Neurodegenerative diseases: shared biology, Parkinson and Alzheimer
Why some brain cells slowly die in Parkinson and Alzheimer disease, which proteins build up, and what current medicines can and cannot do.
Neurodegenerative diseases share a pattern: misfolded proteins accumulate, particular groups of neurons are especially vulnerable, and symptoms appear only after much of the population is lost. Most current drugs replace or boost the missing transmitter; few slow the disease itself.
Common features
The major neurodegenerative diseases are proteinopathies: specific proteins misfold and form aggregates inside or outside cells. Most cases are sporadic, with a smaller fraction caused by gene variants, and the same proteins appear in both. Each disease damages particular neuron groups first (selective vulnerability), which shapes its symptoms and the transmitter that current drugs try to restore: dopamine in Parkinson, acetylcholine in Alzheimer. Risk rises with age. Autophagy, which clears damaged proteins and organelles, appears protective. Disease-modifying research uses antibodies and antisense oligonucleotides against alpha-synuclein, tau, TDP-43 and huntingtin.
Parkinson disease: pathophysiology
Dopamine neurons of the substantia nigra pars compacta, which project to the striatum (caudate and putamen), degenerate. Surviving neurons contain Lewy bodies, whose main component is aggregated alpha-synuclein. In the basal ganglia model, dopamine excites the direct pathway through D1 receptors and inhibits the indirect pathway through D2 receptors; loss of dopamine reverses this balance and reduces thalamic drive to the motor cortex, producing slowness, rigidity and rest tremor. Loss of smell and REM sleep behaviour disorder may precede motor signs. About fifteen percent of people have a family history; genes include SNCA and LRRK2 (dominant) and PRKN, PINK1 and PARK7 (recessive), with GBA1 as a risk modifier.
Parkinson disease: drug strategy
- Levodopa with carbidopa or benserazide: replaces dopamine and is the mainstay of symptomatic treatment.
- Dopamine agonists and MAO-B inhibitors: alternatives early, or add-ons later.
- COMT inhibitors: prolong the effect of each levodopa dose.
- Amantadine: modest benefit; it alters dopamine release, has anticholinergic effects and blocks NMDA receptors.
- These drugs treat symptoms; they replace the missing transmitter rather than stopping neuron loss.
Alzheimer disease: pathophysiology and genetics
The medial temporal lobe (entorhinal cortex and hippocampus) is affected first. Amyloid-beta, cut from the amyloid precursor protein by beta- and gamma-secretase (whose catalytic core is presenilin), forms extracellular plaques; soluble small aggregates may be the most toxic form. Tau forms intracellular neurofibrillary tangles. Cholinergic neurons of the basal forebrain degenerate, together with glutamate and other systems. Early-onset familial Alzheimer, inherited in an autosomal dominant way, comes from APP, PSEN1 or PSEN2 variants and is less than one in ten cases. For late-onset disease, the APOE e4 allele raises risk, more with two copies than one, but does not guarantee disease.
Alzheimer disease: drug strategy
- Cholinesterase inhibitors (donepezil, rivastigmine, galantamine): boost acetylcholine for symptomatic benefit.
- Memantine: an NMDA glutamate receptor antagonist, used for symptoms.
- Anti-amyloid antibodies (lecanemab, donanemab): lower amyloid plaque in people with mild cognitive impairment or mild dementia and confirmed amyloid. Their boxed warning concerns amyloid-related imaging abnormalities (usually temporary brain swelling, sometimes bleeding); APOE e4 homozygotes have the highest rate, so genotype is tested first, and anticoagulants add bleeding risk.
Test yourself
Think of the answer, then tap the question to see it.
Which protein is the main component of Lewy bodies?
Aggregated alpha-synuclein.
How does dopamine loss alter the basal ganglia in Parkinson disease?
The D1 direct pathway is less active and the D2 indirect pathway more active, so thalamic drive to the motor cortex falls.
Which enzyme complex contains presenilin, and why does that matter in Alzheimer disease?
Gamma-secretase; with beta-secretase it cuts APP to make amyloid-beta, so PSEN1 and PSEN2 variants can cause familial Alzheimer.
Does carrying APOE e4 mean a person will develop Alzheimer disease?
No. It raises risk, more with two copies, but many carriers never develop the disease.
Example drugs
Connections
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Parkinson's disease: MedlinePlus Genetics (MedlinePlus (U.S. National Library of Medicine), 2026); Alzheimer's disease: MedlinePlus Genetics (MedlinePlus (U.S. National Library of Medicine), 2026); FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval (U.S. Food and Drug Administration, 2026).
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Representative model, for educational purposes only.