Spotlight on Alzheimer’s: Looking for the earliest signs
Volume 10, Issue 6 | August 15, 2024
Also in This Issue
Biomarkers can show which neurodegenerative dz came first
The critical biomarker for Alzheimer’s is p-tau217 - for now
Routine lab tests can’t diagnose Long COVID
In Africa, the “new” mpox still a major threat
Bird flu update
New and Noteworthy
Neurodegenerative Disease, Part 1: Which came first?
Many patients suffering from Lewy body disease (LBD) or Parkinson’s disease also have Alzheimer’s disease (AD), but which is chicken and which is egg has remained a question. Recent work published in NPJ Parkinson’s Disease clearly shows that LBD and Parkinson’s biomarkers (neurofilament light chain (NfL) and alpha-synuclein, respectively) are detectable in blood before Alzheimer’s biomarkers appear (amyloid beta - Aβ, and phosphorylated tau - p-tau). This suggests that concurrent AD can be collateral damage from LBD and Parkinson’s progression, not its cause.
Commentary: NfL is a key structural protein in neurons, so its presence is directly related to neuronal damage from any cause. The conclusions here are even more striking because in the case of Alzheimer’s, Aβ42, p-tau and NfL become elevated in cerebrospinal fluid long before cognitive decline is apparent (18 years, 11 years, and 9 years, respectively, per a groundbreaking 20-year Alzheimer’s study published earlier this year in NEJM).
Neurodegenerative disease, Part 2: For Alzheimer’s Dx, can p-tau217 alone “do it all”?
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) recently released key details of its comparison testing of six blood tests for the disease that are currently available to physicians. Two only analyze phosphorylated tau217 (p-tau217) (ALZpath Qanterix, Janssen LucentAD Quanterix), two more include p-tau217 in a broader panel (C2N, Fujirebio), and the final two are broad panels but include p-tau181 instead of p-tau217 (Roche NeuroToolKit, Quanterix Neurology 4-plex). Levels of p-tau217 levels were checked in comparison to each of the following:
Cognitive decline
PET scans showing amyloid beta42 (Aβ42) plaques and/or p-tau tangles
MRI scans showing cortical brain atrophy
The result? Blood testing for p-tau217 was about 90% accurate (as measured by AUC). But there’s a catch. That number refers to p-tau217’s accuracy when compared only to imaging (the PET scans). When compared to cognitive decline, it was only about 65% accurate (see chart extract), and remember that an accuracy of 50% is the same as random chance.
Commentary: There are several possible reasons for this outcome:
Alzheimer’s may not be causing the cognitive decline in some cases, and/or
The test could be detecting Alzheimer’s cases before cognitive decline happens, and/or
Higher but necessary sensitivity may be generating many false positives.
As noted elsewhere in this newsletter, a long-term Chinese study published this year in NEJM showed that the Alzheimer’s biomarker Aβ42 was detectable in cerebrospinal fluid 12 years prior to cognitive decline and 18 years before Alzheimer’s diagnosis, with p-tau detectable in CSF eight years later. The ADNI cohort was on average 17 years older than that of the NEJM cohort (at least at the start), and the ADNI study wasn’t powered to detect early biomarker signals. It’s quite possible that, despite the results of the ADNI study, a broader panel including Aβ42 could be better at detecting asymptomatic earlier onset. We will know more when the full ADNI results are published.
Neurodegenerative disease, Part 3: What causes the Aβ42 plaques and tau tangles of Alzheimer’s?
Enormous progress has been made in diagnostics that look for amyloid beta42 (Aβ42) and p-tau217 in blood to either confirm a diagnosis of Alzheimer’s disease or detect the disease before symptoms appear. Which begs another diagnostic question: Yes, Aβ42 plaques and tau tangles form in the brain in Alzheimer’s, but why? What makes this happen?
A paper in Cell Reports Medicine this week uses an in-depth proteomic investigation to look for answers to these questions. It adds two new-ish potential Alzheimer’s biomarkers to the list: midkine (Mdk) and pleiotrophin (PTN; see also this 2022 paper). The job of these two proteins is to gather together different bits of the extracellular matrix (the proteins and other molecules that surround cells). Under normal circumstances, that’s both a good and essential thing. But this paper hypothesizes a dark side: When the brain has too much of these proteins, they may pull together too much Aβ42 and tau and keep them from breaking down normally.
Commentary: Mdk and PTN levels are quite a long way from being bona-fide diagnostics, but understanding them may help to understand Alzheimer’s progression which is essential to both diagnosis and treatment. One of the biggest challenges to moving the Alzheimer’s diagnostics ball down the field is separating causes from both passengers and effects.
That said, this study is another example of the importance of the proteome, especially in protein-aggregation brain disorders. Genomic mutations do not drive the vast majority of Alzheimer’s cases (with exceptions, e.g., the Colombian Alzheimer’s cluster), and mRNA transcriptomics is not helpful because it is protein longevity that drives this disease, not the creation of new proteins from mRNA.
Bird flu update: CDC Risk Assessment results; no virus found in raw cheese
Last week, the CDC published the results of its Influenza Risk Assessment Tool (IRAT) for the current version of the H5N1 virus. The agency said the virus poses a “moderate” risk of causing a pandemic, similar to past H5N1 influenza viruses. They also estimate that the current risk to the general public is low.
FDA and USDA scientists found no live virus in 23 samples of aged raw-milk cheeses they tested, according to a preprint published earlier this week. They said that more testing is needed to confirm that the cheese-aging process inactivates the virus consistently.
Food for Thought
Routine lab tests can’t diagnose Long COVID
Modern medicine is good at a lot of things. Unfortunately, objectively diagnosing syndromes like post-acute sequelae of SARS-CoV-2 infection (PASC, aka Long COVID) and myalgic encephalomyelitis (aka Chronic Fatigue Syndrome) isn’t one of them. A large study published this week (10,094 subjects) highlights that fact. It looked at 25 of the most commonly run blood and urine tests and found that none of them could reliably diagnose patients with Long COVID. For now, diagnosis based on symptoms remains the closest to a gold standard we have.
Mpox is still killing, even if Americans aren’t paying attention
Most Americans have forgotten about mpox, according to a nationally representative survey published last week. While the disease hasn’t been causing problems in the US lately, that’s not the case in central Africa. There, a more dangerous form of the disease (clade 1) has evolved to become even more deadly, with a death rate of between 4.3% and 5.7%.
Over the past month, an outbreak of this version of the virus has spread past the Democratic Republic of Congo, where it originated, into four neighboring countries. Earlier this week, the Africa Centres for Disease Control and Prevention declared the disease a continent-wide public-health emergency (the first the group has ever declared). Yesterday, the World Health Organization declared that it is a worldwide public-health emergency, as well. WHO cited the fact that this mpox clade has already crossed borders in Africa.
Commentary: While we don’t want to be Henny Penny (“the sky is falling!”), we do want to strongly encourage federal government decision-makers to take notice. The last US mpox spread was contained rapidly, thanks to aggressive testing, strong communications with high-risk groups, and effective vaccine distribution. As outlined in the Testing Playbook for Biological Emergencies, as soon as a pathogen is spreading outside of the US, we need to closely monitor that spread and the potential for that pathogen to come to the US.