrupt cessation risks adrenal insufficiency
• Harrison's Principles of Internal Medicine 22e; Campbell Walsh Wein Urology

5. Core Pathophysiology - What Excess Cortisol Does

A. Metabolic Effects (Fat & Carbohydrate)

• Central obesity / buffalo hump / moon face: Excess cortisol promotes redistribution of fat from peripheral (limbs) to central (visceral, dorsal cervical, facial) depots. The mechanism involves differential glucocorticoid receptor density and differential sensitivity of fat depots to cortisol-stimulated lipolysis and insulin-stimulated lipogenesis
• Hyperglycemia / diabetes: Cortisol enhances hepatic gluconeogenesis and induces insulin resistance in peripheral tissues (liver, muscle, adipose). Excess cortisol drives overproduction of glucose and impairs glucose uptake
• A 2025 review (DeFronzo & Auchus, Diabetes 2025, PMID 40663715) specifically addresses how hypercortisolism drives glucose dysregulation through multiple mechanisms including hepatic insulin resistance and impaired beta-cell compensation

B. Protein Catabolism (Muscle & Skin)

• Cortisol promotes protein breakdown in muscle, skin, and connective tissue
• In muscle: protein catabolism → proximal myopathy (difficulty rising from chairs, climbing stairs)
• In skin: loss of dermal collagen → thin skin, easy bruising, broad purple striae (stretch marks from dermal tearing as skin cannot accommodate rapid fat deposition)
• In bone: inhibits osteoblast activity and calcium absorption → osteoporosis and vertebral fractures

C. Mineralocorticoid Overflow Effect

• At very high levels, cortisol overwhelms the enzyme 11β-HSD2 (which normally converts active cortisol to inactive cortisone in mineralocorticoid-sensitive cells)
• Excess cortisol then activates mineralocorticoid receptors in the kidney → sodium retention, potassium wasting
• Result: hypertension, hypokalemia, metabolic alkalosis - especially severe in ectopic ACTH syndrome

D. Immune Suppression

• Cortisol suppresses the immune system at multiple levels: reduces cytokine synthesis, inhibits leukocyte trafficking, induces lymphocyte apoptosis
• Clinical result: increased susceptibility to infections, impaired wound healing

E. HPA Axis Disruption

• In ACTH-dependent Cushing's: pituitary tumor cells lose sensitivity to cortisol's normal negative feedback - they keep secreting ACTH despite high cortisol levels
• Loss of circadian rhythm: cortisol remains elevated throughout the day, particularly at the normal 11 PM nadir. This is one of the most sensitive diagnostic indicators
• In ACTH-independent Cushing's: autonomous adrenal cortisol secretion suppresses pituitary ACTH → the normal (contralateral or remaining) adrenal tissue undergoes atrophy

F. Androgenic Effects (in adrenal causes)

• Adrenocortical tumors and ectopic ACTH tumors often co-secrete adrenal androgens (DHEA, androstenedione)
• Result in women: hirsutism, acne, virilization, menstrual irregularity
• Adrenal carcinomas particularly notable for excess androgen co-secretion

G. CNS & Psychiatric Effects

• Glucocorticoid receptors are abundant in the hippocampus and limbic system
• Chronic excess cortisol causes hippocampal atrophy, neuronal damage
• Clinical: depression, anxiety, cognitive impairment, psychosis, insomnia

H. Cardiovascular Effects

• Hypertension from: (1) mineralocorticoid receptor activation, (2) increased angiotensinogen synthesis, (3) enhanced vascular sensitivity to catecholamines
• Insulin resistance and dyslipidemia → accelerated atherosclerosis
• Increased thrombotic risk (cortisol upregulates coagulation factors, reduces fibrinolysis)

6. Signs & Symptoms Summary (From Harrison's Table 398-2)

7. Key Physiological Principles Used in Diagnosis

1. Loss of the cortisol diurnal nadir - Late-night salivary cortisol or midnight plasma cortisol is elevated (normally near zero at 11 PM)
2. Loss of feedback sensitivity - The dexamethasone suppression test: exogenous glucocorticoid normally suppresses ACTH/cortisol; in Cushing's, this suppression fails (low-dose DST)
3. Excess free cortisol excretion - 24-hour urine free cortisol is elevated because protein-binding capacity is exceeded

8. Genetics (Brief)

• Somatic PRKACA mutations (PKA catalytic subunit): found in ~40% of cortisol-producing adrenal adenomas
• PRKAR1A germline mutations: Carney complex (PPNAD)
• ARMC5 mutations: most common cause of bilateral macronodular adrenal hyperplasia
• GNAS activating mutations: McCune-Albright syndrome
• MEN1, AIP: rare pituitary Cushing's disease associations

Recent Evidence

• Nieman LK et al. Nat Rev Dis Primers 2025 (PMID 39848955) - Comprehensive 2025 primer on Cushing syndrome covering all aspects of pathophysiology through management
• DeFronzo & Auchus, Diabetes 2025 (PMID 40663715) - Deep dive into the mechanisms of glucose dysregulation in hypercortisolism

