Alzheimer Disease

Slide 1 · Alzheimer Disease

Pathogenesis • Morphology • Clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain amyloid-β and tau accumulation in Alzheimer disease

Interpret the genetic evidence implicating APP processing

Recognize the defining gross and microscopic lesions

Connect neuropathology to cognitive impairment and biomarkers

Clinical focus

Link the lesion, vulnerable brain region, and resulting functional deficit.

Slide 3 · Alzheimer disease: Defining context

A progressive neurodegenerative disorder and the leading cause of dementia in older adults

Core presentation

Insidious deterioration of higher cognitive functions, typically beginning with memory disturbance.

Core pathology

Neuritic amyloid plaques, tau-containing tangles, neuronal loss and gliosis.

Slide 4 · Age is the dominant epidemiologic determinant

Symptoms are uncommon before age 50

Incidence rises markedly with advancing age

Increasing longevity magnifies population-level disease burden

Interpretation

Risk increases with age, but dementia is not an inevitable consequence of normal aging.

Slide 5 · Sporadic and familial disease

Sporadic presentation

Most Alzheimer disease is not explained by a recognized single-gene pathogenic variant; Age and susceptibility factors matter.

Familial presentation

A minority of cases occur in families; Inherited variants have illuminated APP cleavage, Aβ42 generation and aggregation.

Slide 6 · From protein pathology to cognitive dysfunction

Protein changes

Aβ and altered tau accumulate

Circuit disruption

Synapses and neurons become dysfunctional

Tissue injury

Neuronal loss and reactive gliosis

Clinical syndrome

Progressive cognitive decline

A disease model: The precise causal interplay between amyloid and tau remains incompletely resolved.

Slide 7 · Two defining protein lesions

Neuritic plaques

Extracellular aggregates of amyloid-β in neuropil, often surrounded by dystrophic neuronal processes.

Neurofibrillary tangles

Abnormal intracellular tau filaments; Residual extracellular tangles persist after neuronal loss.

Slide 8 · Neurodegeneration is not just aggregation

Loss of neurons is a major component of advanced disease

Synaptic dysfunction contributes to impaired cognition

Reactive glial responses accompany vulnerable regions

Lesions are regionally selective rather than uniform

Read pathology functionally

Connect the cellular lesion with network failure and regional vulnerability.

Slide 9 · An amyloid-initiated working model

APP processing

Generation of aggregation-prone Aβ

Aβ species

Small toxic oligomers and deposits

Tau alterations

Redistribution, phosphorylation, aggregation

Neurodegeneration

Loss of synapses, neurons and function

This is a model supported by genetics and therapy, not a fully settled sequence for every patient.

Slide 10 · Why amyloid generation is placed upstream

Familial AD genes change APP biology or presenilin function

Variants reducing Aβ generation can protect against disease

Tau-only neurodegenerative disorders do not reproduce the full AD process

Anti-amyloid treatment can modestly slow early cognitive decline

Evidence hierarchy

Convergent genetic and therapeutic data support Aβ as a major initiating driver.

Slide 11 · Tau pathology alone does not define AD

Tau-only disorders

Several neurodegenerative diseases show abundant tau aggregates without the characteristic amyloid deposition of AD.

Alzheimer disease

The characteristic pathologic combination is Aβ deposition plus tau aggregation in a vulnerable distribution.

Slide 12 · Amyloid precursor protein topology

EXTRACELLULAR

Plasma membrane

APP

N-terminus

C-terminus

INTRACELLULAR

Single-pass membrane protein; The Aβ region spans the extracellular segment and membrane.

Slide 13 · APP has two processing routes

Nonamyloidogenic pathway

α-secretase cleavage prevents formation of the intact Aβ peptide; γ-secretase processes the remnant.

Amyloidogenic pathway

β-secretase cleavage followed by γ-secretase produces amyloid-β peptides, including aggregation-prone Aβ42.

Slide 14 · Nonamyloidogenic processing

Surface APP

Transmembrane precursor

α-secretase

Cleavage within Aβ sequence

γ-secretase

Intramembranous processing

Outcome

No intact Aβ peptide generated

α-secretase cleavage is predominantly associated with the cell surface.

