Pathological Protein Accumulation

• Amyloid-beta (Aβ) Pathway: Overproduction or impaired clearance of Aβ peptides leads to extracellular aggregation into oligomers and amyloid plaques. These structures trigger chronic neuroinflammation through microglial activation, cytokine release, and complement activation, ultimately resulting in neuritic plaque formation, synaptic loss, and neuronal death.
• Tau Pathology: Hyperphosphorylated tau, a microtubule-stabilising protein, aggregates into intracellular neurofibrillary tangles (NFTs) and dystrophic neurites, disrupting axonal transport and neuronal integrity.
  
  

Genetic Contributions

• Caused by autosomal dominant mutations, mostly affecting younger individuals (<65 years).
• Involves mutations in:
  • APP (chromosome 21)
  • Presenilin 1 (PSEN1) (chromosome 14)
  • Presenilin 2 (PSEN2) (chromosome 1)
• These mutations increase production of the neurotoxic Aβ42 peptide.
  
  

• Individuals with trisomy 21 possess three copies of the APP gene, resulting in early and universal amyloid plaque formation by midlife.
  
  

• Strongly associated with the APOE ε4 allele:
  • Homozygous carriers (ε4/4) have a significantly elevated risk and earlier onset.
  • APOE ε2 is protective, whereas ε3 confers intermediate risk.
• Gene-environment interactions (e.g. air pollution exposure) further modulate the impact of APOE ε4 on AD risk.
  
  

• CLU, PICALM, CR1, ABCA7, MS4A6A/MS4A4E, EPHA1, CD33, CD2AP
  
  

Metabolic and Vascular Risk Factors

• Associated with reduced cerebral glucose metabolism and altered neural activation in preclinical AD.
• May hasten progression to symptomatic disease by accelerating neurodegeneration.
  
  

• Promote systemic inflammation and impair amyloid clearance.
  
  

• Particularly in midlife, contributes to both vascular and Alzheimer-type dementia.
• Some evidence suggests β-blocker use may reduce AD pathology at autopsy.
  
  

• Elevated serum levels are linked to neurotoxicity and increased AD risk.
  
  
  

Lifestyle and Environmental Influences

• Moderate intake (1–14 units/week) appears protective.
• Both abstinence and heavy consumption (>14 units/week) in midlife are associated with increased risk.
  
  

• Smoking and high saturated fat intake elevate AD risk.
  
  

• Higher educational attainment is a well-established protective factor, likely via enhancement of cognitive reserve.
  
  

Infectious and Inflammatory Triggers

• Chronic infections by spirochetes (e.g. Borrelia burgdorferi, Treponema spp.) and herpes simplex virus-1 have been implicated in AD pathogenesis.
• Aβ may serve an antimicrobial role, suggesting its accumulation could be a defence response to chronic infection, though ultimately neurotoxic.
  
  

Psychiatric and Neurological Factors

• A significant and independent risk factor for AD, especially with early-onset or recurrent episodes.
• Both early-life and late-life depression increase AD incidence.
  
  

• Moderate to severe TBI correlates with increased AD risk, potentially via increased APP expression and Aβ deposition.
• The APOE ε4 genotype may amplify this risk.
  
  
  

Emerging Concepts: Epigenetics and Oxidative Stress

• Environmental exposures (e.g. lead) can induce changes in gene expression without altering DNA sequence, influencing AD risk.
• Mechanisms include DNA methylation and oxidative stress–induced transcriptional dysregulation.
  
  

• Excess reactive oxygen species can damage neurons, alter tau phosphorylation, and impair DNA repair.
• While antioxidants are conceptually attractive, clinical trials (e.g. with vitamin E) have shown limited benefit to date.
  
  

• AD pathology may begin decades before clinical symptoms.
• Biomarkers (e.g. CSF Aβ42, phosphorylated tau, amyloid PET imaging) can identify individuals at risk.
• Though promising for research and early intervention, biomarker positivity without symptoms is not yet sufficient for a clinical diagnosis.
   

Macroscopic and Microscopic Neuropathology

• AD brains typically exhibit marked cortical atrophy, most prominently in the temporal, parietal, and frontal lobes.
• Brain weight is reduced by 100–200 g or more, depending on disease severity.
• Hippocampal and entorhinal cortex atrophy is especially pronounced, reflecting early involvement in memory processing.
• Subcortical structures (thalamus, brainstem, basal ganglia, cerebellum) are generally preserved in size and weight.
  
  

• Senile Plaques (SPs): Extracellular aggregates composed of β-amyloid (Aβ) surrounded by dystrophic neurites and reactive glial cells.
• Neurofibrillary Tangles (NFTs): Intraneuronal accumulations of hyperphosphorylated tau disrupting cytoskeletal integrity.
• NFT burden correlates more closely with cognitive impairment than SPs.
• Additional findings include granulovacuolar degeneration in the hippocampus and neuropil threads representing diffuse dendritic pathology.
  
