2 Neuroscience2.13 Neurodegeneration
2.13.2 Alzheimer's disease
5 min read3 figures
Written by Resident Doctor Committee · Published
Hallmark pathology
Alzheimer's disease is defined by extracellular beta-amyloid plaques together with intraneuronal neurofibrillary tangles of hyperphosphorylated tau. It combines amyloid with mixed-isoform tau, so it is not a pure tauopathy.
Lesion | Site | What it is |
|---|---|---|
Neurofibrillary tangle | Intraneuronal | Flame-shaped, insoluble aggregates of paired helical filaments of hyperphosphorylated tau |
Senile plaque | Extracellular | Deposit of beta-amyloid, also seen in normal ageing |
Neuritic plaque | Extracellular | Core of beta-pleated sheet amyloid with a corona of dystrophic neurites |
Tangles are shared across the tauopathies, including Pick's disease, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy, so they are not unique to Alzheimer's disease.
Tangle burden and neocortical spread track the severity of cognitive impairment more closely than amyloid, vascular or glial measures.
Other lesions
These lesions accompany plaques and tangles.
Lesion | Description | Where and how specific |
|---|---|---|
Granulovacuolar degeneration | Clear vacuoles in the neuronal cytoplasm, each holding a single dark granule | Hippocampal pyramidal cells; seen to a lesser degree in normal ageing |
Hirano bodies | Eosinophilic, rod-shaped, actin-rich intracytoplasmic inclusions | Hippocampal pyramidal neurones, densest in CA1; a non-specific marker of neurodegeneration |
Cerebral amyloid angiopathy | Amyloid in the walls of small cortical and leptomeningeal arteries | Accompanies most Alzheimer's disease; causes recurrent lobar haemorrhage in older adults |
Actin is the principal protein of Hirano bodies, which usually lack the ubiquitin carried by most degenerative inclusions.
Where degeneration starts and how it spreads
Pathology starts in the entorhinal cortex, the gateway to the hippocampus, and spreads in a fixed order before reaching the neocortex. Braak staging follows the spread of tangles.
Order | Regions | Clinical correlate |
|---|---|---|
Earliest | Transentorhinal and entorhinal cortex, then hippocampus | Impaired learning of new episodic memories |
Next | Temporal neocortex and temporoparietal association cortex | Naming, navigation, visuospatial and praxis difficulty |
Later | Wider association cortex | Executive and behavioural change |
Last | Primary sensory and motor cortex | Basic sensation and movement outlast complex abilities |
Macroscopic change and imaging
Gross atrophy is cortical and medial temporal, with narrow gyri, wide sulci and low brain weight; plaques and tangles are seen only under the microscope.
Ventricular dilatation is secondary and passive, most marked in the temporal horns.
Medial temporal lobe atrophy (hippocampal and entorhinal) is the earliest and characteristic structural change on imaging, and the entorhinal cortex shrinks before the hippocampus.
Single-photon emission computed tomography (SPECT) shows bilateral posterior temporal and parietal hypoperfusion, whereas frontal and anterior temporal hypoperfusion marks frontotemporal dementia.
Neurochemistry
Acetylcholine falls, while glutamatergic signalling becomes excessive as inhibition by gamma-aminobutyric acid (GABA) fails.
The nucleus basalis of Meynert is the principal cholinergic supply to the neocortex, and its degeneration causes the cortical cholinergic deficit.
Both choline acetyltransferase and acetylcholinesterase fall.
Cholinesterase inhibitors target the cholinergic deficit and memantine targets abnormal N-methyl-D-aspartate (NMDA) glutamate signalling; both treat symptoms only.
Biomarkers and mild cognitive impairment
In cerebrospinal fluid, amyloid-beta 42 falls and phosphorylated tau (p-tau) rises, so a raised p-tau to amyloid-beta 42 ratio predicts cognitive decline in mild cognitive impairment.
Amnestic mild cognitive impairment is an isolated episodic memory deficit with independence preserved. It is a prodrome of Alzheimer's disease, and about 10 to 15% of clinic patients convert each year.
Amyloid processing
Amyloid-beta is cut from amyloid precursor protein (APP) in two sequential steps.
Route | Enzymes, in order | Products |
|---|---|---|
Amyloidogenic | Beta-secretase, then gamma-secretase | Amyloid-beta |
Non-amyloidogenic | Alpha-secretase, then gamma-secretase | Soluble APP-alpha and C83, no amyloid-beta |
The gamma-secretase cut lies inside the membrane, releases the peptide and fixes its length; presenilins form the enzyme's catalytic component.
Alpha-secretase cuts within the amyloid-beta sequence, so no amyloid-beta can form.
SORL1 encodes a sorting receptor that keeps APP away from amyloidogenic processing; loss-of-function variants raise amyloid-beta and add risk in early- and late-onset disease.
Genetics
Gene | Chromosome | Role |
|---|---|---|
PSEN1 (presenilin-1) | 14 | Commonest single-gene cause of autosomal dominant early-onset familial disease |
PSEN2 (presenilin-2) | 1 | Autosomal dominant early-onset disease |
APP | 21 | Autosomal dominant early-onset disease; extra copy in Down syndrome |
APOE (apolipoprotein E) | 19 | Susceptibility gene for late-onset sporadic disease |
Familial Alzheimer's disease is rare and early in onset.
PSEN1 disease is close to fully penetrant: each child of an affected parent has a one in two chance of inheriting the variant, and disease is near certain by the family's age of onset.
In Down syndrome, trisomy 21 gives a third copy of the APP gene, so amyloid-beta is overproduced from early life.
APOE
Genotype | Risk of late-onset disease |
|---|---|
e3/e3 | Reference: e3 is the common, risk-neutral allele |
One e4 copy | About 3 times (2 to 4) |
Two e4 copies | About 10 to 15 times (reported 8 to 30) |
e2 carrier | Lower: e2 is protective |
APOE e4 raises risk by impairing apolipoprotein E-mediated clearance of amyloid-beta, not by increasing its production, and it tends to lower the age of onset.
Genetic testing
Testing is reserved for a suspected monogenic or syndromic picture: young onset with a dominant family history, young-onset frontotemporal dementia, or Down syndrome.
Typical late-onset disease does not warrant testing, and neither does APOE genotyping.
Amyloid cascade and immunotherapy
The amyloid cascade hypothesis proposes that amyloid build-up starts the chain leading to tau pathology, synaptic failure and cognitive decline.
Familial mutations and APP gene dose support it; the poor match between plaque burden and severity, and amyloid-positive people without symptoms, count against it.
Amyloid-beta is the target of the licensed passive immunotherapy antibodies, lecanemab and donanemab, which modestly slow decline in selected early disease.
Tau and neuroinflammatory targets remain experimental.
ARIA-E (amyloid-related imaging abnormality with oedema or effusion) is a common, dose-dependent class effect, more frequent in APOE e4 carriers and usually benign; ARIA-H is the haemorrhagic form.