Slide 15 · Amyloidogenic processing

APP endocytosis

Surface protein internalized

β-secretase

Initial cut at amyloidogenic site

γ-secretase

Second cut within membrane

Aβ release

Aβ42 is aggregation-prone

Endosomal processing is important; Accumulation reflects generation as well as clearance.

Slide 16 · Secretase cleavage is biologically consequential

Component

Principal role

Significance

α-secretase

Nonamyloidogenic first cleavage

Precludes intact Aβ generation

β-secretase

Amyloidogenic first cleavage

Permits Aβ peptide formation

γ-secretase complex

Intramembranous cleavage

Contains presenilin and processes several substrates

Slide 17 · The γ-secretase complex

Presenilin-1 or presenilin-2 is part of the catalytic complex

Other components include nicastrin, PEN2 and APH1

Processes APP and additional membrane proteins, including Notch

Mechanistic implication

Secretase-targeting interventions can affect substrates other than APP.

Slide 18 · Aβ42: An aggregation-prone peptide

Soluble Aβ42

Released after APP processing

Oligomers

Small aggregates; Likely important for dysfunction

Fibrils

Larger insoluble assemblies

Plaques

Microscopically visible deposits

Aggregation state matters: Plaque visibility is not equivalent to direct toxicity

Slide 19 · Oligomers and plaques are not interchangeable

Small Aβ oligomers

Appear especially important for neuronal and synaptic dysfunction; May precede overt plaque accumulation.

Large Aβ deposits

Aggregates and fibrils form microscopically identifiable extracellular plaques, a defining morphologic lesion.

Slide 20 · Where could Aβ aggregates originate?

APP reaches intracellular vesicular compartments after endocytosis

Some Aβ may aggregate in abnormally alkalinized lysosomes

Release into extracellular tissue can follow neuronal death

Degree of certainty

Lysosomal aggregation is presented as a developing observation, not the only established origin of plaques.

Slide 21 · Excess generation versus impaired removal

Net Aβ burden depends on production and clearance

Production

APP processing determines the amount and molecular species of Aβ released.

Removal

Defective degradation and clearance pathways can increase the tissue burden of aggregated peptide.

Slide 22 · Familial Alzheimer disease: Key genes

Gene / locus

Mechanistic connection

Pathologic meaning

PSEN1 · chr 14

Presenilin-1 in γ-secretase

Altered amyloidogenic processing

PSEN2 · chr 1

Presenilin-2 in γ-secretase

Altered Aβ generation

APP · chr 21

Substrate for secretase cleavage

Altered generation or aggregation of Aβ

Slide 23 · PSEN1 and PSEN2 pathogenic variants

Encode presenilin components of γ-secretase

Pathogenic variants can change γ-secretase processing outcomes

Increased production of Aβ, especially Aβ42

Provide causal evidence connecting APP cleavage to familial AD

Teaching distinction

Inherited pathogenic variants differ from common APOE susceptibility alleles.

Slide 24 · Pathogenic APP variants

Cleavage-site variants

Some substitutions occur near β- or γ-secretase sites and modify the generation of amyloid-β peptides.

Aβ-sequence variants

Other substitutions occur within the peptide sequence and increase its intrinsic propensity to aggregate.

Slide 25 · Chromosome 21 gene dosage and AD

Extra APP copies

Trisomy 21 or duplication including APP

Increased substrate

More APP available for processing

Amyloid pathology

Earlier Alzheimer-type deposits

Clinical impact

Age-dependent cognitive deterioration

Chromosome 21 dosage implicates APP abundance in amyloid pathology.

Slide 26 · Protective APP A673T variant

Reduced Aβ generation can confer protection

Molecular observation

The APP A673T variant decreases generation of amyloid-β.

Population phenotype

Carriers have lower amyloid burden and reduced likelihood of age-associated cognitive decline.

Slide 27 · Genetic proof and genetic susceptibility

Causal Mendelian variants

Rare familial variants in APP, PSEN1 and PSEN2 directly alter the disease-driving amyloid pathway.

Susceptibility alleles

APOE genotype modifies probability and age of onset; It is not sufficient to diagnose AD.

