20 Feb 2025

Most people with neurodegenerative disease have a mix of protein pathologies in their brain, but there is no easy way to identify them all separately. Indeed, clinicians are urgently awaiting blood tests to tell them what proteopathies are present in the patient before them. In the February 10 JAMA Neurology, researchers led by Lawren VandeVrede at the University of California, San Francisco, offer a solution. In an autopsy-confirmed cohort, they found that plasma p-Tau217 flagged the presence of amyloid and tau pathology with high accuracy in people with frontotemporal dementia. This matters, because FTD patients with AD co-pathology had worse cognition than did those without it, the authors found. The deficits appeared in abilities typically affected by AD, such as memory and executive function. The findings could open the door to testing anti-amyloid therapies in FTD patients with plaques and tangles, VandeVrede told Alzforum.

“This is a wonderful piece of work,” said Henrik Zetterberg at the University of Gothenburg, Sweden. He was not involved in the research. “It now seems possible to use [plasma p-Tau217] to track the Alzheimer component of any progressive cognitive disorder, irrespective of anatomic location and co-pathologies.”

Previous brain imaging, cerebrospinal fluid, and neuropathological analyses found that plaques and tangles are present in a quarter to a third of people with FTD (Padovani et al., 2013; Tan et al., 2017). One previous study reported that AD co-pathology in 4R tauopathies affected clinical symptoms and patterns of brain atrophy and connectivity, but not cognition (Garcia-Cordero et al., 2024).

To take a broader look at the effects of AD co-pathology in FTD, first author VandeVrede and colleagues turned to the UCSF Neurodegenerative Disease Brain Bank, which also stores blood samples. The cohort comprised brains from 198 people who had been diagnosed with some form of FTD, 125 with AD, 10 with dementia with Lewy bodies, and 16 age-matched controls. The FTD group comprised 76 people with behavioral variant FTD, 40 with progressive supranuclear palsy-Richardson syndrome, 35 with corticobasal syndrome, 21 with semantic variant primary progressive aphasia, 21 with nonfluent variant PPA, and five with amyotrophic lateral sclerosis. Consistent with previous studies, AD pathology was present in 23 percent of FTD patients and 70 percent of DLB patients at autopsy.

For the whole cohort, plasma p-Tau217 picked out cases with intermediate or higher levels of plaques and tangles with 95 percent accuracy. “Intermediate” means Braak stage of at least III for neurofibrillary tangles, combined with a CERAD score of 2 or more or a Thal phase of 3 or more, indicating moderate plaque density. Intermediate AD pathology is considered likely to cause clinical symptoms (Hyman et al., 2012). For FTD cases only, plasma p-Tau217 was 89 percent accurate in detecting plaques and tangles; for AD cases, 98 percent. Plasma p-Tau217 also tracked with plaque and tangle pathology in DLB patients, but the number of cases was too small to be certain. Plasma p-Tau217 concentrations of 0.125 pg/mL or higher provided the optimum cutoff for distinguishing AD pathology, the authors found.

Distinct Atrophy Patterns. In FTD, some brain regions (blue) shrink faster if AD co-pathology is present, other regions shrink faster if it is not (red and yellow). [Courtesy of VandeVrede et al., JAMA Neurology.]

Among people with FTD, those with AD co-pathology had performed worse on tests of memory, executive function, and visuospatial abilities during life, and had scored about three points lower on the MMSE than did FTD patients without AD co-pathology. Their language abilities were unaffected. Cognitive evaluations were done on average three years before death. FTD patients with plaques and tangles also had an AD-like pattern of atrophy, with shrinkage in posterior cortical regions (image above). These findings suggest AD co-pathology is clinically meaningful, VandeVrede noted.

The authors also tested plasma GFAP and NfL, but on their own these markers poorly distinguished AD pathology. When combined with p-Tau217, they added nothing to diagnostic accuracy.

“Even in patients with non-AD syndromes, plasma p-Tau217 accurately detects the presence of clinically relevant AD neuropathology,” VandeVrede concluded.

