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Summary Table

Category	Detail
Risk Factors	Age > 65 (strongest risk factor), family history of Alzheimer's, Down syndrome (trisomy 21), female sex, ApoE4 allele carrier, history of traumatic brain injury, low educational attainment, cardiovascular risk factors (hypertension, diabetes, obesity, smoking)
Etiology	Progressive neurodegenerative disease caused by extracellular amyloid-beta (A-beta) plaque deposition and intracellular neurofibrillary tangles (hyperphosphorylated tau protein), leading to cortical atrophy beginning in the hippocampus and temporal lobes
Patient Presentation	Insidious onset of progressive short-term memory loss over months to years; family reports the patient repeating questions, getting lost in familiar places, misplacing items, and forgetting recent conversations; the patient may be unaware of or minimize these deficits
Classic Physical Exam	Normal neurological exam early in the disease; impaired recall on cognitive testing (Mini-Mental State Examination or Montreal Cognitive Assessment); language difficulties and visuospatial deficits emerge later; no focal neurological deficits early on
Key Diagnostic Results	MRI brain: diffuse cortical atrophy with early hippocampal atrophy and ventricular enlargement; CSF: decreased A-beta 42, elevated phosphorylated tau and total tau; PET: amyloid-positive or tau-positive uptake; labs to exclude reversible causes are normal (TSH, B12, RPR, metabolic panel)
Management	Mild-to-moderate: cholinesterase inhibitors (donepezil, rivastigmine, galantamine); Moderate-to-severe: add memantine (NMDA receptor antagonist); non-pharmacologic: caregiver education, structured environment, physical activity, cognitive stimulation; manage behavioral symptoms with environmental modification first, then low-dose atypical antipsychotics only if necessary
Keywords	"Insidious memory loss," "progressive cognitive decline," "hippocampal atrophy," "amyloid plaques and neurofibrillary tangles," "repeats questions," "gets lost in familiar places," "cortical atrophy on MRI," "decreased A-beta 42 in CSF"

1. Pathophysiology

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia, accounting for 60 to 80 percent of all dementia cases. Understanding the pathophysiology is essential because every clinical feature you see in a vignette traces directly back to the underlying molecular pathology.

The disease is driven by two hallmark pathological processes. The first is the extracellular accumulation of amyloid-beta (A-beta) plaques. The amyloid precursor protein (APP), a transmembrane protein normally found on neuronal surfaces, is cleaved by beta-secretase and gamma-secretase to produce A-beta 42 peptide fragments. These fragments are insoluble and aggregate into plaques in the brain parenchyma. This is why patients with Down syndrome (trisomy 21) develop early-onset Alzheimer's: the APP gene is located on chromosome 21, so having three copies leads to overproduction of APP and consequently A-beta. The ApoE4 allele is the strongest genetic risk factor for late-onset Alzheimer's because ApoE4 impairs A-beta clearance, accelerating plaque accumulation.

The second hallmark is the intracellular formation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. Tau normally stabilizes microtubules within axons, facilitating intracellular transport. When tau becomes hyperphosphorylated, it dissociates from microtubules and aggregates into insoluble tangles. This disrupts axonal transport and leads to neuronal dysfunction and death. While amyloid plaques are found diffusely, the distribution of NFTs correlates more closely with clinical severity, which is why CSF phosphorylated tau levels serve as a marker of disease progression.

The earliest and most severely affected region is the hippocampus and entorhinal cortex, which are the structures responsible for encoding new memories. This is why the hallmark presentation is progressive short-term memory loss with relative preservation of remote memories early in the course. Patients can recall events from decades ago but cannot remember what happened an hour ago. As the disease progresses, neurodegeneration spreads to the temporal, parietal, and eventually the frontal cortex, producing language deficits (anomia, then fluent aphasia), visuospatial dysfunction (getting lost), executive dysfunction, and eventually behavioral changes including apathy, agitation, and psychosis.

The cholinergic hypothesis explains the pharmacologic approach. There is a selective loss of cholinergic neurons in the nucleus basalis of Meynert, which projects widely to the cortex and hippocampus. The resulting acetylcholine deficiency contributes directly to memory and attention deficits. This is the rationale for using cholinesterase inhibitors as first-line therapy. Later in the disease, there is glutamate-mediated excitotoxicity through overactivation of NMDA receptors, which is the basis for memantine use.

