Monthly Archives: July 2026

Turning on the data tap at GP2

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A new paper in the journal JAMA Neurology presents a progress report from the Global Parkinson Genetics Program, or “GP2.” That’s a world-wide collaboration to study the genetics not only Parkinson’s disease, but also dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration — and PSP.  Started in 2020, GP2 eventually plans to enroll 250,000 participants at 415 academic centers in 70 countries.  Its funding is mostly from the Sergey Brin Family Foundation to Aligning Science Across Parkinson’s (ASAP), and the complicated nuts and bolts of the project are organized by the Michael J. Fox Foundation. The paper is entitled “Pathology and Genetics in a Global Cohort of Parkinsonian Disorders,” with first author Dr. Lesley Wu and senior author Dr. Huw Morris, both of UCL Queen Square Institute of Neurology in London.

Our knowledge of the genetics of PSP, PD and the other Parkinsonian disorders remains insufficient, and the little we do know is based almost entirely on studies of white, European-derived populations.  The goal of GP2 is to extend our knowledge of the genetics of the Parkinsonian disorders to include non-European-derived populations as well.  Why?  Two reasons:

  • The most obvious justification is to allow all to benefit from tests and treatments arising from genetic knowledge. 
  • Another is to Identify genetic variants associated with the disease in previously under-studied gene pools.  That could identify previously unsuspected brain chemical processes that could in turn point to new treatment targets — not only for members of those ethnic groups or with those gene variants, but for the diseases in general, world-wide.

Examples of the groundbreaking success of this approach in neurodegenerative diseases have been a family in rural Venezuela with a mutation in the huntingtin gene causing Huntington’s disease, and one in rural southern Italy with a mutation in the alpha-synuclein gene causing a form of Parkinson’s disease.  In each case, the gene was not previously known to have any relationship to its respective disease.  In each, the genetic insight has resulted in new scientific understanding, diagnostic tests and experimental neuroprotective treatment for the disease in anyone.  Both examples, however, are based on dominant-acting mutations manifesting mostly in the young or middle-aged, where a familial pattern is obvious.  But in the vast majority of neurodegenerative diseases, any genetic component is more subtle, with each genetic “risk variant” contributing only a smidge to the overall disease likelihood, and familial patterns are often undetectable by laypersons or ordinary medical testing.

One of the first tasks for the GP2 study is to use autopsies to make sure that the people whose DNA samples have been obtained really do have the disease their neurologist has diagnosed. 

The analysis included 3,403 autopsies. Of those individuals:

• 1,171 had been diagnosed during life with PD
• 399 with Parkinson’s disease dementia (PDD)
• 227 with dementia with Lewy bodies (DLB)
• 491 with PSP
• 244 with MSA
• 76 with CBS

Here’s a table comparing the pre-mortem (or “clinical”) diagnoses with autopsy results:  The columns are the clinical diagnoses and the rows are those made at autopsy.  So, for example, of those with corticobasal syndrome diagnosed during life, 16% turned out to have Alzheimer’s disease at autopsy.

Autopsy diagnosisPercentage with Clinical Diagnosis
PDPDDDLBPSPMSACBSControls
Lewy body disease90%96%94%7%17%8%4%
Alzheimer’s1%1%3%0%0%16%1%
PSP3%2%1%88%7%36%0%
MSA3%0%0%2%75%5%0%
CBD0%0%0%1%0%24%0%
Other neuro-degen.2%1%0%2%1%12%2%
No neuro-degen.0%0%1%0%0%0%93%

Footnotes for this table:

  • “Lewy body disease” is the autopsy picture underlying the clinical spectrum that includes Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies.  Those three conditions are now widely considered to be sub-types of the same disease, just as PSP-Richardson syndrome and PSP-Parkinsonism are sub-types of PSP.
  • For visual simplicity, I’ve rounded all percentages to the nearest integer, so some of the “0%” figures are actually 0.1% to 0.4%.
  • “Other neurodegen.” comprises aging-related tau astrogliopathy, argyrophilic grain disease, chronic traumatic encephalopathy, primary age-related tauopathy, Pick disease, tauopathy not otherwise specified, and vascular pathology.

Take-homes from this table:

  • A clinical diagnosis of PSP is highly accurate, but far from optimal, with 88% confirmed at autopsy.  The next most common autopsy result in such individuals is Lewy body disease, at 7%.
  • Of those with a clinical diagnosis of CBS, only 24% proved to have CBD at autopsy.  A more typical figure from the literature is 40-50%. 
  • Of those with a clinical diagnosis of CBS, 36% proved to have PSP at autopsy.  A more typical figure from the literature is 25%.

The main point of the project, however, is the genetics.  The 20 genes analyzed in this paper were selected because of their known association with the Lewy body diseases.  However, six of them did appear in at least one of the 531 people with PSP who underwent genetic analysis.  They are:

