Neuroscience · Unit 7: Evidence and disease

When Mature Neurons Fail: Neurodegeneration

Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis each destroy a particular set of adult neurons, each leaves a particular protein clumped in the tissue, and each has genes that cause it in families and genes that only raise risk. This lesson compares the three on those points, tests the amyloid hypothesis against the antibody trials, and asks why some neurons fail while their neighbours survive. Afterwards you can read a trial result as absolute and relative slowing, and keep a biomarker change apart from a clinical benefit.

Watch first Slower Worsening Is Still Worsening · 2:36

In the Clarity AD trial, people with early Alzheimer disease who received lecanemab for 18 months worsened by 1.21 points on a dementia rating scale. People on placebo worsened by 1.66. That gap is some of the strongest evidence that removing amyloid changes the disease. It is also evidence that the drug did not stop it.

To read that result you need to know which neurons die, what clumps in them, and which genes cause disease or only raise risk. This lesson compares three diseases: Alzheimer disease (AD), Parkinson disease (PD) and amyotrophic lateral sclerosis (ALS). Then it tests the amyloid hypothesis against the trials and asks why some neurons fail while their neighbours survive. How a committed neuron dies is in death machinery in neurons, and the cell’s protein disposal systems are in quality control and autophagy.

Three diseases, three neuron populations

A neurodegenerative disease is a progressive loss of particular neurons in the adult nervous system. The important word is particular. Selective vulnerability means that the pathology strikes some neuronal populations and spares others, often close neighbours (reviewed by Fu, Hardy and Duff, 2018).

In Alzheimer disease, neurons lost early include the pyramidal neurons of layer II of the entorhinal cortex, the main gateway between neocortex and hippocampus, and pyramidal neurons of hippocampal field CA1. Both belong to the circuit for new declarative memories (memory systems).

In Parkinson disease, the defining loss is of dopamine neurons in the substantia nigra pars compacta (SNpc), the midbrain nucleus whose axons supply the striatum. Their loss unbalances the loops described in the basal ganglia. Even “dopamine neurons” is too broad. Kamath and colleagues (2022) sequenced RNA from single nuclei of postmortem human substantia nigra, sorted the dopamine neurons into ten populations, and mapped them within the substantia nigra with Slide-seq in macaque midbrain, with human tissue used to confirm the locations. One population, marked by expression of the gene AGTR1, was highly susceptible to loss in PD.

In ALS, the targets are motor neurons. Upper motor neurons have their cell bodies in motor cortex and send axons down the corticospinal tract to the spinal cord and the corticobulbar projection to brainstem motor nuclei. Lower motor neurons sit in the brainstem and the ventral horn of the spinal cord and send axons to muscle. Both the cell bodies and their axons degenerate. As lower motor neurons die, whole motor units (one motor neuron and all the muscle fibres it supplies; see motor units and reflexes) drop out.

Proteins that clump

Each disease has a protein that misfolds and gathers into insoluble deposits seen at autopsy.

  • AD has two. Amyloid plaques lie outside cells and contain amyloid-β (Aβ), peptides cut from amyloid precursor protein (APP) by β-secretase and then γ-secretase. Neurofibrillary tangles lie inside neurons and contain misfolded, hyperphosphorylated tau, a protein that normally binds microtubules.
  • PD has Lewy bodies and Lewy neurites, inclusions in neuronal cell bodies and processes. In 1998 Spillantini, Goedert and colleagues extracted Lewy body filaments from postmortem brain, labelled them with anti-α-synuclein antibodies under the electron microscope, and found α-synuclein to be the major filament component.
  • ALS in most cases has inclusions of TDP-43, an RNA-binding protein that leaves the nucleus and gathers in the cytoplasm. Neumann and colleagues identified it in 2006. There are exceptions: in a 2007 postmortem series, Mackenzie and colleagues found that ALS cases with SOD1 mutations lacked TDP-43 inclusions. In FUS-linked familial ALS, mutant FUS accumulates in neuronal cytoplasm.

A deposit tells you what a lesion is made of. It does not tell you the deposit kills the cell. Small soluble aggregates, loss of the protein’s normal job, or the cell’s response could do the damage. The idea that misfolded seeds pass from cell to cell and template more misfolding (“prion-like spread”) is a hypothesis, tested mostly in animal and cell models. It concerns spread within one nervous system, not catching the disease from another person.