He cautioned that blood biomarkers should only be used in tandem with a clinical exam by a dementia specialist, who can look at the full picture of a patient’s symptoms to determine the primary diagnosis. In the absence of this clinical judgment, indiscriminate use of AD biomarkers could cause FTD patients with co-pathology to be misdiagnosed as AD, he noted. “Biomarkers are illuminating, but they can also be blinding,” VandeVrede said.

Plasma p-Tau217 holds particular promise for people who have corticobasal syndrome, which sits at the nexus of AD and FTD. Some CBS cases are caused by AD pathology, and some by 4R tauopathy found in FTD. Plasma p-Tau217 can distinguish the two, enabling clinical trials (VandeVrede et al., 2023). VandeVrede plans to test tau therapeutics in people with CBS. He would not say which therapeutic, but is completing the trial design and expects to begin enrolling this year. This could help determine how these drugs perform against AD-like tangles and non-AD tau deposits alike.—Madolyn Bowman Rogers

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References

Paper Citations

1. Padovani A, Premi E, Pilotto A, Gazzina S, Cosseddu M, Archetti S, Cancelli V, Paghera B, Borroni B. Overlap between Frontotemporal Dementia and Alzheimer's Disease: Cerebrospinal Fluid Pattern and Neuroimaging Study. J Alzheimers Dis. 2013 Jan 1;36(1):49-55. PubMed.
2. Tan RH, Kril JJ, Yang Y, Tom N, Hodges JR, Villemagne VL, Rowe CC, Leyton CE, Kwok JB, Ittner LM, Halliday GM. Assessment of amyloid β in pathologically confirmed frontotemporal dementia syndromes. Alzheimers Dement (Amst). 2017;9:10-20. Epub 2017 May 29 PubMed.
3. Garcia-Cordero I, Anastassiadis C, Khoja A, Morales-Rivero A, Thapa S, Vasilevskaya A, Davenport C, Sumra V, Couto B, Multani N, Taghdiri F, Anor C, Misquitta K, Vandevrede L, Heuer H, Tang-Wai D, Dickerson B, Pantelyat A, Litvan I, Boeve B, Rojas JC, Ljubenkov P, Huey E, Fox S, Kovacs GG, Boxer A, Lang A, Tartaglia MC, 4‐R‐Tauopathy Neuroimaging Initiative Consortium, and the Alzheimer's Disease Neuroimaging Initiative. Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy. Ann Neurol. 2024 Jul;96(1):99-109. Epub 2024 Apr 5 PubMed.
4. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012 Jan;8(1):1-13. PubMed.
5. VandeVrede L, La Joie R, Thijssen EH, Asken BM, Vento SA, Tsuei T, Baker SL, Cobigo Y, Fonseca C, Heuer HW, Kramer JH, Ljubenkov PA, Rabinovici GD, Rojas JC, Rosen HJ, Staffaroni AM, Boeve BF, Dickerson BC, Grossman M, Huey ED, Irwin DJ, Litvan I, Pantelyat AY, Tartaglia MC, Dage JL, Boxer AL. Evaluation of Plasma Phosphorylated Tau217 for Differentiation Between Alzheimer Disease and Frontotemporal Lobar Degeneration Subtypes Among Patients With Corticobasal Syndrome. JAMA Neurol. 2023 May 1;80(5):495-505. PubMed.

Further Reading

Papers

1. Rudolph MD, Sutphen CL, Register TC, Lockhart SN, Rundle MM, Hughes TM, Bateman JR, Solingapuram Sai KK, Whitlow CT, Craft S, Mielke MM. Evaluation of plasma p-tau217 for detecting amyloid pathology in a diverse and heterogeneous community-based cohort. medRxiv. 2025 Jan 20; PubMed.

News

1. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics 29 Jul 2020
2. Meta-Analyses Deliver Most Definitive Data Yet on Amyloid Prevalence 19 May 2015