Slide 28 · APOE alleles: ε2, ε3 and ε4

The APOE gene maps to chromosome 19

Common variants encode ε2, ε3 and ε4 isoforms

Greater ε4 allele dosage increases susceptibility to AD

ε4 is associated with an earlier typical age of onset

Critical distinction

Risk alleles alter probability; An APOE ε4 carrier is not necessarily affected.

Slide 29 · How APOE ε4 may promote pathology

Amyloid biology

May augment Aβ generation and deposition.

Tau-mediated injury

May enhance tau-related neurodegeneration through Aβ-dependent and other mechanisms.

Brain resilience

May impair lysosomal handling and astrocytic maintenance of synapses.

Slide 30 · APOE ε4 and neuronal networks

APOE ε4 effects

Altered glial and neuronal biology

GABAergic vulnerability

Reported selective harm to inhibitory neurons

Network imbalance

Early neuronal hyperexcitability

The source frames GABAergic toxicity and hyperexcitability as emerging mechanistic findings.

Slide 31 · Inflammation has opposing roles

Potentially protective

Microglial and astrocytic responses may facilitate clearance of misfolded or aggregated Aβ.

Potentially damaging

Activated glia may release injurious mediators, amplify oxidative stress, and alter synaptic connections.

Slide 32 · Microglial activation around amyloid

Aβ aggregates

Deposits and oligomers are sensed

Microglia

Local activation and response

Clearance + mediators

Phagocytic activity and inflammatory signaling

Tissue outcome

Possible clearance and collateral injury

Inflammation is not a single uniformly protective or harmful pathway.

Slide 33 · Astrocytes: Support and injury

Astrocytes react in brain regions burdened by deposits

Normal astrocyte-dependent synapse maintenance may be impaired

Inflammatory signaling can interact with tau pathology

Glial changes influence both clearance and neural resilience

Clinicopathologic link

Synaptic maintenance deficits help explain dysfunction beyond visible plaque counts.

Slide 34 · Inflammation, oxidative damage, synapse loss

Aβ accumulation

Peptide aggregates develop

Glial activation

Microglia and astrocytes respond

Inflammatory effects

Oxidative stress; Abnormal synapse pruning

Network dysfunction

Synaptic signaling becomes impaired

The cascade is a plausible contributory mechanism; Causality and magnitude remain unresolved.

Slide 35 · Tau in the healthy neuron

Tau associates with microtubules in axons

Microtubules provide essential internal structural support

Tau–microtubule binding is altered by phosphorylation

Normal tau distribution is predominantly axonal

Functional meaning

Dysfunctional tau can affect axonal support as well as aggregate within neurons.

Slide 36 · Tau redistribution and aggregation

Normal tau

Axonal microtubule binding

Altered tau

Hyperphosphorylation and mislocalization

Aggregation

Somatodendritic filaments and tangles

Both microtubule destabilization and aggregate-induced stress are proposed injury mechanisms

Slide 37 · Hyperphosphorylated tau

Tau loses normal microtubule-binding capacity

Abnormal tau shifts toward somatodendritic compartments

Insoluble filaments accumulate as neurofibrillary tangles

Tangles can remain visible after the parent neuron dies

Morphologic consequence

The lesion outlasts the neuron that originally produced it.

Slide 38 · What makes aggregated tau injurious?

Aggregate-associated stress

Accumulation of abnormal tau filaments may provoke cellular stress responses.

Loss of normal function

Reduced microtubule stabilization may compromise neuronal structure and function.

Slide 39 · The amyloid–tau relationship remains incomplete

Aβ oligomers may promote abnormal tau phosphorylation

The molecular steps connecting Aβ to tau are not fully established

Later tangle accumulation may become less dependent on ongoing Aβ burden

Both processes are implicated in neuronal dysfunction

Do not overstate

Correlation and experimental mechanistic support do not establish one universal linear pathway.

Slide 40 · MAPT mutations are an important differential clue

MAPT pathogenic variants

Cause selected frontotemporal lobar degenerations with tau pathology.

Alzheimer disease

Defined by a combined amyloid-β and tau pathologic phenotype; MAPT variants are not a recognized canonical cause.

