Medicine – Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia. It causes gradual deterioration in memory, cognition, language, orientation, judgment, and behaviour, eventually interfering substantially with activities of daily living.

The disease usually develops insidiously over years rather than abruptly, and early impairment of episodic memory is particularly characteristic.

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1. Progressive Memory Loss

The earliest and most typical feature is:

Progressive impairment of recent memory.

Patients may repeatedly:

Forget recent conversations.

Misplace objects.

Ask the same questions.

Miss appointments.

Forget recently learned information.

Older, well-established memories may initially be relatively preserved.

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2. Cognitive Decline

As the disease progresses, cognitive impairment becomes broader.

Patients may develop difficulty with:

Attention.

Planning.

Problem solving.

Judgment.

Executive function.

Recognition of people or objects.

Eventually, cognitive impairment affects independence and daily functioning.

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3. Language Deterioration

Language gradually deteriorates.

Common abnormalities include:

Word-finding difficulty.

Reduced vocabulary.

Difficulty naming objects.

Impaired comprehension in later disease.

Progressively less fluent communication.

This language impairment is often referred to as:

Aphasia.

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4. Disorientation

Patients may become disorientated to:

Time.

Place.

Eventually person.

Early on, they may become confused about dates or unfamiliar environments.

Later, they may become lost even in familiar surroundings.

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5. Personality and Behavioural Change

Behavioural and personality changes can develop as cortical dysfunction progresses.

Possible features include:

Apathy.

Irritability.

Anxiety.

Depression.

Agitation.

Suspiciousness.

Social withdrawal.

Psychotic symptoms such as hallucinations or delusions may occur in later disease.

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6. Pathological Basis

The two classic pathological hallmarks are:

Extracellular beta-amyloid plaques.

and

Intracellular neurofibrillary tangles composed of abnormal tau protein.

These abnormalities are associated with synaptic dysfunction, neuronal loss, and progressive cerebral atrophy.

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7. Beta-Amyloid Plaques

Beta-amyloid is produced from:

Amyloid precursor protein, APP.

Abnormal processing can result in accumulation of amyloid-beta peptides, especially:

Aβ42.

These peptides aggregate and form extracellular plaques.

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8. Neurotoxicity of Amyloid

Beta-amyloid accumulation is associated with:

Synaptic dysfunction.

Neuroinflammation.

Oxidative stress.

Neuronal injury.

The older note describes plaques simply as “neurotoxic,” which captures the concept, although modern understanding recognises a much more complex disease mechanism.

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9. Neurofibrillary Tangles

Neurofibrillary tangles are composed of abnormally phosphorylated:

Tau protein.

Tau normally helps stabilise neuronal microtubules.

When it becomes abnormally phosphorylated, it detaches from microtubules and aggregates inside neurons.

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10. Effect of Tau Abnormality

Abnormal tau causes disruption of:

Axonal transport.

Microtubule stability.

Neuronal function.

Eventually, affected neurons degenerate.

Therefore:

Abnormal tau → neurofibrillary tangles → neuronal dysfunction and death.

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11. Hippocampal Involvement

The hippocampus is particularly affected early in Alzheimer’s disease.

The hippocampus is essential for:

Formation of new memories.

This explains why early impairment of recent memory is such a prominent clinical feature.

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12. Medial Temporal Lobe Atrophy

Because the hippocampus and adjacent medial temporal structures are affected, imaging may demonstrate:

Hippocampal atrophy.

and

Medial temporal lobe atrophy.

As disease progresses, more widespread cortical atrophy develops.

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13. Cholinergic Neuron Loss

Alzheimer’s disease is associated with degeneration of cholinergic neurons, particularly those projecting from the:

Basal forebrain.

There is reduced activity of:

Choline acetyltransferase.

This leads to reduced synthesis and availability of:

Acetylcholine.

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14. Importance of Acetylcholine

Acetylcholine is important for:

Memory.

Attention.

Learning.

Loss of cholinergic activity contributes to cognitive impairment.

This provides the basis for the use of:

Cholinesterase inhibitors.

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15. Risk Factors

Important risk factors include:

Increasing age.

Family history.

Genetic susceptibility.

Down syndrome.

Vascular risk factors.

Previous significant head injury.

Age is the strongest overall risk factor.

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16. APOE

The APOE ε4 allele increases the risk of developing late-onset Alzheimer’s disease.