Lesions of the Visual Pathway

1. The Visual Pathway - Anatomy Overview

Key Anatomical Principle at the Chiasm

• Temporal visual fields project onto the nasal hemiretina → fibers cross at the chiasm to the contralateral optic tract
• Nasal visual fields project onto the temporal hemiretina → fibers remain uncrossed and ascend ipsilaterally
• The ratio of crossed to uncrossed fibers at the chiasm is approximately 53:47
• Each optic tract therefore carries signals from the contralateral visual hemifield of both eyes

2. Lesion-by-Lesion: Visual Field Defects

Lesion 1 - Optic Nerve (Prechiasmal)

• All visual information from that eye is lost because the cut occurs before any fibers cross at the chiasm
• Example: left optic nerve lesion → complete blindness in the left eye
• RAPD (Relative Afferent Pupillary Defect / Marcus Gunn pupil): This is the hallmark of optic nerve disease - the injured eye shows a diminished direct pupillary response to light compared to the consensual response
• Partial optic nerve lesions produce: central scotoma, cecocentral scotoma, arcuate scotoma, or altitudinal defect

Lesion 2 - Optic Chiasm (Central)

• The crossing nasal fibers from both eyes are disrupted
• Both temporal visual fields are lost (the "blinkers" effect)
• Called heteronymous because the defect is on opposite sides of the vertical meridian in each eye
• Most commonly caused by pituitary adenoma (suprasellar extension)

• Craniopharyngioma
• Rathke cleft cyst
• Meningioma of the tuberculum sellae
• Saccular aneurysm (anterior communicating or carotid artery)
• Sarcoidosis
• Metastatic carcinoma
• Hydrocephalus (downward herniation of the third ventricle)

• Lesion at the junction of one optic nerve and the chiasm
• Result: ipsilateral central scotoma (optic nerve involvement) PLUS contralateral superior temporal quadrantanopia (from disruption of Wilbrand's knee - inferior nasal fibers that loop forward into the contralateral optic nerve before crossing)

• A posteriorly placed (post-fixed) chiasm → pituitary tumors present with an optic neuropathy pattern rather than bitemporal hemianopia
• An anteriorly placed (pre-fixed) chiasm → pituitary tumors may compress the optic tract instead, producing a homonymous defect

Lesion 3 - Optic Tract (Retrochiasmal - Anterior)

• Cutting the left optic tract causes loss of the right visual field in both eyes:
  • Loss of the temporal visual field of the right eye (crossed fibers)
  • Loss of the nasal visual field of the left eye (uncrossed fibers)
• Incongruous = the defect pattern differs between the two eyes (one eye shows more loss than the other, but both on the same side of the vertical meridian)
  • Incongruity indicates the lesion is anterior in the retrochiasmal pathway (fibers from the two eyes are not yet fully paired)
• RAPD may be present with optic tract lesions because of asymmetric crossing of pupillary fibers at the chiasm (~53% cross)

Lesion 4 - Lateral Geniculate Body (LGB)

• Rare as an isolated lesion
• Lesion of the LGB may spare the pupillary reflex (pupillary fibers leave the optic tract to go to the pretectal area before the LGB)

Lesion 5 - Optic Radiation (Geniculocalcarine Tract)

A. Temporal Lobe - Meyer's Loop (Inferior Division)

• The lower fibers of the optic radiation swing in a wide arc anteriorly and inferiorly over the temporal horn of the lateral ventricle before sweeping posteriorly to the calcarine cortex - this is Meyer's (Archambault's) loop
• These fibers carry information from the inferior retina / superior visual field
• Damage produces a contralateral superior quadrantanopia: upper temporal field of the contralateral eye + upper nasal field of the ipsilateral eye lost
• First described by Harvey Cushing (before his description of the syndrome!)

B. Parietal Lobe (Superior Division)

• The upper fibers pass through the parietal lobe
• Carry information from the superior retina / inferior visual field
• Parietal lobe lesions affect inferior visual field quadrants more than superior

Lesion 6 - Primary Visual Cortex (Area 17, Occipital Lobe)

• The calcarine cortex contains a precise retinotopic map of the contralateral visual hemifield
• The macula (central vision, highest acuity) is represented at the occipital pole and has a disproportionately large cortical representation (cortical magnification)
• Macular sparing occurs because:
  1. The occipital pole has a dual blood supply (both PCA and MCA branches)
  2. Lesions rarely destroy all neurons representing the macula
• Congruous defect = identical pattern in both eyes → indicates the lesion is posterior in the visual pathway (cortex), where fibers from corresponding retinal points are tightly grouped
• Bilateral occipital lesions → cortical blindness (Anton syndrome - patient may deny blindness)

3. Summary Table

4. Key Distinguishing Points

5. Clinically Important Causes by Location