Slide 41 · Gross morphology: Cortical atrophy

Less atrophic cortex

Advanced cortical atrophy

Schematic: Thinner cortical gyri, wider sulci, and enlarged ventricular spaces with tissue loss

Slide 42 · Anatomic distribution of neurodegeneration

Early vulnerable

Entorhinal cortex, hippocampus, medial temporal network

Wider involvement

Association neocortex; Frontal, temporal and parietal lobes

Relative sparing

Primary motor and sensory cortices until later phases

Slide 43 · Medial temporal vulnerability

Entorhinal cortex and hippocampus are involved early

Amygdala and related medial temporal structures become affected

These structures are typically severely atrophic in later disease

The regional pattern helps explain the prominence of early memory deficits

Anatomy to symptom

Medial temporal circuit disruption maps to impaired memory formation and retrieval.

Slide 44 · Hydrocephalus ex vacuo is volume loss

Primary event

Neuronal and cortical tissue are progressively lost, producing narrowed gyri and widened sulci.

Secondary appearance

Ventricles enlarge to occupy space lost from surrounding parenchyma; This is not primary CSF outflow obstruction.

Slide 45 · Microscopic disease is not only plaques

Neuritic plaques

Focal neuropil deposits containing amyloid and damaged axodendritic processes.

Neurofibrillary tangles

Intraneuronal abnormal tau aggregates; Ghosts persist extracellularly.

Neuronal loss / gliosis

Progressive tissue injury with reactive glial cells in affected brain regions.

Slide 46 · Neuritic plaque: Essential architecture

Aβ-rich core

Dystrophic neuritic processes

Resident microglia and reactive astrocytes at the periphery

Schematic representation of a neuritic plaque — not a photomicrograph

Slide 47 · The neuritic plaque core

Central amyloid-rich core surrounded by abnormal neurites

Aβ is the dominant amyloid component

Other associated proteins may include complement and apolipoproteins

Microglia and reactive astrocytes may lie at the periphery

Staining principle

Aβ immunostaining or Congo red can identify amyloid in a plaque core.

Slide 48 · Diffuse plaques differ from neuritic plaques

Diffuse amyloid plaques

Aβ deposition without a prominent collar of dystrophic neurites; Can involve superficial cortex, basal ganglia and cerebellum.

Neuritic plaques

Aβ-rich core with adjacent damaged neuritic profiles; One of the classic pathologic hallmarks of AD.

Slide 49 · Recognizing plaques in tissue

Method

What it highlights

Interpretive point

H&E

Some plaque-associated neuropil abnormalities

Not optimally sensitive for amyloid typing

Congo red

Amyloid-containing core

Demonstrates amyloid chemistry

Aβ immunohistochemistry

Amyloid-β peptide deposits

Connects visible deposit to Aβ biology

Slide 50 · Neurofibrillary tangles: Cellular morphology

Tau-containing intracellular filaments

Nucleus displaced or encircled by tangle

Schematic neuron; Not histologic evidence

Slide 51 · Tangle shape depends on neuronal form

Flame-shaped tangles

In pyramidal neurons, filament bundles often form an elongated profile.

Globose tangles

Rounder neuronal profiles can show filaments distributed around the nucleus.

Slide 52 · Tangles in H&E, silver and tau stains

Technique

Typical appearance

Purpose

H&E

Basophilic fibrillar neuronal structures

Initial morphology

Bielschowsky silver

Strong highlighting of neuronal fibrils

Increased morphologic conspicuity

Tau immunohistochemistry

Tau-positive tangles, neurites and threads

Protein identity / distribution

Slide 53 · Neuropil threads extend tau pathology

Aggregated tau is not restricted to neuronal perikarya

Tau-positive filaments also occur in affected axons

Dystrophic neurites in neuritic plaques can contain tau

Neuropil thread burden reflects widespread neuritic pathology

Morphologic synthesis

Amyloid plaques and tau pathology can coexist within the same microscopic region.

Slide 54 · Ghost tangles persist after neuronal loss

Tau aggregates

Intraneuronal tangle formed

Neuron dies

Cellular structure is lost

Residual material

Insoluble extracellular tangle remains

Ghost or tombstone tangles are tissue footprints of neuronal death.