  

• AD disrupts three essential neuronal functions: communication, metabolism, and repair.
• Neuronal death in AD is attributed to:
  • Oxidative stress
  • Excitotoxicity from calcium dysregulation
  • Protein misfolding and aggregation
  • Neuroinflammation
    
    

Amyloid and Tau Hypotheses

• Aβ peptides are cleaved from amyloid precursor protein (APP) and aggregate extracellularly into plaques.
• Mutations in APP, PSEN1, and PSEN2 genes enhance production of the neurotoxic Aβ42 isoform.
• Aβ aggregates activate inflammatory pathways and induce oxidative damage and apoptosis.
• The receptor for advanced glycation end-products (RAGE) and scavenger receptors mediate microglial activation and cytokine release in response to amyloid.
  
  

• Tau stabilises microtubules; in AD, it becomes hyperphosphorylated and aggregates into NFTs.
• Tau pathology disrupts axonal transport, destabilises the cytoskeleton, and contributes to synaptic degeneration.
• Tauopathy often begins in the brainstem or entorhinal cortex and progresses to association cortices.
• The relationship between Aβ and tau remains debated. Amyloid pathology may precede tau accumulation, but NFTs correlate better with disease severity.
  
  

Neurochemical Abnormalities

• Loss of cholinergic neurons in the basal forebrain, particularly the nucleus basalis of Meynert, contributes to memory impairment.
• Reduced acetylcholine synthesis and choline acetyltransferase activity are evident in affected brain regions.
• These deficits underpin the rationale for cholinesterase inhibitor therapy.

• Degeneration of the locus coeruleus and raphe nuclei leads to reduced levels of noradrenaline and serotonin, contributing to neuropsychiatric symptoms.
  
  

• Oxidative damage is selective for brain regions involved in cognition.
• Mechanisms include lipid peroxidation, protein carbonylation, DNA damage, and impaired protein synthesis.
• Disruption of calcium homeostasis leads to activation of calcium-dependent enzymes (e.g. protein kinase C), contributing to abnormal APP processing and tau phosphorylation.
• Antioxidant defences are impaired, and oxidative stress is believed to initiate and propagate neuronal injury.
  
  

• Aβ aggregates activate microglia and astrocytes, triggering cytokine release (e.g. IL-1, IL-6, TNF-α).
• Complement cascade activation occurs in an antibody-independent manner, contributing to synaptic pruning and neuronal loss.
• Anti-inflammatory mediators like TGF-β1 may paradoxically promote Aβ deposition.
• NSAID use may reduce microglial activation despite unchanged plaque load, suggesting symptomatic benefit via inflammation modulation.
  
  

• AD pathology evolves over decades:
  • First: Amyloid accumulation (detected via PET imaging and CSF Aβ42 decline)
  • Then: Decreased glucose metabolism (FDG-PET)
  • Finally: Structural atrophy (MRI volumetrics)
• These biomarker trajectories precede clinical symptoms by 10–20 years, particularly in autosomal dominant AD mutation carriers.
  
  

Emerging Concepts and Alternative Pathologies

• Mimics AD but involves TDP-43 proteinopathy, primarily in the hippocampus and amygdala.
• Present in ~25% of individuals over age 85 and contributes to memory impairment independently of amyloid or tau.
  
  

• A chaperone protein implicated in Aβ clearance and neuronal injury.
• Associated with disease severity, entorhinal cortex atrophy, and clinical progression.
  
  

• PS1 and PS2 proteins are involved in γ-secretase activity affecting APP cleavage.
• Mutations alter Aβ42/43 production and are localised to intracellular organelles involved in protein trafficking.
  
  

• Postmenopausal loss of oestrogen may reduce neurotrophic support and enhance vulnerability to amyloid toxicity.
• However, hormone replacement therapy has not demonstrated neuroprotection in clinical trials and may elevate risk of stroke or dementia.
   

Global Prevalence and Projections

• AD is the most prevalent cause of dementia globally, accounting for approximately 60–70% of all dementia cases.
• The worldwide prevalence of dementia rose from 20.3 million in 1990 to 43.8 million in 2016—a 116% increase—largely due to population growth and ageing.
• Projections estimate that dementia will affect:
  • 82 million individuals by 2030.
  • 152 million by 2050, signifying a near fourfold rise in global burden.
• The estimated prevalence of dementia in people aged ≥60 years is between 5% and 8%.
  
  

United States Data

• In 2024, an estimated 6.9 million people in the US were living with AD, including ~200,000 individuals younger than 65 with early-onset AD.
• By 2050, the number of affected individuals is projected to rise to 13.8–14 million.
• AD is one of the leading causes of death in the US:
  • It ranked as the fifth leading cause of death among individuals aged ≥65 in 2021.
  • Mortality from AD has increased, in contrast to declines seen in other major conditions.
• Mild cognitive impairment (MCI), often a precursor to AD, affects a larger group and contributes to this increasing burden.
  
  

Incidence and Age Association

• The risk of AD escalates with advancing age:
  • Incidence doubles approximately every 5 years after the age of 65.
  • Incidence rates:
    • <1% per year before age 65.
    • ~6% per year after age 85.
  • Prevalence rates:
    • ~10% after age 65.
    • Up to 40% by age 85.
• Most AD cases (over 90%) are sporadic and occur after the age of 60.
• Early-onset familial AD, often inherited in an autosomal dominant pattern, constitutes <10% of all AD cases and may present before age 60.