2. Classification and Clinical Manifestation

Stage	Cognitive Domain	Functional Status	Behavioral Features	Typical Duration
Preclinical (Asymptomatic)	No subjective or objective cognitive complaints; biomarker-positive only (amyloid PET or CSF)	Fully independent	None	Years to decades before symptom onset
Mild Cognitive Impairment (MCI) due to Alzheimer's	Subjective memory complaints with objective impairment on testing (especially delayed recall); other cognitive domains relatively preserved	Independent in daily activities; may have subtle difficulty with complex tasks (finances, medication management)	Mild anxiety or depression may be present	2 to 4 years before progression to dementia
Mild Dementia	Short-term memory loss is prominent; word-finding difficulty (anomia); mild visuospatial deficits (getting lost in unfamiliar places)	Needs assistance with instrumental activities of daily living (IADLs): finances, cooking, shopping, medications	Apathy, social withdrawal, mild depression, denial of deficits (anosognosia)	2 to 4 years
Moderate Dementia	Worsening memory (now affecting remote memory); language deteriorates to fluent aphasia; cannot learn new information; disorientation to time and place	Needs help with basic activities of daily living (ADLs): dressing, bathing, grooming; cannot live alone safely	Agitation, wandering, sundowning (worsened confusion in the evening), paranoia, hallucinations (usually visual), sleep disturbances	2 to 3 years
Severe Dementia	Profound memory loss; minimal or no meaningful verbal communication; failure to recognize family members	Fully dependent for all ADLs; wheelchair-bound or bedbound; incontinence of bowel and bladder	Motor rigidity, dysphagia, mutism, seizures may occur	1 to 3 years until death

A critical exam concept: the distinction between MCI and dementia hinges on functional status. In MCI, the patient has objective cognitive impairment but remains independent. Once cognitive decline impairs the ability to perform daily activities independently, the threshold for dementia has been crossed.

3. Diagnostic Workup

Test	Role	Key Findings
Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA)	Best initial screening tool for cognitive impairment	Score below 24/30 (MMSE) or below 26/30 (MoCA) suggests cognitive impairment; MoCA is more sensitive for mild deficits
Basic laboratory panel (TSH, vitamin B12, CBC, CMP, RPR/VDRL)	Exclude reversible causes of dementia	All should be normal in Alzheimer's; abnormal results point to hypothyroidism, B12 deficiency, neurosyphilis, metabolic encephalopathy
MRI brain without contrast	Best initial imaging study	Diffuse cortical atrophy with disproportionate hippocampal and medial temporal lobe atrophy; enlarged ventricles (hydrocephalus ex vacuo); no focal lesions, strokes, or masses
CT head	Alternative if MRI is contraindicated	Shows atrophy but with less resolution than MRI; used mainly to exclude other structural causes
CSF biomarkers (A-beta 42, phosphorylated tau, total tau)	Supports diagnosis when clinical picture is ambiguous	Decreased A-beta 42 (trapped in plaques, less reaches CSF), elevated phosphorylated tau and total tau
Amyloid PET scan (e.g., florbetapir)	Confirmatory imaging for amyloid deposition	Positive uptake confirms cerebral amyloid plaques; high sensitivity
Tau PET scan	Research and emerging clinical use	Correlates with disease staging and severity
FDG-PET	Functional imaging	Temporoparietal hypometabolism is the classic pattern; helps differentiate from frontotemporal dementia
Brain biopsy / Autopsy	Definitive gold standard (rarely performed in living patients)	Amyloid plaques and neurofibrillary tangles on histopathology

The workup follows a logical sequence driven by one core principle: Alzheimer's is a clinical diagnosis of exclusion first, then a diagnosis supported by biomarkers.

When a patient presents with progressive memory loss, the first step is to perform a standardized cognitive assessment. The MoCA is preferred over the MMSE because it is more sensitive for detecting mild cognitive impairment, especially in educated patients. A low score quantifies the deficit but does not tell you the cause.

The second step is to rule out reversible causes of dementia. This means ordering TSH (hypothyroidism), vitamin B12 level (B12 deficiency), RPR or VDRL (neurosyphilis), CBC, and a comprehensive metabolic panel (hepatic or renal encephalopathy, electrolyte disturbances). Depression screening is also essential because pseudodementia (depression mimicking dementia) is a classic exam distractor. If all reversible causes are excluded and the history fits an insidious progressive course, Alzheimer's becomes the leading diagnosis.