Genes that cause and genes that raise risk

Genetics separates two kinds of evidence (see pedigrees and complex traits and GWAS). A Mendelian variant causes disease in most or all of those who carry it, though penetrance can be incomplete (for LRRK2 G2019S, one consortium estimate was 74% by age 79), and it segregates with disease through a family. A risk allele shifts the odds and is neither necessary nor sufficient.

DiseaseMendelian genes (examples)What the families showed
ADAPP, PSEN1, PSEN2 (dominant)APP variant cosegregating in a family (Goate and colleagues, 1991)
PDSNCA, LRRK2 (dominant); parkin (recessive, juvenile)SNCA in Italian and Greek-origin kindreds (1997); parkin deletions in Japanese juvenile parkinsonism (1998)
ALSSOD1, TARDBP, FUS; C9ORF72 repeat11 SOD1 missense mutations in 13 families (Rosen and colleagues, 1993); a GGGGCC repeat expansion in C9ORF72 (2011)

APOE ε4 is the best-known risk allele: it raises the risk of late-onset AD, yet even in old age it is not sufficient to produce clinical disease. The C9ORF72 change is an expanded stretch of noncoding DNA in an intron, not a change in a protein’s sequence. Percentages need denominators: the often-quoted 46.0% for C9ORF72 refers to familial ALS in a Finnish study population.

The AD row has a pattern. Presenilin, the product of PSEN1 and PSEN2, is the catalytic core of γ-secretase, so all three dominant AD genes act on making Aβ. In 1992 Hardy and Higgins turned that into the amyloid cascade hypothesis: Aβ accumulation starts a process that leads to tangles, neuron loss and dementia. Mendelian genetics supports an initiating role for Aβ in familial disease. It does not show that Aβ alone explains the common late-onset form.

Testing amyloid in trials

If Aβ starts the disease, removing it should change the course. Antibodies against Aβ have now tested that.

Worked problem: what does “27% slowing” mean? Clarity AD (van Dyck and colleagues, 2023) randomized 1,795 people with mild cognitive impairment or mild dementia due to AD, with amyloid confirmed, to lecanemab or placebo for 18 months. The primary outcome was the change in CDR-SB (Clinical Dementia Rating, Sum of Boxes), a clinician’s rating of cognition and daily function that runs from 0 to 18, higher meaning worse. Adjusted mean changes at 18 months were +1.21 points with lecanemab and +1.66 with placebo. Assume these group means are the quantities of interest.

Step 1. Absolute difference. 1.66 − 1.21 = 0.45 points less worsening. The paper subtracts the other way (lecanemab minus placebo), so it reports a difference of −0.45 points, 95% confidence interval −0.67 to −0.23.

Step 2. Relative slowing, using the placebo change as the base:

relative slowing = (placebo change − drug change) / placebo change = 0.45 / 1.66 = 0.271, about 27%

Check: 1.66 × (1 − 0.271) = 1.66 × 0.729 = 1.21.

Step 3. Did the treated group improve? No. Its mean change was +1.21, a worsening. The 27% compares two amounts of decline. It is not a 27% gain in memory, not a fraction of patients helped, and not anyone’s prognosis.

Step 4. Safety is part of the result. In TRAILBLAZER-ALZ 2 (Sims and colleagues, 2023), donanemab was tested in 1,736 people with early symptomatic AD and PET evidence of amyloid and tau. ARIA with edema or effusion, amyloid-related imaging abnormalities seen on MRI as fluid or swelling in the brain, occurred in 24.0% of donanemab recipients and 2.1% on placebo: 21.9 percentage points apart, a ratio of 24.0 / 2.1 ≈ 11.4. Three deaths with donanemab and one with placebo were considered treatment related. Donanemab slowed decline by 35.1% in people with low or medium tau and by 22.3% in the combined population, on a different scale (iADRS) over 76 weeks. Setting 27% beside 35.1% does not rank the drugs: the scales, populations and durations differ.

Reading a trial result — absolute and relative difference⚙ original · interactive
Dataset

In this sketch: group means only, no individual courses; each bar is one number (a reported figure at the published values) drawn from zero, not a trajectory over time. Mechanism-level reading of published trials, not advice.

Rule to keep: a relative figure such as 27% compares two amounts of decline. It is not a 27% gain in memory, a fraction of patients helped or anyone’s prognosis, and setting it beside another trial’s percentage does not rank the drugs, because the scales, populations and durations differ.