However:

APOE ε4 is a risk factor, not a deterministic diagnostic mutation.

Many people carrying APOE ε4 never develop Alzheimer’s disease, and many patients with Alzheimer’s disease do not carry it.

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17. Familial Early-Onset Alzheimer’s Disease

Rare familial forms of early-onset Alzheimer’s disease can result from mutations in genes such as:

APP.

PSEN1.

PSEN2.

These mutations can produce autosomal dominant inheritance.

They account for only a small proportion of total Alzheimer’s disease cases.

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18. Down Syndrome

People with Down syndrome have an increased risk of Alzheimer-type pathology.

This is partly because the APP gene is located on chromosome 21.

An extra copy of chromosome 21 can increase amyloid precursor protein production.

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19. Clinical Course

Alzheimer’s disease typically progresses gradually through:

Mild cognitive impairment or early dementia.

Then:

Moderate dementia.

Then:

Severe dementia.

Progression usually occurs over years.

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20. Early Stage

Early features commonly include:

Recent memory loss.

Word-finding difficulty.

Difficulty with complex tasks.

Reduced organisation.

Disorientation to time.

Patients may still retain considerable independence.

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21. Moderate Stage

With progression, patients may develop:

Increasing memory impairment.

Difficulty recognising people.

Impaired activities of daily living.

Behavioural symptoms.

Wandering.

Sleep disturbance.

Urinary problems in later stages.

Supervision becomes increasingly necessary.

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22. Severe Stage

Advanced Alzheimer’s disease can lead to:

Profound cognitive impairment.

Severe language loss.

Loss of mobility.

Dysphagia.

Incontinence.

Dependence for all daily activities.

Complications such as aspiration, infections, malnutrition, and immobility become increasingly important.

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23. Diagnosis

Diagnosis is based on:

Clinical history.

Collateral history from family or carers.

Cognitive assessment.

Neurological examination.

Laboratory investigation for reversible causes.

Brain imaging.

Biomarker testing may be used in selected cases.

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24. Cognitive Assessment

Cognitive testing may assess:

Memory.

Attention.

Language.

Executive function.

Visuospatial ability.

Examples include:

MMSE.

MoCA.

However, no single score establishes the diagnosis by itself.

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25. Excluding Reversible Causes

Investigations may be performed to exclude other causes of cognitive impairment.

Examples include:

Thyroid dysfunction.

Vitamin B12 deficiency.

Electrolyte abnormalities.

Medication effects.

Depression.

Normal pressure hydrocephalus.

Subdural haematoma.

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26. Brain Imaging

CT or MRI may demonstrate:

Generalised cerebral atrophy.

Medial temporal lobe atrophy.

Hippocampal volume loss.

Imaging also helps exclude structural causes such as tumour, stroke, or subdural collections.

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27. Biomarkers

Modern diagnostic assessment may include biomarkers of Alzheimer pathology.

These can include measures of:

Amyloid-beta.

Phosphorylated tau.

in CSF or through approved blood-based or imaging approaches in appropriate specialist settings.

These biomarkers can support diagnosis, especially when the clinical picture is uncertain.

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28. Treatment Goals

Traditional symptomatic treatments do not reverse established neuronal loss.

Their goals are to:

Temporarily improve or stabilise cognition.

Improve daily function.

Reduce some behavioural symptoms.

The overall benefit is usually modest.

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29. Cholinesterase Inhibitors

Cholinesterase inhibitors reduce the breakdown of:

Acetylcholine.

This increases acetylcholine availability at synapses.

Therefore:

Acetylcholinesterase inhibition → ↑ acetylcholine → improved cholinergic transmission.

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30. Donepezil

Donepezil is a commonly used acetylcholinesterase inhibitor.

It may produce modest improvement or stabilisation in:

Cognition.

Daily functioning.

Behavioural symptoms.

The effect varies between individuals.

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31. Rivastigmine

Rivastigmine also enhances cholinergic transmission.

It inhibits:

Acetylcholinesterase.

and

Butyrylcholinesterase.

It is used in Alzheimer’s disease and is also particularly associated with treatment of dementia in Parkinson disease.

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32. Galantamine

An additional cholinesterase inhibitor is:

Galantamine.

It is also used for mild-to-moderate Alzheimer’s disease in appropriate patients.

This is an important modern addition to the older list.