Sex Differences

• Approximately two-thirds of AD patients in the US are women.
• Some studies suggest women may be at greater risk due to higher longevity or potential genetic susceptibility.
• Women who are heterozygous for the APOE ε4 allele may have up to twice the risk of AD compared to men with the same genotype.
  
  

Ethnic and Racial Disparities

• African Americans and Hispanic Americans have a higher prevalence of AD and other dementias compared to white populations:
  • Among individuals aged ≥71:
    • 21.3% of African Americans and 18.4% of Hispanics had dementia, compared to 11.2% of whites.
  • Among Medicare beneficiaries ≥65:
    • 6.9% of whites, 9.4% of African Americans, and 11.5% of Hispanics were diagnosed with AD or other dementias.
• Racial differences may also be observed in AD biomarkers:
  • African American individuals have been found to have lower cerebrospinal fluid tau levels, despite similar rates of cognitive impairment as white individuals, suggesting the need for race-adjusted biomarker thresholds.
    
    

International Patterns

• In Europe, the prevalence of AD is estimated at approximately 5%, with an incidence of around 11 per 1,000 person-years.
• Industrialised nations generally report similar prevalence rates of AD and dementia to those in the US.
• In Asian populations:
  • AD is now nearly twice as common as vascular dementia (VaD) in countries such as China, Japan, and South Korea.
  • However, prevalence rates for AD in some Chinese populations have historically been lower than those seen in Western populations.
• In sub-Saharan Africa (e.g. Nigeria), the prevalence of dementia is lower, though estimates may be limited by underdiagnosis and reporting biases.
• Indian studies have produced inconsistent findings regarding whether AD or VaD is more prevalent.
  
  

Influence of Extreme Age

• While the risk of AD generally increases with age, studies suggest a possible attenuation of this trend in individuals over 90 years.
• For instance, the correlation between dementia symptoms and AD pathology (plaques and tangles) weakens in very old individuals.
• This observation implies that other age-related neurobiological mechanisms may play a role beyond classic AD pathology in the oldest-old.
  
  
  

Lifetime Risk and Genetic Influence

• Lifetime risk at age 85:
  • Without reference to genotype: ~11% in men and ~14% in women.
  • APOE ε4/ε4 carriers: up to 60% for women and 51% for men.
  • APOE ε3/ε4 carriers: 30% for women and 23% for men.
• These figures underscore the interaction between age, sex, and genotype in determining AD risk.
   

Key Goals of History-Taking

• AD typically presents with an insidious onset and a gradual, progressive decline in memory and other cognitive domains.
• Determining the tempo of change helps differentiate AD from other dementias with abrupt or stepwise progression (e.g. vascular dementia).
  
  

• Early deficits are often observed in instrumental activities of daily living (IADLs) such as managing finances, medication, shopping, and cooking.
• Later stages involve decline in basic ADLs including dressing, feeding, and toileting.
  
  

• The earliest and most characteristic symptom is recent memory impairment, specifically anterograde episodic memory loss (inability to form new memories).
• Over time, this expands to affect semantic memory, word-finding, visuospatial abilities, executive functioning, and problem-solving.
  
  

• While memory loss is classic, early presentations can include language dysfunction, visuospatial disorientation, or changes in personality and behaviour.
• Atypical presentations such as posterior cortical atrophy or primary progressive aphasia may mimic other pathologies and require specific history probing.

Collateral History from Informants

• Crucial for assessing the accuracy of the patient’s report due to impaired insight (anosognosia).
• Helps evaluate real-world functional status and track cognitive decline over time.
• Informant observations often reveal deficits that patients themselves underreport or deny.
  
  

Neuropsychiatric and Behavioural Symptoms

• Early signs may include apathy, irritability, or mood changes such as depression or anxiety.
• Later stages may feature psychosis, agitation, wandering, and sleep disturbances.
• Distinguishing apathy from depression is important, as they have different management strategies.
  
  

Risk Factor Assessment in the History

• Advanced age is the strongest risk factor; incidence doubles approximately every five years after 65.
• Female sex and low educational attainment are also associated with higher risk.
  
  

• A family history of AD, especially early-onset cases, should prompt consideration of genetic forms (APP, PSEN1, PSEN2 mutations).
• In Down syndrome, symptoms appear earlier due to triplication of the APP gene on chromosome 21.
  
  

• Hypertension, diabetes, obesity, hyperlipidaemia, and cerebrovascular disease increase risk.
• Smoking, alcohol misuse, and physical inactivity are modifiable contributors.
• Midlife factors are particularly influential in determining late-life dementia risk.

• Prior traumatic brain injury (even without loss of consciousness) is a recognised risk.
• Depression, especially in late life, may be a prodrome or risk factor.
• Certain medications (e.g., anticholinergics, hormone therapies) may worsen cognition.
  
  

• Alcohol use, street drug use, and social isolation should be explored for confounding or contributory effects.
  