A negative result marks the limit. In the A4 study (Sperling and colleagues, 2023), cognitively unimpaired adults aged 65 to 85 with elevated amyloid received solanezumab, an antibody to the single-molecule (monomeric) form of Aβ, or placebo for 240 weeks. Cognitive decline was not slowed. Amyloid PET rose in both arms, by 11.6 centiloids with drug and 19.3 with placebo. A slower rise in a biomarker did not bring clinical benefit.

ALS gives the same lesson from another angle. In a 28-week randomized trial in SOD1-mutant ALS, tofersen, an antisense drug that lowers SOD1 production, reduced SOD1 in cerebrospinal fluid and neurofilament light (a protein released from damaged axons) in plasma more than placebo, but clinical endpoints did not improve over those 28 weeks (Miller and colleagues, 2022).

None of these trials showed reversal of decline, return of lost neurons, or benefit beyond the populations and durations studied, and the Clarity AD authors called for longer trials. Together the results support a contribution of amyloid that treatment can reach, without establishing amyloid as the sole cause.

Why these neurons

No one yet knows why an entorhinal layer II neuron or an SNpc dopamine neuron fails first. Nigral dopamine neurons have very large axonal arbors and high energy demand, which may contribute to their vulnerability compared with neighbouring dopamine neurons of the ventral tegmental area.

Selectivity also works within a cell class. Gamma motor neurons, small motor neurons that set the sensitivity of muscle spindles, were completely spared while alpha motor neurons degenerated in SOD1, TDP-43 and FUS mutant mouse models (Lalancette-Hebert and colleagues, 2016). In the same study, genetically reducing the number of gamma motor neurons, and so the activation of spindle afferents, delayed onset and prolonged lifespan in SOD1G93A mice, which overexpress a mutant human SOD1. So circuit input can change how fast a vulnerable neuron dies, at least in that model.

Axons and synapses degenerate in injury and in these diseases alike, and injury offers a well-defined mechanism to compare. After a cut, the distal axon fragments in Wallerian degeneration, an active program that requires SARM1 in flies and mice; the purified TIR domain of SARM1 has intrinsic NAD+-cleaving activity. The full story is in injury and regeneration. Whether that program drives chronic disease is a separate question, and one test came out negative.

Design problem

Loss of Sarm1 preserves cut axons in flies and mice (Osterloh and colleagues, 2012). Yet when Peters and colleagues (2018) crossed Sarm1-null mice with SOD1G93A mice, Sarm1 deletion did not improve survival or the behavioural, electrophysiological or histological outcomes they measured. A colleague concludes that axon degeneration does not matter in ALS. Is that justified, and what would you do next?

One way to do it

The conclusion goes too far. The 2012 result shows Sarm1 is needed for Wallerian degeneration after a cut. It does not show that chronic disease uses the same program. Motor neurons in SOD1G93A mice may die by another route, such as an apoptotic pathway in the cell body, or axons might be saved in part without any gain in survival.

Design: measure separate endpoints in the same mice, with genotype hidden from the scorers. Count axons in ventral roots and peripheral nerve, score neuromuscular junction innervation, estimate motor units electrophysiologically (motor unit number estimation), count spinal motor neuron cell bodies, and record onset and survival. Include a positive control in the same animals: cut a nerve on one side and confirm that Sarm1-null axons resist degeneration there, so a negative result in disease cannot be blamed on a failed knockout. Then test a second model, such as a TDP-43 model, because one SOD1 overexpression line is not human ALS. A clean answer would read: “Sarm1 loss protects cut axons in these mice but does not change the measured course of disease in this model.”

How we measure it

Pedigree linkage and cosegregation

You follow genetic markers and candidate variants through a family with an inherited disease and ask whether one variant travels with affected relatives and not with unaffected ones. Replication in an unrelated family strengthens the case that the variant causes disease in those families, not in every patient.

Immunoelectron microscopy of extracted filaments

Insoluble filaments are extracted from postmortem brain, labelled with antibodies carrying gold particles, and imaged in the electron microscope. Gold on the filaments identifies a component. It tells you composition, not whether the filaments cause cell death.

Axotomy with genetic loss of function

You cut an identified nerve in flies or mice lacking a gene and compare the distal axon with that of controls over days to weeks. Surviving axons show that the gene is needed for degeneration after injury, in that preparation.

Randomized placebo-controlled trial

Participants are assigned at random, and blind, to drug or placebo and followed for a fixed time on a prespecified clinical endpoint, with biomarkers and safety measured alongside. The difference between arms estimates the drug's effect in the enrolled population.