The third step is neuroimaging. MRI brain without contrast is the best initial imaging study. You are looking for cortical atrophy with prominent hippocampal volume loss and ventriculomegaly. Critically, MRI also helps exclude other structural causes such as normal pressure hydrocephalus (NPH), subdural hematoma, or brain tumor. On the exam, if the vignette describes a patient with progressive memory loss and the MRI shows diffuse atrophy with hippocampal involvement and no focal findings, the answer is Alzheimer's.

CSF biomarkers and amyloid PET are used when the diagnosis is uncertain or when early confirmation is needed. The classic CSF profile of low A-beta 42 with high phosphorylated tau is highly suggestive. Remember: A-beta 42 is low in CSF because it is being deposited in the brain rather than circulating freely.

The true gold standard is histopathological confirmation at autopsy, showing amyloid plaques and neurofibrillary tangles. In clinical practice, however, the diagnosis is made on clinical and biomarker grounds.

4. Management and Treatment

Setting	Intervention	Details
Mild to Moderate Alzheimer's	Donepezil (cholinesterase inhibitor)	5 mg orally once daily, increase to 10 mg daily after 4 to 6 weeks; can be used across all stages
Mild to Moderate Alzheimer's	Rivastigmine (cholinesterase inhibitor)	Available as oral (1.5 mg twice daily, titrate up to 6 mg twice daily) or transdermal patch (4.6 mg/24h, increase to 9.5 or 13.3 mg/24h); patch preferred for fewer GI side effects
Mild to Moderate Alzheimer's	Galantamine (cholinesterase inhibitor)	4 mg twice daily, titrate to 12 mg twice daily; extended-release: 8 mg daily, titrate to 24 mg daily
Moderate to Severe Alzheimer's	Memantine (NMDA receptor antagonist)	5 mg orally once daily, titrate by 5 mg weekly to target of 10 mg twice daily; often combined with donepezil
Moderate to Severe Alzheimer's	Donepezil + Memantine combination	Available as fixed-dose combination (memantine ER 28 mg / donepezil 10 mg); the standard regimen for moderate-to-severe disease
Behavioral and Psychological Symptoms	Non-pharmacologic first	Structured routines, redirection, caregiver education, minimize triggers, music therapy, exercise
Behavioral and Psychological Symptoms	Low-dose atypical antipsychotics (if non-pharmacologic measures fail and patient is a danger)	Risperidone or quetiapine at lowest effective dose; note FDA black box warning for increased mortality in elderly dementia patients
Caregiver Support	Education, respite care, support groups	Critical component of management; caregiver burnout is common
Safety Planning	Driving assessment, fall prevention, wandering precautions, advance directives	Address early while patient can participate in decision-making

Acute management in Alzheimer's is rarely the focus of exam questions because the disease is chronic. However, you may encounter vignettes about managing acute agitation or psychosis in a demented patient. The first step is always non-pharmacologic intervention: remove triggers, ensure a calm environment, rule out delirium from an underlying medical cause (UTI, constipation, pain, medication side effects). Pharmacologic intervention with antipsychotics is reserved for patients who are a danger to themselves or others, and it should be time-limited because of the black box warning for increased mortality (cerebrovascular events) in elderly patients with dementia.

For long-term management, the cornerstone is cholinesterase inhibitors. Donepezil is the most commonly tested because it is dosed once daily and can be used across all stages of disease. The mechanism is straightforward: by inhibiting acetylcholinesterase, you increase synaptic acetylcholine levels to partially compensate for the cholinergic neuron loss. Common side effects to know include nausea, diarrhea, bradycardia, and vivid dreams (the GI and cardiac effects reflect increased cholinergic tone peripherally). Cholinesterase inhibitors are contraindicated in patients with significant bradycardia or heart block because of their vagotonic effects.

Memantine is added for moderate-to-severe disease. It works by blocking excessive NMDA receptor activation, thereby reducing glutamate-mediated excitotoxicity. It is well tolerated and the most common side effects are dizziness, headache, and constipation. On the exam, the "next best step" for a patient already on donepezil whose disease has progressed to the moderate or severe stage is to add memantine, not to switch medications.