  

Specific Cognitive and Behavioural Symptoms to Explore

• Inability to retain new information, repetitive questioning, misplacing items, forgetting recent events or appointments.
• Long-term memory (e.g., personal history) tends to be preserved until later stages.
  
  

• Word-finding difficulty (anomic aphasia), reduced verbal fluency, circumlocutions, or impaired comprehension.
  
  

• Getting lost in familiar environments, difficulty navigating, trouble copying shapes or reading maps.
  
  

• Impaired planning, poor judgement, difficulty with multistep tasks (e.g., preparing meals or organising travel).
  
  

• Apathy, loss of initiative, socially inappropriate behaviour, or disinhibition.
  
  
  

Advanced Symptoms Revealed in Longitudinal History

• Difficulty performing learned movements or tasks despite preserved motor function.
  
  

• Failure to recognise familiar faces (prosopagnosia), objects, or self (autoprosopagnosia) in later stages.
  
  

• Patients may become mute, bedbound, and eventually enter a persistent vegetative state.
  
  

• Fragmented sleep, increased nocturnal wakefulness, or reversal of sleep-wake cycles may emerge.

• Occur in 10–20% of patients, usually in late stages; more common in younger patients with familial forms.
  
  

Informant Tools and Cognitive Screening in the History Context

• Mini-Mental State Examination (MMSE): Less sensitive in early disease and influenced by educational level.
• Montreal Cognitive Assessment (MoCA): More sensitive for detecting early deficits, especially mild cognitive impairment.
• Mini-Cog: Brief screening including 3-word recall and clock-drawing; not influenced by education level.
  
  
  

Atypical Presentations to Consider from the History

• Posterior Cortical Atrophy: Visual disorientation, object perception deficits, simultanagnosia, dressing apraxia.
• Primary Progressive Aphasia: Isolated language difficulty; the logopenic variant is most commonly associated with AD.
• Frontal variant AD: Prominent dysexecutive symptoms with relative sparing of memory early on.
• Corticobasal Syndrome: Asymmetric motor signs with speech and visuospatial deficits; may reflect AD pathology in ~50% of cases.
  
  
  

History to Identify Mixed Dementias

• AD may coexist with:
  • Vascular dementia: Suggestive history includes prior strokes, stepwise decline, or vascular risk factors.
  • Lewy body disease: Features include visual hallucinations, fluctuations in cognition, and parkinsonism.
  • TDP-43 proteinopathy (LATE): Associated with faster decline and severe memory loss in very elderly patients.
    
    

• Early stages: Often unremarkable, with patients appearing well-groomed and cooperative.
• Later stages: Physical appearance may include poor grooming, apathetic facial expression, slow shuffling gait, and stooped posture.
• End-stage features: Patients may become mute, rigid, bedbound, and unable to walk or speak, ultimately progressing to a vegetative state.
  
  

Mental Status Examination

• Attention and concentration: Impaired sustained attention is often subtle early in disease.
• Memory:
  • Recent (episodic) memory is most profoundly affected early, particularly in tasks requiring recall of newly learned information.
  • Remote and immediate memory are typically preserved in early stages.
• Language:
  • Nominal dysphasia is common—patients have word-finding difficulty and may struggle to name low-frequency words.
• Praxis:
  • Ideomotor apraxia may be evident when patients are asked to mimic the use of tools.
• Visuospatial function:
  • Difficulty with tasks such as drawing a clock or copying geometric figures.
• Executive function:
  • Impaired problem-solving, abstraction, sequencing, and judgment.
    
    

• MMSE: Widely used but less sensitive in early stages.
• MoCA: More sensitive to mild cognitive impairment.
• SLUMS and Mini-Cog: Additional validated tools; Mini-Cog is less influenced by education level.
  
  

Neurological Examination

• Early stages: Typically normal aside from cognitive deficits.
• Subtle findings may include:
  • Anosmia or hyposmia, occasionally present early.
  • Constructional dyspraxia, especially in parietal involvement.
  • Primitive reflexes (e.g. grasp, snout, palmomental) in more advanced disease.
  • Increased tone, rigidity, and gegenhalten in end-stage.
    
    

Specific Cognitive Deficits Detectable on Examination

• Temporal and spatial disorientation is common.
• May manifest as misplacing items, getting lost, or repeating questions.
  
  

• Blunted affect, social withdrawal, and reduced initiative are common.
• May mimic or coexist with depression; distinction can be clinically challenging.
  
  

• Impaired ability to interpret proverbs or identify similarities between objects.
• Inappropriate social or financial decisions may signal frontal lobe dysfunction.
  
  
  

Motor and Gait Abnormalities

• Generally absent until late stages.
• Myoclonus may occur, especially in rapidly progressive forms.
• Seizures are observed in 10–20% of patients, particularly with early-onset forms.
• Extrapyramidal signs (e.g. tremor, rigidity) suggest coexistent pathology (e.g. dementia with Lewy bodies or Parkinsonism).
  
  

• Emerges later, with a slow shuffling gait and postural instability.
• Not characteristic in early disease—early gait disturbance suggests alternative or mixed pathology.
  