Finish line

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Recording Many Neurons: Imaging, Arrays and Atlases

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α-synuclein bound to a lipid micelle — the Lewy body protein in a membrane-bound form
α-synuclein bound to a lipid micelle — the Lewy body protein in a membrane-bound form ● LIVE · RCSB PDB 1XQ8
open on RCSB PDB ↗
Loading live structure 1XQ8 from RCSB PDB…

Look for the two curved helices of the amino-terminal half, which lie on the lipid surface. The acidic tail is disordered. In Lewy bodies the same chain is stacked into β-sheet filaments instead.

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Tau filament core from Alzheimer disease brain — the protein of the tangles
Tau filament core from Alzheimer disease brain — the protein of the tangles ● LIVE · RCSB PDB 5O3L
open on RCSB PDB ↗
Loading live structure 5O3L from RCSB PDB…

Each tau molecule contributes a flat C-shaped layer, and layers stack along the filament axis. Only part of the protein forms the ordered core; the rest is a fuzzy coat.

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Amyloid-β(1–42) fibril — the peptide of the plaques
Amyloid-β(1–42) fibril — the peptide of the plaques ● LIVE · RCSB PDB 2NAO
open on RCSB PDB ↗
Loading live structure 2NAO from RCSB PDB…

Peptides stack in register as parallel β-strands. The structure is of fibrils grown in vitro, and fibrils from patient brain can differ in fold.

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Alison Goate

Alison Goate

With John Hardy and colleagues, reported in 1991 that Alzheimer disease cosegregated with an APP variant in an autopsy-confirmed family, the first evidence that a mutation in the amyloid precursor gene can cause the disease in some families.

By the late 1980s researchers knew that the plaques of Alzheimer disease contained a peptide, amyloid-β, cut from a larger protein called APP whose gene sits on chromosome 21. Whether the peptide caused the disease or merely accompanied it was open. Families in which Alzheimer disease passed from parent to child offered a test. Goate, Hardy and colleagues followed chromosome 21 markers through a family whose diagnosis had been confirmed at autopsy. Disease travelled with a valine-to-isoleucine change in APP. The same variant then turned up in a second, unrelated family. The authors kept to the hedge that some cases of Alzheimer disease could be caused by mutations in APP. A year later Hardy and Gerald Higgins set out the amyloid cascade hypothesis, in which amyloid-β build-up starts the process that ends in tangles and neuron loss. The family genetics gave the field a causal anchor and, decades later, a rationale for removing amyloid in clinical trials.

✓ verbatim Goate et al., Nature 349:704–706 (1991); Hardy & Higgins, Science 256:184–185 (1992).
Maria Grazia Spillantini

Maria Grazia Spillantini

With Michel Goedert and colleagues in Cambridge, showed in 1997 that Lewy bodies stain for α-synuclein and in 1998 that α-synuclein is the major component of the filaments extracted from them.

Lewy bodies, round inclusions inside surviving neurons of the substantia nigra, had been the microscopic signature of Parkinson disease for most of the twentieth century, but what they were made of was unclear. In 1997 Polymeropoulos and colleagues reported a mutation in the gene for α-synuclein, a small presynaptic protein, in families with dominantly inherited Parkinson disease. Spillantini, Goedert and colleagues in Cambridge asked whether the same protein was in the inclusions of ordinary cases. Antibodies to α-synuclein stained Lewy bodies and Lewy neurites strongly. In the 1998 PNAS paper the team went further: they extracted Lewy body filaments from postmortem brain and labelled them with anti-α-synuclein antibodies under immunoelectron microscopy, finding α-synuclein to be the major filament component. That established what the inclusions are made of. It did not establish whether the inclusions themselves kill neurons, which is still argued. The work made α-synuclein the shared molecular thread between familial and sporadic Parkinson disease.

✓ verbatim Spillantini et al., Nature 388:839–840 (1997); Spillantini et al., PNAS 95:6469–6473 (1998).
Virginia M.-Y. Lee

Virginia M.-Y. Lee

With John Trojanowski and colleagues at the University of Pennsylvania, identified TDP-43 as a major disease protein in the inclusions of ALS and of frontotemporal lobar degeneration with ubiquitin-positive inclusions (Neumann et al., 2006).