An important exam pearl: none of these medications cure or halt the progression of Alzheimer's disease. They provide modest symptomatic improvement and may slow functional decline for 6 to 12 months, but the disease continues to progress. Families should be counseled about realistic expectations.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Vascular Dementia	Progressive cognitive decline in an elderly patient; overlapping risk factors (hypertension, diabetes)	Stepwise decline rather than gradual; history of strokes or TIAs; focal neurological deficits on exam; MRI shows white matter disease, lacunar infarcts, or cortical strokes; temporal relationship between cerebrovascular events and cognitive worsening
Frontotemporal Dementia (FTD)	Progressive dementia in a younger patient (ages 45 to 65)	Personality and behavioral changes precede memory loss; early disinhibition, apathy, compulsive behaviors, or language variants (progressive nonfluent aphasia or semantic dementia); frontal and temporal atrophy on MRI with relative sparing of hippocampi early on
Lewy Body Dementia (DLB)	Progressive cognitive decline with memory impairment	Visual hallucinations early in the course (often well-formed, detailed); fluctuating cognition (good days and bad days); parkinsonism (rigidity, bradykinesia, shuffling gait); REM sleep behavior disorder; severe sensitivity to antipsychotics (neuroleptic sensitivity)
Normal Pressure Hydrocephalus (NPH)	Dementia and gait abnormality in an elderly patient	Classic triad: "wet, wacky, and wobbly" (urinary incontinence, dementia, magnetic gait); MRI shows ventriculomegaly out of proportion to cortical atrophy; potentially reversible with VP shunt; improvement after large-volume lumbar puncture is diagnostic
Pseudodementia (Depression)	Elderly patient with memory complaints and poor performance on cognitive testing	Patient complains actively about memory loss (Alzheimer's patients often lack insight); onset is more acute (weeks to months, not years); patient answers "I don't know" rather than confabulating; history of depressive symptoms (anhedonia, sleep disturbance, guilt); cognitive function improves with antidepressant treatment
Hypothyroidism	Cognitive slowing, memory complaints, fatigue in elderly patient	Elevated TSH with low free T4; other features include cold intolerance, weight gain, constipation, dry skin, delayed relaxation of deep tendon reflexes; cognitive symptoms are reversible with thyroid replacement
Vitamin B12 Deficiency	Memory loss and cognitive impairment	Megaloblastic anemia (macrocytic anemia with hypersegmented neutrophils); subacute combined degeneration (loss of vibration and proprioception, positive Romberg); elevated methylmalonic acid and homocysteine; low serum B12; reversible with supplementation
Creutzfeldt-Jakob Disease (CJD)	Rapidly progressive dementia	Rapid progression (weeks to months, not years); myoclonus; characteristic periodic sharp wave complexes on EEG; MRI shows cortical ribboning with DWI/FLAIR abnormalities; CSF 14-3-3 protein elevated; invariably fatal

6. Traps and High-Yield Pearls

The most common trap on this topic is failing to rule out reversible causes of dementia before committing to the diagnosis of Alzheimer's. A vignette will present an elderly patient with progressive memory loss, and among the answer choices will be "start donepezil" and "check TSH and B12." The correct answer is always to exclude reversible causes first, even when the clinical picture strongly suggests Alzheimer's. Until you have a normal TSH, a normal B12, a normal metabolic panel, and a negative RPR, you cannot finalize the diagnosis. Test writers use this to evaluate whether you follow the correct diagnostic sequence rather than jumping to treatment.

A second common pitfall is confusing Alzheimer's with Lewy Body Dementia. Both present with progressive cognitive decline, and both can feature hallucinations. The critical difference is timing: in Alzheimer's, hallucinations appear late in the disease course, while in DLB, visual hallucinations and fluctuating cognition appear early, often within the first year or even before memory loss becomes prominent. If the vignette mentions early well-formed visual hallucinations, parkinsonism, or REM sleep behavior disorder, pivot to DLB. Furthermore, DLB patients have dangerous sensitivity to antipsychotic medications, which can precipitate irreversible parkinsonism or neuroleptic malignant syndrome.

A third trap involves the question of what to add when a patient on donepezil worsens. Students often want to switch to a different cholinesterase inhibitor, but the correct answer for progression to moderate-to-severe disease is to add memantine, not to switch within the same drug class.

Finally, remember that Down syndrome patients develop Alzheimer's pathology early, often by age 40. A vignette describing progressive memory loss in a middle-aged patient with Down syndrome should immediately point you toward Alzheimer's, not toward an intellectual disability plateau. The APP gene on chromosome 21 is the connection, and this is a frequently tested genetic association.

The core competency being tested across all Alzheimer's questions is your ability to recognize an insidious, progressive amnestic syndrome, systematically exclude reversible mimics, correctly sequence diagnostic studies before initiating therapy, and match treatment intensity to disease stage.

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