  

• Anosmia or hyposmia may be present early in AD.
• Not routinely tested, but research supports its correlation with medial temporal lobe pathology.
• Has low specificity as olfactory deficits also occur in Parkinson disease, Lewy body dementia, and normal ageing.
  
  
  

Sleep-Wake Disturbances

• Sleep fragmentation, prolonged sleep latency, and nocturnal awakenings are frequent but not always reported.
• Can precede overt cognitive symptoms in patients with early amyloid pathology.
  
  
  

Neuropsychiatric Features Elicitable on Mental State Exam

• Delusions and hallucinations: More common in middle-to-late stages.
• Agitation or aggression: Often triggered by unmet needs or misinterpretation of environment.
• Anosognosia: Many patients lack insight into their impairments, despite objective evidence of decline.
  
  
  

Findings in Atypical and Mixed Presentations

• Visual symptoms dominate: simultanagnosia, optic ataxia, dressing apraxia.
• Preservation of memory and language early; examination reveals visuospatial and visuoperceptual deficits.
  
  

• Fluent but hesitant speech, impaired repetition, intact grammar and comprehension early on.
• Naming and word retrieval are impaired; examination shows preserved memory initially.
  
  

• Prominent executive dysfunction: disinhibition, poor impulse control, impaired planning.
• Language and memory relatively spared early; mimics frontotemporal dementia.
  
  

• Asymmetric rigidity, apraxia, alien limb phenomenon.
• Examination shows cortical sensory loss, limb dystonia, myoclonus, and constructional apraxia.
  
  

• Visual hallucinations, parkinsonism, fluctuating cognition suggest Lewy body co-pathology.
• Stepwise decline, focal deficits, or early gait impairment suggest vascular component.
  
  

Clinical and Cognitive Evaluation

• Initial Clinical Suspicion: AD should be considered in older adults presenting with insidious and progressive decline in memory and/or other cognitive domains affecting daily life.
• History and Informant Input: A detailed history, including corroboration from a reliable informant, is essential. Assessment of functional decline and behavioural symptoms enhances diagnostic accuracy.
• Mental Status Testing:
  • Montreal Cognitive Assessment (MoCA) is preferred for detecting mild cognitive impairment due to its superior sensitivity for executive and language dysfunction.
  • Mini-Mental State Examination (MMSE) remains widely used but is less sensitive for early stages.
  • Other tools include the Saint Louis University Mental Status (SLUMS) exam and Mini-Cog, both of which are useful for screening.
• Neuropsychological Testing: Formal assessment under standardised conditions helps distinguish AD from other neurodegenerative or psychiatric causes. It is also useful for monitoring progression, assessing competency (e.g., for driving), and planning rehabilitation.
  
  

Laboratory Investigations to Exclude Reversible Causes

• Full blood count to rule out anaemia.
• Electrolytes and glucose to exclude metabolic encephalopathy (hypo-/hypernatraemia, hypo-/hyperglycaemia, hyper-/hypocalcaemia).
• Thyroid function (TSH) to detect hypo- or hyperthyroidism.
• Vitamin B12 levels to exclude deficiency-related cognitive dysfunction.
  
  

• Urine drug screen for recreational or iatrogenic substances that may impair cognition.
  
  

• Serum rapid plasma reagin (RPR) or VDRL for syphilis.
• HIV testing.
  
  
  

Neuroimaging

• Helps exclude mass lesions, subdural haematoma, and normal pressure hydrocephalus.
• AD-specific findings include medial temporal lobe and hippocampal atrophy.
• T2*-weighted sequences are needed to assess for cerebral microhaemorrhages in the context of amyloid therapies.

• Less sensitive than MRI but useful if MRI is contraindicated. May show global atrophy or exclude treatable lesions.
  
  

• Demonstrates hypometabolism in temporoparietal regions, hippocampus, and precuneus.
• Valuable in distinguishing AD from frontotemporal dementia or depression, especially in atypical cases.

• Shows bilateral temporoparietal hypoperfusion. Less commonly used due to lower availability.
  
  

• Generally not recommended for routine evaluation in AD.
• May assist in differentiating other conditions (e.g., Creutzfeldt–Jakob disease, seizure disorders).
  
  
  

Biomarkers

• Typical AD profile: ↓ Aβ42, ↑ total tau and ↑ phosphorylated tau (p-tau).
• May be useful in young-onset or atypical cases, or to support a diagnosis of prodromal AD.
  
  

• Approved tracers include florbetapir F-18, flutemetamol F-18, and florbetaben F-18.
• Positive results indicate amyloid pathology; negative scans significantly reduce likelihood of AD.
  
  

• Flortaucipir F-18 tracks tau pathology and correlates with disease severity.
• Approved for identifying neurofibrillary tangle burden, but not non-AD tauopathies.
  
  

• Plasma phospho-tau217 and phospho-tau181 correlate with CSF and PET findings.
• Blood β42/β40 ratio is less sensitive but may provide adjunctive diagnostic information.
• Not yet standard in clinical practice but show promise for non-invasive testing.
  