For years pathologists could see inclusions in the motor neurons of people who died with ALS, and in the cortex of some people with frontotemporal dementia, that were tagged with ubiquitin, the cell's marker for protein disposal, yet contained neither tau nor α-synuclein. The protein underneath the ubiquitin was unknown. The Penn group led by Lee and Trojanowski, with Manuela Neumann as first author, made monoclonal antibodies to the insoluble material from such brains, and mass spectrometry of the bands detected by two of these antibodies identified the main component as TDP-43, an RNA-binding protein that normally lives in the nucleus. In diseased neurons it was modified and found in cytoplasmic inclusions. The 2006 paper linked two diseases, ALS and this form of frontotemporal degeneration, through one protein. A year later a postmortem series by Mackenzie and colleagues, including members of the same group, showed the limit: ALS cases caused by SOD1 mutations lacked TDP-43 inclusions. The discovery gave ALS research a common pathology for most cases and was followed in 2008 by the finding of TARDBP mutations in familial and sporadic ALS (Sreedharan and colleagues).

✓ verbatim Neumann et al., Science 314:130–133 (2006); Mackenzie et al., Annals of Neurology 61:427–434 (2007); Sreedharan et al., Science 319:1668–1672 (2008).
Marc Freeman

Marc Freeman

With Jeannette Osterloh and colleagues, found in a Drosophila screen that loss of dSarm keeps severed axons alive for weeks, and that Sarm1-null mouse axons also resist degeneration after a cut (2012).

When an axon is cut, the piece separated from the cell body breaks into fragments within days. For a long time this Wallerian degeneration was thought of as passive wasting. A mouse strain whose cut axons survived for weeks, carrying a gene fusion called Wld-S, hinted that something active was at work. Osterloh, Freeman and colleagues ran a forward genetic screen in the fly: they cut the axons of olfactory receptor neurons and looked for mutants whose severed axons did not fragment. Loss of dSarm suppressed Wallerian degeneration for weeks, acting in the neurons themselves. Severed axons from Sarm1-null mice survived long term in vivo and in culture. A cut axon, it turned out, runs a genetically controlled destruction program. The laboratory later tested whether removing Sarm1 helps a chronic disease model, SOD1G93A mice, and found no improvement in the outcomes measured. The pair of results made SARM1 a drug target for axon injury while showing where the pathway stops explaining disease.

✓ verbatim Osterloh et al., Science 337:481–484 (2012); Peters et al., Human Molecular Genetics (2018), doi:10.1093/hmg/ddy260.
Test yourself
Question 1 of 8 Score 0 / 0

Which protein forms the major filamentous component of Lewy bodies in Parkinson disease?
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Every structure, slide, simulation, and clip on this page is listed below with the source it came from. None of the 3D structures is drawn by hand or by AI: each one loads by accession ID from RCSB PDB or PubChem. This panel is generated from the lesson's own data file, so what it lists is what the page loads.

Molecular structures live data

  • α-synuclein bound to a lipid micelle — the Lewy body protein in a membrane-bound form — RCSB PDB 1XQ8 · coordinates CC0 · Solution NMR structure of micelle-bound human α-synuclein (Ulmer et al., 2005).
  • Tau filament core from Alzheimer disease brain — the protein of the tangles — RCSB PDB 5O3L · coordinates CC0 · Cryo-EM structure of tau paired helical filaments extracted from human Alzheimer disease brain (Fitzpatrick et al., 2017).
  • Amyloid-β(1–42) fibril — the peptide of the plaques — RCSB PDB 2NAO · coordinates CC0 · Solid-state NMR structure of an Aβ42 fibril (Wälti et al., 2016).

Simulations

  • Absolute and relative · Original interactive — Biochemistrypedia (Deppmann Lab).

Scientist profiles & quotes

  • Alison Goate — Goate et al., Nature 349:704–706 (1991); Hardy & Higgins, Science 256:184–185 (1992).
  • Maria Grazia Spillantini — Spillantini et al., Nature 388:839–840 (1997); Spillantini et al., PNAS 95:6469–6473 (1998).
  • Virginia M.-Y. Lee — Neumann et al., Science 314:130–133 (2006); Mackenzie et al., Annals of Neurology 61:427–434 (2007); Sreedharan et al., Science 319:1668–1672 (2008).
  • Marc Freeman — Osterloh et al., Science 337:481–484 (2012); Peters et al., Human Molecular Genetics (2018), doi:10.1093/hmg/ddy260.

Quotes are verbatim from the cited source. Profile text is original to this site and was checked against the sources cited.

Animated explainer

Slower Worsening Is Still Worsening · narration: an AI narrator voice (Gemini, Charon) reading narration written from this lesson's text · animation: AI-generated in code (Manim) by Claude, a schematic with no drawn molecular structures, plots computed from their equations · captions from the narration script.