  • The MAPT gene, which encodes the tau protein.  The H1/H1 haplotype (where each of the two copies of chromosome 17 carries the variant) occurred in 83% of people with PSP and in 48-72% of the other groups.  This was first discovered in 1998, so no news there.
  • The LRRK2 (“lark-two”) gene, which encodes an enzyme involved in breakdown of abnormal tau by the lysosomes, showed a variant in 2 people (0.4%) with PSP and in 0.8% with the Lewy body diseases.  This is also no different from previously known statistics.  The lysosomes are one of the cell’s most important mechanisms for disposing of defective, worn-out or excessive proteins such as tau.
  • 29 (16%) of the people with PSP carried one of the known disease-associated variants in the GBA1 gene.  That encodes the enzyme glucocerebrosidase, which like LRRK2, relates to the lysosomes.  This percentage was less than for LBD but did not differ from the other diseases.  Also no surprise, based on previous research.
  • Two results related to ethnicity: 
    • Ashkenazi Jews, regardless of diagnosis, were more likely than all other groups to carry variants in the GBA1 gene.  This has been known since the original description of a GBA1-Parkinson’s relationship in 1996. 
    • South Asians, regardless of genetic results, were more likely to have PSP than other ethnic groups.  This has been informally suspected, but as far as I know, this paper provides the first (admittedly meagre) actual statistics. A deeper dive into the association must now be done:  For example, are neurologists in South Asia better informed when it comes to PSP than neurologists elsewhere?  In the US, where South Asians are a relatively prosperous community with a disproportionate number of physicians, does that group tend have better access to PSP expertise than other ethnicities?  When I know, you’ll know.

  Overall take-homes:

  • This genetic analysis included only 20 genes, of which only two have been reported elsewhere to be related to PSP.  The GP2 study will eventually perform whole-genome sequencing in search of gene variations not previously known to associate with PSP and the other disorders.  To date, the number of DNA samples from under-studied populations remains too small for any results to be reported.
  • The comparison of clinical and autopsy diagnoses shows that while the positive predictive value of a clinical diagnosis of PSP is very good, it could be better.  (The PPV is the percentage of people with the clinical diagnosis who eventually prove to have the disease, in this case by autopsy.) 
  • For most of the Parkinsonian disorders, better biomarkers in living patients are urgently needed.  That, we knew.

One last take-home:  I’d say that the GP2 study shows medical science at its best, combining the latest technology with concern for – and active involvement of – populations and their physicians world-wide.  

We tauopathies have to stick together

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A post from two months ago explained why some positive results from a trial of an antisense oligonucleotide (ASO) drug for amyotrophic lateral sclerosis (ALS) is good news for PSP. Now, there’s similar but even better news about an ASO drug for Alzheimer’s disease called “diranersen.” Why better? Because unlike ALS, Alzheimer’s disease is a tau-based disorder, like PSP.

Quickie review: ASO drugs interfere with the action of messenger RNA, which is produced by a gene in the cell’s nucleus and carries it out to the ribosomes, where it’s translated into that gene’s specific protein. Trials of “neuroprotective” treatments hope to demonstrate a decline in the rate of worsening relative to placebo, affording the participant more time at each disease stage. Neuroprotective treatments like ASOs are not designed to produce improvement relative to the study’s baseline.

Yesterday (July 14, 2026) the results of a Phase 2 trial were released at the Alzheimer’s Association’s annual research conference in London. The double-blind design included 406 people with either “mild cognitive impairment” (MCI) or mild dementia caused by Alzheimer’s. (MCI does not include difficulties in performing daily activities and dementia does. For the purposes of the trial, MCI is defined as a score of 21-27 on the 30-point Mini-Mental Status Exam and dementia as 20 or less.) The participants were randomly assigned to one of three dosage levels or placebo for the 76 weeks of the double-blind period. The improvement was calculated as the difference between the first and last visit scores divided by the the first visit score.

The testing included five standard cognitive tests, tau levels in the spinal fluid, and positron emission tomography (PET) scans to image brain tau deposits. The drug, like all ASOs to date, is administered by injection into the spinal fluid space at the base of the spine, as for a spinal tap. Of those seven tests, the “primary outcome measure” was the Clinical Dementia Rating Sum of Boxes (CDR-SB), presumably because it’s the one with the most experience behind it.

Officially, the trial was negative because the CDR-SB failed to show a statistically significant slowing of the rate of worsening. But for two of the other four cognitive measures, there were statistically significant degrees of slowing of 50% in one and 42% in the other. The benefits shown by the PET and spinal fluid look equally impressive to my eyeballs, but their degree of statistical significance was not provided.

Transient pain in the head, limbs and/or back from the spinal taps were by far the most common side effects, occurring in about half of all participants, but no worse on diranersen than on placebo. The only side effect clearly worse on diranersen was a temporary confusional state (about 25% vs 5% on placbo). In all cases, it was gone within a week.

You can see and download the company’s detailed announcement here. Keep in mind that the drug company sponsor, Biogen, wrote it for public relations purposes. It is not sufficiently detailed for a research journal and has not been peer-reviewed, but Biogen has announced plans for an expensive Phase 3 trial, proving that they’re willing to put their money where their mouth is.

Biogen hasn’t parted with further details on the Phase 3, but if it starts in 2027 and is similar in design to the Phase 2 (but larger), one might expect results in 2030 and if all goes well, FDA approval shortly thereafter. Too long, I know, and besides, that’s Alzheimer’s — not PSP.

Of course, the elephant in the room is the trial of NIO-752, the ASO from Novartis, currently in a Phase 3 trial for PSP and stated for completion in mid-2029. The success to date of diranersen in Alzheimer’s, is excellent news for the prospects of a similar anti-tau ASO for PSP. As far as I know, there’s no clinically relevant difference between the two ASOs.

On behalf of the PSP community, I’ll thank Novartis for its efforts behind NIO-752 and encourage Biogen to extend its so-far-favorable Alzheimer’s program to PSP. Any other Pharma companies interested? The opportunity is ripe!

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Disclosure: In the past, I have consulted for both Novartis and Biogen, but have never had a financial interest in either company. The only possible exception is that Rutgers University, which owns the rights to the PSP Rating Scale because I was a professor there when I developed it, shares a fraction of its licensing fees with me.