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33. Adverse Effects of Cholinesterase Inhibitors

Common adverse effects include:

Nausea.

Vomiting.

Diarrhoea.

Loss of appetite.

Weight loss.

Bradycardia.

Syncope.

Because of their cholinergic effects, caution is needed in patients with conduction disease or significant bradycardia.

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34. Memantine

Memantine acts as an antagonist at:

NMDA glutamate receptors.

It is used particularly in:

Moderate-to-severe Alzheimer’s disease.

It may also be combined with a cholinesterase inhibitor in selected patients.

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35. Mechanism of Memantine

The older note states that memantine “improves function of hippocampal neurons.”

A more accurate mechanism is:

Memantine reduces pathological excessive glutamatergic NMDA receptor activity while preserving much normal neurotransmission.

This may reduce excitotoxic neuronal stress and provide modest symptomatic benefit.

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36. NMDA Receptors

NMDA receptors are glutamate receptors involved in:

Learning.

Memory.

Synaptic plasticity.

Excessive activation can contribute to:

Excitotoxicity.

Memantine partially limits this excessive stimulation.

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37. Disease-Modifying Therapy

Modern Alzheimer treatment also includes anti-amyloid monoclonal antibodies for selected patients with early symptomatic disease and confirmed amyloid pathology.

These therapies aim to reduce amyloid burden rather than simply improve neurotransmitter function.

They are not suitable for every patient and require specialist assessment because benefits are modest and important adverse effects, including amyloid-related imaging abnormalities (ARIA), can occur.

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38. Non-Drug Management

Management should also include:

Regular physical activity.

Optimisation of hearing and vision.

Management of vascular risk factors.

Medication review.

Cognitive and social stimulation.

Support for carers.

Home safety assessment.

Advance care planning when appropriate.

These measures are important throughout the disease course.

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39. Alzheimer’s Disease – Note Form

Main presentation: progressive memory loss + cognitive decline.

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Other features: language deterioration + disorientation + behavioural/personality change.

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Early structure affected: hippocampus and medial temporal lobe.

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Plaques: extracellular beta-amyloid.

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Tangles: intracellular abnormal tau.

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Neurotransmitter change: loss of cholinergic neurons → reduced acetylcholine.

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Choline acetyltransferase: reduced activity.

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Course: gradual progressive decline over years.

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40. Treatment – Note Form

Cholinesterase inhibitors:

Donepezil.

Rivastigmine.

Galantamine.

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Mechanism:

Reduce acetylcholine breakdown.

Increase synaptic acetylcholine.

Produce modest symptomatic benefit.

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NMDA antagonist:

Memantine.

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Mechanism:

Reduces excessive NMDA-mediated glutamatergic activity.

Used particularly in moderate-to-severe disease.

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41. Pathology – Note Form

Beta-amyloid plaques → extracellular.

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Tau neurofibrillary tangles → intracellular.

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Hippocampal degeneration → early episodic memory loss.

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Basal forebrain cholinergic neuron loss → reduced acetylcholine.

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42. Alzheimer’s Disease versus Normal Pressure Hydrocephalus

Alzheimer’s disease:

Memory impairment often prominent early.

Gradual progression.

Hippocampal/medial temporal atrophy.

Gait disturbance usually not the dominant early feature.

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Normal pressure hydrocephalus:

Magnetic gait often appears early.

Cognitive slowing follows.

Urinary urgency/incontinence is characteristic.

Imaging shows disproportionate ventriculomegaly.

This distinction is useful because NPH may improve with CSF shunting.

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Key Clinical Pattern

Think of Alzheimer’s disease as:

PROGRESSIVE RECENT MEMORY LOSS → LANGUAGE AND ORIENTATION PROBLEMS → GLOBAL COGNITIVE AND FUNCTIONAL DECLINE.

The classic pathology is:

BETA-AMYLOID PLAQUES + TAU TANGLES + HIPPOCAMPAL ATROPHY + CHOLINERGIC NEURON LOSS.

The classic symptomatic treatments are:

DONEPEZIL / RIVASTIGMINE / GALANTAMINE → inhibit cholinesterase → ↑ acetylcholine.

and

MEMANTINE → NMDA receptor antagonist → reduces pathological glutamate-mediated excitation.

The key treatment principle is that these drugs may modestly improve or stabilise symptoms, but they do not fully restore lost neurons or reverse established dementia.