  

Genetic Testing

• Not routinely indicated in late-onset AD.
• APOE genotyping:
  • Adds limited diagnostic value, though presence of APOE ε4 allele increases risk.
  • Important in evaluating risk-benefit for amyloid-targeted therapy due to risk stratification.
• PSEN1, PSEN2, and APP mutations:
  • Should only be tested in early-onset familial cases with clear autosomal-dominant inheritance.
  • Requires pre- and post-test genetic counselling.
    
    
    

Diagnostic Criteria and Classification

• Progressive impairment in ≥2 cognitive domains.
• Functional decline interfering with independence.
• Insidious onset and gradual progression.
• Absence of other medical or psychiatric explanations.
• Subtypes include amnestic and non-amnestic (e.g., language, visuospatial, executive) variants.
  
  

• Atypical presentation or co-existing pathology.
  
  

• Now termed major neurocognitive disorder due to AD.
• Requires memory impairment and deficits in at least one other cognitive domain.

• Objective evidence of cognitive decline, preserved independence, absence of dementia.
• Biomarkers support diagnosis; high conversion rate to AD dementia.
  
  

• Biomarker-defined amyloid pathology in asymptomatic individuals.
• Categorised under the research-only ATN (amyloid, tau, neurodegeneration) framework.
  
  
  

Differential Diagnosis

• May coexist with AD. Suggestive features include stepwise decline and focal neurological signs.
  
  

• Hallucinations, parkinsonism, fluctuating cognition, and REM sleep behaviour disorder.
  
  

• Prominent early changes in behaviour, executive dysfunction, or primary progressive aphasia.
  
  

• Mimics AD with prominent memory loss, slower progression, and more severe hippocampal atrophy.

Neurodegenerative and Vascular Mimics

• Accounts for up to 15% of dementia cases.
• Core features: cognitive fluctuations, recurrent visual hallucinations, and parkinsonian features.
• Suggestive features: REM sleep behaviour disorder, severe sensitivity to antipsychotics.
• Indicative biomarkers:
  • Low dopamine transporter uptake in basal ganglia on SPECT/PET.
  • Abnormal polysomnography showing REM sleep without atonia.
  • Reduced cardiac MIBG uptake.
• Neuropathology: cortical Lewy bodies containing α-synuclein and ubiquitin.
• Diagnosis is probable if two core features are present, or one core and one suggestive feature.
  
  

• Second most common dementia subtype after AD.
• Clinical features:
  • Stepwise cognitive decline.
  • Focal neurological deficits.
  • Executive dysfunction, subcortical depression, and apathy.
• Risk factors: hypertension, diabetes, atrial fibrillation, hyperlipidaemia.
• Imaging:
  • MRI or CT reveals infarcts, white matter ischaemia, or perivascular changes.
• Often coexists with AD in elderly patients (mixed dementia).
  
  

• Accounts for 5–10% of dementias; younger age of onset (typically <65 years).
• Subtypes:
  • Behavioural variant: disinhibition, apathy, loss of empathy, compulsive behaviours, hyperorality.
  • Language variants: non-fluent/agrammatic aphasia, semantic dementia, logopenic variant (often AD pathology).
• Imaging: MRI or PET/SPECT shows frontal and/or temporal lobe atrophy or hypometabolism.
• Neuropathology: may involve tau, TDP-43, or FUS proteinopathies.
  
  

• Primarily affects individuals >75 years old.
• Features:
  • Progressive amnestic syndrome.
  • Relative preservation of executive and visuospatial abilities.
• Imaging: disproportionate medial temporal lobe atrophy.
• Often misdiagnosed as AD; more indolent course.
  
  
  

Other Dementia Syndromes and Mimics

• Dementia arising in established Parkinson’s disease.
• Features:
  • Visual hallucinations.
  • Bradykinesia, rigidity, postural instability precede cognitive symptoms.
• Imaging: non-specific; may show global atrophy.
  
  

• Rapidly progressive dementia over weeks to months.
• Neurological signs: myoclonus, paraesthesias, ataxia, and mutism.
• Investigations:
  • MRI: cortical ribboning, basal ganglia hyperintensities.
  • EEG: periodic sharp wave complexes.
  • CSF: 14-3-3 protein assay.
  • Tonsillar biopsy (variant CJD) under research.
    
    

• Rare consequence of long-term dialysis.
• Previously linked to aluminium toxicity.
• Mechanisms: multifactorial, including vascular and metabolic causes.
  
  

Reversible and Non-neurodegenerative Conditions

• Acute onset with fluctuating consciousness and inattention.
• Hallucinations (often visual), disorientation, worse at night.
• Assessment: Confusion Assessment Method (CAM).
• Triggers include infection, drugs, metabolic imbalance.
  
  

• Can mimic dementia, especially in elderly.
• Features:
  • Low mood, anhedonia, negative cognitions.
  • Memory complaints with preserved cognitive testing.
• Assessment tools: Geriatric Depression Scale, Cornell Scale for Depression in Dementia.
• Responsive to antidepressants or therapy.
  
  

• Chronic substance use may cause cognitive decline.
• Investigations: drug screening, liver function, thiamine levels.
  