Images & figures

This lesson carries no raster figures. Every structure is rendered live from RCSB PDB or PubChem, and every plot is drawn from its equation in the browser.

integrity Machines check the mechanics. The build confirms that every local file exists, that every question's answer key points at a real choice, and that any AI-generated scientific figure names the person who checked it; a weekly job re-resolves every accession ID against its database. Questions are original; MCAT-style items are written for this site and are not real AAMC questions. Banned sources (the Tymoczko textbook, publisher decks, copyrighted figures) are not used.

Like I'm five

In some illnesses of older age, certain brain cells slowly stop working and die, while the cells next to them stay fine. Inside or around the sick cells, a protein has bunched up into sticky clumps, like tangled string. Doctors have medicines that can clear one kind of clump, and they make people get worse a little more slowly, but they do not make anyone better.
High school

Alzheimer disease, Parkinson disease and ALS each kill a different set of neurons: memory circuit neurons, dopamine neurons in the midbrain, and motor neurons. Each leaves a different protein clumped in the tissue. A few families carry mutations that cause these diseases, and those genes point to the proteins involved. In Alzheimer disease the genes point to a peptide called amyloid-β. Antibodies that clear it slowed worsening by roughly a quarter to a third in trials of people with early disease, but patients still declined, and the drugs caused brain swelling in some people.
College

Neurodegeneration is selective. Alzheimer disease removes entorhinal layer II and CA1 neurons early and deposits extracellular Aβ plaques and intracellular tau tangles. Parkinson disease removes substantia nigra pars compacta dopamine neurons, an AGTR1-marked subtype most of all, and forms α-synuclein Lewy bodies. ALS removes upper and lower motor neurons, usually with TDP-43 inclusions, though SOD1-mutant cases lack them. Mendelian genes (APP, PSEN1 and PSEN2; SNCA, LRRK2 and parkin; SOD1, TARDBP, FUS and the C9ORF72 repeat) differ from risk alleles such as APOE ε4. The amyloid hypothesis draws its strongest support from APP and presenilin genetics. Lecanemab reduced 18-month CDR-SB worsening from 1.66 to 1.21 points, a 27% relative slowing, with amyloid-related imaging abnormalities as a cost; solanezumab in unimpaired people slowed amyloid build-up without slowing decline.
Graduate

The causal chain from aggregate to neuron loss remains unresolved for all three diseases: inclusions establish composition, and Mendelian genetics establishes that perturbing APP processing, α-synuclein dosage or SOD1 can initiate disease, but neither identifies the toxic species or the cell-intrinsic step that makes one population fail first. Candidate drivers of vulnerability include large axonal arbors and high bioenergetic demand in nigral dopamine neurons, and circuit input, as in SOD1G93A mice where reducing gamma motor neuron number, and so the drive of proprioceptive afferents delayed onset. Axon destruction by the SARM1 NADase is clearly required after transection, yet Sarm1 deletion did not change survival or pathology in SOD1G93A mice. Trials have shown that lowering amyloid or SOD1 can be achieved, and that amyloid removal in early symptomatic disease slows decline modestly. Open question: is the residual decline under amyloid removal driven by tau and other processes that become independent of amyloid once started, and would treating earlier, before symptoms, change that?
The gene and the inclusion in the same year

In 1997 Polymeropoulos and colleagues reported a mutation in the α-synuclein gene that segregated with Parkinson disease in an Italian kindred and in three unrelated families of Greek origin. Families like these are rare, so the result could have been a curiosity. Later the same year Spillantini, Goedert and colleagues reported that α-synuclein antibodies strongly stained the Lewy bodies of ordinary, non-familial Parkinson disease. A gene found in a handful of families had named the protein that accumulates in most patients, and the inclusion that pathologists had drawn for decades acquired a molecular identity.

— Polymeropoulos et al., Science 276:2045–2047 (1997); Spillantini et al., Nature 388:839–840 (1997).
A percentage with a passport

In 2011 two groups, led by Bryan Traynor and by Rosa Rademakers, independently reported a large GGGGCC repeat expansion in the first intron of C9ORF72 in families with ALS and frontotemporal dementia. The change is not a missense mutation in a protein but an expanded stretch of noncoding DNA. In Renton and colleagues' Finnish study population the expansion accounted for 46.0% of familial ALS. That number is often repeated without its denominator. It describes familial cases in one population, not all ALS and not every country.

— Renton et al., Neuron 72:257–268 (2011); DeJesus-Hernandez et al., Neuron 72:245–256 (2011).

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