Slide 55 · Tangles are not specific for AD

Several primary tauopathies show neurofibrillary pathology

Abundant tangles alone cannot define Alzheimer disease

Lesion combination and distribution inform attribution

Correlate microscopy with the broader disease context

Diagnostic caution

Tau immunoreactivity is a protein-identification test, not an AD-specific test.

Slide 56 · Cerebral amyloid angiopathy

Vessel lumen

Aβ deposits in vessel wall

Predominantly Aβ40 rather than plaque-enriched Aβ42

Schematic cerebral amyloid angiopathy; Not a photomicrograph

Slide 57 · Plaque Aβ42 versus vascular Aβ40

Parenchymal plaque deposits

Neuritic and diffuse plaques are relatively enriched in amyloid-β42.

Vascular amyloid deposition

Cerebral amyloid angiopathy predominantly contains amyloid-β40.

Slide 58 · Amyloid angiopathy is not unique to AD

Cerebral amyloid angiopathy commonly accompanies AD

CAA also occurs in people without Alzheimer dementia

Tissue location and peptide composition differ from plaque amyloid

Interpretation

Vascular amyloid is a related but non-specific pathologic finding.

Slide 59 · Tangle burden and dementia severity

Tau tangle burden

The number of tangles generally correlates more closely with the severity of dementia.

Plaque burden

Large plaque loads are strongly associated with AD, but plaque number alone is less tightly linked with cognitive severity.

Slide 60 · Additional correlates of cognitive dysfunction

Choline acetyltransferase loss

Biochemical evidence of impaired cholinergic neuronal function.

Synaptophysin reduction

Reduced immunoreactivity reflects a loss of synaptic markers.

Combined lesion burden

Severe cognitive impairment is associated with extensive plaques and tangles.

Slide 61 · The clinical course is progressive

Initial phase

Forgetfulness and memory disturbance predominate; Subtle higher-cognitive deficits may be present.

Established disease

Language, mathematical abilities and learned motor skills progressively deteriorate.

Advanced disease

Incontinence, mutism and loss of independent ambulation can develop.

Slide 62 · Early manifestations reflect memory networks

Insidious impairment is typical rather than abrupt onset

Memory disturbance is often the first major manifestation

Medial temporal neuronal loss is anatomically relevant

Progressive change over time distinguishes disease from a static deficit

Clinical inference

A typical phenotype is consistent with AD but is not by itself pathognomonic.

Slide 63 · Multidomain cognitive decline develops

Language

Progressive difficulty with linguistic functions.

Calculation

Impairment of mathematical skills.

Praxis

Loss of previously learned motor skills.

Slide 64 · End-stage disease and complications

Profound loss of independence may occur

Individuals may become mute or unable to walk

Incontinence develops in advanced disease

Intercurrent illness—often pneumonia—commonly precipitates death

Clinical severity

Late-stage dependence reflects extensive network and neuronal injury.

Slide 65 · Diagnosis is multimodal

Clinical assessment

Progressive characteristic cognitive syndrome

Neuroimaging

Supportive patterns and other causes

Biomarkers

Evidence of amyloid-related pathobiology

Neuropathology

Definitive lesion assessment in tissue

Neuropathologic examination as the definitive diagnostic reference.

Slide 66 · Amyloid PET demonstrates cerebral deposits

18F-labeled amyloid-binding compounds visualize brain Aβ deposits

Positive imaging can precede clinical dementia

Amyloid positivity indicates pathology, not a complete measurement of impairment

Interpret alongside the clinical phenotype and other evidence

Use of biomarkers

Biologic evidence and clinical functional severity are distinct concepts.

Slide 67 · Plasma Aβ42:Aβ40 ratio

A reduced plasma Aβ42:Aβ40 ratio supports amyloid-related pathobiology

What is measured

Relative concentrations of amyloid-β peptide species in blood.

What it cannot replace

Clinical evaluation, differential diagnosis, or contextual biomarker interpretation.