  

• Vitamin B12 deficiency: reversible cause; may cause neuropsychiatric symptoms.
• Thyroid dysfunction: both hypo- and hyperthyroidism can impair cognition.
• Polypharmacy: medications with anticholinergic or sedative properties may contribute.
  
  

Atypical Presentations of Alzheimer’s Disease

• Progressive visuospatial dysfunction.
• Symptoms: simultanagnosia, dressing apraxia, alexia, visual agnosia.
• Imaging: occipitoparietal atrophy.
  
  

• Language dysfunction as presenting feature.
• Logopenic variant often associated with AD pathology.
  
  

• Impairment in planning, judgement, and working memory more prominent than amnesia.
• Often misattributed to FTD unless biomarkers support AD.
  
  

Individualised Care Planning

Education and Support

• Initial post-diagnosis care should focus on providing emotional support, information on disease progression, and practical guidance.
• Referral to community resources (e.g. Alzheimer’s Association, National Institute on Aging) is strongly encouraged.
• Support groups for both patients and carers may reduce stress, delay institutionalisation, and improve coping.
• Advanced care planning discussions, including directives and end-of-life preferences, should be initiated early while decision-making capacity is preserved.
  
  

Environmental and Functional Safety

• Home safety assessments by occupational therapists should evaluate for fall risks, wandering, and hazards.
• Driving capability must be reviewed regularly.
• Fall prevention is particularly important due to the association between AD and altered gait, medication side effects, and frailty.
  
  
  

Pharmacological Management of Cognitive Symptoms

• Agents: Donepezil (mild–severe), rivastigmine (oral and transdermal; mild–severe), galantamine (mild–moderate).
• Benefits: Modest cognitive and functional benefits; may delay institutionalisation.
• Dosing considerations:
  • Start low, titrate slowly.
  • Monitor for gastrointestinal and cholinergic side effects.
  • Transdermal rivastigmine is preferred in intolerant patients.
• Discontinuation: Should not be abrupt; no consensus on withdrawal timing.
  
  

• Memantine: Approved for moderate–severe AD; sometimes used off-label in mild cases.
• Use:
  • Alone if AChEIs are not tolerated or contraindicated.
  • In combination with AChEIs in advancing disease.
• Effectiveness: Modest improvement in function and behaviour, especially when combined with AChEIs.
  
  

Non-Pharmacological Cognitive and Functional Interventions

• Exercise (especially aerobic): Modest improvements in cognitive function and daily living activities.
• Cognitive stimulation and occupational therapy: May delay functional decline; low to moderate quality evidence.
• Reminiscence therapy and music therapy: Helpful for mood and carer interaction; not cognition-specific.
• Assistive devices: Calendars, clocks, memory boards, and location tracking can improve autonomy and safety.

Behavioural and Psychological Symptoms Management

• First-line approach for agitation, anxiety, psychosis, and depression.
• Strategies include:
  • Structured routine.
  • Carer education and counselling.
  • Environmental modifications to ensure safety.
  • Pain control, social engagement, and sleep hygiene (e.g., light therapy).
  • Activities with personal meaning (e.g., gardening, music).
    
    
    

• SSRIs (sertraline, citalopram, escitalopram) are first-line.
• Mirtazapine useful with insomnia or appetite loss.
• Avoid TCAs due to anticholinergic side effects.
  
  

• Citalopram has demonstrated efficacy but requires ECG monitoring due to QT prolongation risk.
• Carbamazepine and trazodone may offer benefit; trazodone has a favourable safety profile compared to antipsychotics.
  
  

• Antipsychotics (e.g., risperidone) are reserved for severe symptoms posing safety risks.
• Use at lowest effective dose with careful monitoring due to increased mortality and stroke risk.
• Regularly reassess need; discontinue if side effects occur or benefit ceases.
  
  

Therapies Lacking Strong Evidence or Not Recommended

• NSAIDs, aspirin, vitamin E, and Ginkgo biloba have not shown consistent cognitive benefits and may present safety concerns
• Validation therapy and other unproven behavioural techniques lack sufficient evidence for routine recommendation.
  
  

Late-Stage and Palliative Care

• Focus shifts to comfort, dignity, and quality of life.
• Feeding tubes, overly aggressive interventions, and hospitalisations should be avoided unless aligned with patient/family goals.
• Palliative care input and revisiting of goals-of-care discussions are essential as disease advances.
• Carer support, including psychological interventions and bereavement support, remains vital throughout.
  
  

Overall Disease Course

• Alzheimer’s disease is a chronic, progressive neurodegenerative disorder, marked initially by memory impairment, with gradual decline in other cognitive and functional capacities.
• The disease progresses through stages: from mild memory problems and disorientation to severe impairments in communication, mobility, and ultimately, basic self-care tasks such as dressing, toileting, and feeding.
  
  

Functional Decline

• In early stages, patients often retain some independence but require increasing support for:
  • Medication management
  • Financial and legal responsibilities
  • Transportation
  • Complex instrumental activities of daily living (IADLs)
• In moderate to severe stages, individuals typically:
  • Lose the ability to manage personal hygiene and daily routines
  • Display neuropsychiatric symptoms such as anxiety, agitation, depression, or paranoia
  • Become dependent on full-time carers or institutional care
• In end-stage disease, further deterioration leads to:
  • Profound motor impairment (including inability to walk)
  • Dysphagia, often resulting in aspiration pneumonia
  • Incontinence and complete dependence for all basic activities
    
    

Influencing Factors and Variability

• The rate of progression varies significantly between individuals:
  • Average survival after diagnosis in older adults is approximately 4 to 8 years, though some may live up to 20 years.
  • Early-onset AD is associated with more rapid progression and shorter survival compared to late-onset AD.
• Disease progression may include periods of relative stability (plateaus) interspersed with periods of rapid decline.
  
  
  

Mortality and Cause of Death

• AD is not directly fatal, but it substantially increases vulnerability to intercurrent illnesses.
• Common causes of death include:
  • Aspiration pneumonia due to dysphagia
  • Sepsis from urinary tract infections or pressure ulcers
  • Complications of immobility, such as venous thromboembolism
  • Malnutrition and dehydration in advanced stages
    
    

Impact of Treatment and Support

• Current pharmacological therapies (cholinesterase inhibitors and NMDA receptor antagonists) do not alter the ultimate disease trajectory, but may offer temporary stabilisation of symptoms or functional capacity in some individuals.
• Treatment discontinuation is appropriate when:
  • Adverse effects outweigh benefits
  • Compliance is poor
  • There is no observed clinical benefit
• Non-pharmacological interventions (e.g., structured activities, environmental modifications, carer education) can improve quality of life and reduce behavioural symptoms.
• Carer support and psychological counselling have demonstrated efficacy in delaying institutionalisation and reducing carer stress and depression.
  
  

Terminal and Palliative Considerations

• End-of-life discussions should be initiated early and revisited as the disease progresses.
• Feeding tubes are generally not recommended as they do not improve survival or quality of life, and may increase complications.
• Hospice and palliative care services should be integrated in advanced stages to focus on comfort, dignity, and support for both patient and family.
  
  

Mental and Behavioural Complications

• Commonly coexists with AD, especially in early to moderate stages.
• Manifestations include low mood, anhedonia, fatigue, poor concentration, insomnia, and social withdrawal.
• Depression exacerbates cognitive and functional decline and increases carer burden.
  
  

• Features such as restlessness, irritability, pacing, and aggression are frequently seen, particularly in moderate to severe stages.
• Delirium, often due to infections, medication changes, or dehydration, may present acutely with fluctuating attention and confusion.
• Sundowning—agitation or confusion worsening in the evening—is a notable behavioural pattern in later stages.
• Antipsychotic medications used to manage behavioural symptoms carry a risk of increased mortality and should be used with extreme caution.
  
  

• Can occur at any stage but is particularly concerning in moderate to severe disease.
• Patients may become lost even in familiar environments, posing risks of injury, exposure, or death.
  
  

• Advanced cognitive decline, dependence, and behavioural issues may increase vulnerability to physical, emotional, or financial abuse, especially in settings with overburdened or unsupported carers.
  
  

Physical Complications

• Dysphagia, particularly with liquids, is common in later stages and may result in aspiration.
• Recurrent lower respiratory tract infections are frequent and a leading cause of death in terminal AD.
  
  

• Incontinence, reduced mobility, and use of indwelling catheters increase UTI risk.
• UTIs may present with atypical features such as delirium rather than fever or dysuria.
• Untreated infections can lead to sepsis and multiorgan failure.

• Gait disturbances, postural instability, impaired judgement, and apraxia increase fall risk.
• Polypharmacy and hypotension further exacerbate this risk.
• Consequences include fractures (e.g., hip), head injuries, and secondary complications such as venous thromboembolism or pneumonia due to immobility.
  
  

• Poor oral intake due to dysphagia, apathy, or cognitive decline may lead to protein-energy malnutrition.
• Consequences include muscle wasting, pressure ulcers, compromised immunity, and increased dependency.
  
  

• In advanced AD, impaired thirst perception, swallowing difficulty, or dependence on others for fluid intake may contribute to dehydration, further predisposing to delirium, renal dysfunction, and hypotension.
  
  

• Incontinence becomes more common in advanced stages, leading to hygiene issues and increased carer strain.
• May also result in skin breakdown and pressure sores.
  
  

Institutionalisation and End-of-Life Challenges

• Loss of functional independence often necessitates long-term residential care.
• Institutionalisation is associated with complications such as:
  • Pressure ulcers
  • Muscle contractures
  • Increased rates of infections
• Psychosocial challenges include depression, isolation, and increased carer guilt or burnout.
• Ethical and legal issues surrounding end-of-life care decisions, particularly regarding feeding tubes or resuscitation, may arise and require proactive advance care planning.
  
  

Epidemiological Note

• As of 2023, Alzheimer’s disease is ranked as the sixth leading cause of death in the United States, with approximately 120,000 deaths annually, primarily due to associated complications such as pneumonia.
  
  

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