Slide 68 · Biomarkers and the preclinical interval

Protein pathology

Aβ accumulates before symptoms

Biologic detection

Amyloid-sensitive imaging or blood assays

Clinical transition

Cognitive changes become apparent

Progressive disease

Broader functional decline

Biologic abnormalities may be identifiable before a patient meets clinical criteria for dementia.

Slide 69 · Clinical and pathologic states are not synonymous

Finding

Can indicate

Does not establish alone

Amyloid PET positivity

Brain amyloid deposition

Current symptomatic dementia

Low plasma Aβ42:Aβ40

Altered amyloid biology

Full phenotype or severity

Tau-containing tangle

Tau pathology

Alzheimer-specific diagnosis

Insidious memory decline

Compatible clinical syndrome

Unique molecular etiology

Slide 70 · Alzheimer disease versus FTLD

Feature

Alzheimer disease

Frontotemporal lobar degeneration

Early emphasis

Memory dysfunction

Behavior / personality or language

Protein profile

Aβ + tau hallmark lesions

Often tau or TDP-43 proteinopathy

Typical anatomy

Medial temporal and association cortex

Predominantly frontal / temporal lobes

Slide 71 · Why plaque–tangle recognition matters

The integrated diagnosis is anatomical, molecular and clinical

Pathology

Which protein? Which cellular compartment? Which regional distribution?

Patient

Which cognitive deficits? How progressive? How much functional impairment?

Slide 72 · Therapeutic strategies arise from mechanisms

Anti-amyloid strategies

Immunologic removal of Aβ aggregates; Modest slowing of decline reported in early disease.

Secretase-directed approaches

Investigational modulation of APP processing and Aβ production.

Tau-directed approaches

Investigational approaches to prevent or modify abnormal tau changes.

Slide 73 · Aβ-directed treatment: Benefit and limits

Reduced amyloid burden under antibody therapy

Cognitive decline can be slowed in selected early AD populations

The observed benefit is described as modest

Amyloid clearance alone does not equate to reversal of established neuronal loss

Therapeutic reasoning

Intervention is most plausible before extensive irreversible circuit injury.

Slide 74 · Integrating protein, compartment and lesion

Protein species

Principal compartment

Characteristic lesion

Aβ42

Extracellular neuropil

Neuritic or diffuse amyloid plaque

Abnormal tau

Intraneuronal then residual extracellular

Neurofibrillary or ghost tangle

Aβ40

Vascular wall

Cerebral amyloid angiopathy

Slide 75 · Case: A progressive amnestic syndrome

Older adult with years of progressive forgetfulness

Subsequent language and calculation difficulties

Imaging reports cortical volume loss

Question: Which two pathologic protein lesions would be expected?

Pause for discussion

Predict the cellular localization of each hallmark lesion before revealing the answer.

Slide 76 · Case explanation: Connect clinical and pathology

Predicted amyloid lesion

Extracellular neuritic plaques containing aggregated Aβ peptides and dystrophic neurites.

Predicted tau lesion

Intraneuronal neurofibrillary tangles, followed by residual extracellular ghost tangles.

Slide 77 · Five mechanistic conclusions

APP cleavage and impaired clearance determine Aβ burden

Genetic findings strongly support an initiating role for amyloid

Abnormal tau disrupts microtubule biology and forms tangles

Inflammation and synaptic injury contribute to degeneration

Clinical dysfunction reflects regional loss of viable networks

Conceptual discipline

The mechanistic connections are supported but not exhaustively resolved.

Slide 78 · Five diagnostic conclusions

Cortical atrophy and ex-vacuo ventricular expansion are gross manifestations

Neuritic plaques and tau tangles are the microscopic hallmarks

CAA is common but not specific and is enriched for Aβ40

Tangle burden generally tracks cognitive severity better than plaque count

Biomarkers can detect amyloid biology before dementia develops

Slide-to-practice principle

Never equate a single morphologic, imaging or blood result with the complete diagnosis.

Slide 79 · Reference and recommended source figures

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026)

Chapter 28, The Central Nervous System, pp. 1161–1165

Figure 28.36: APP cleavage and amyloid processing

Figures 28.37–28.38: gross atrophy and microscopic lesions

Morphology reading

Review authentic gross and histologic photographs in the original textbook alongside these native schematics.