Some older people accumulate tau in their medial temporal lobes but have no amyloid plaques, a condition called primary age-related tauopathy (PART). Do they eventually develop Alzheimer’s disease?
- In primary age-related tauopathy, tangles accrue only in the medial temporal lobe.
- Amyloid plaques are absent, and no-shows over three years.
- Tau accumulates, cognition slips, more slowly than in AD.
- CSF phospho-tau181 rose similarly in PART and AD.
At least not over a span of three years, according to researchers led by Pablo Aguiar, Universidade de Santiago de Compostela, Spain, Michael Schöll, University of Gothenburg, Sweden, and Michel Grothe, Instituto de Biomedicina de Sevilla, Spain. In the August 14 JAMA Neurology, they reported that people with PART continued to amass tangles, but at a slower rate than people with AD. Their cognition marginally declined but no amyloid plaques appeared.
Curiously, cerebrospinal fluid phospho-tau181, a commonly used marker of amyloid-related tauopathy, rose almost as much in PART as in AD. What this means is unclear. “P-tau181 is a work in progress, and the biofluid biomarkers related to AD neuropathologic change are a moving target but a fascinating and all-important one,” wrote Peter Nelson, University of Kentucky, Lexington (comment below).
Still, people with PART and AD clearly declined in distinct ways. “The differing biomarker and cognitive trajectories of the [two] groups refute the idea that [PART] may represent an early stage of, or an alternative pathway to, AD,” wrote Susan Landau, University of California, Berkeley, and Elizabeth Mormino, Stanford University School of Medicine, in a JAMA Neurology editorial.
About a decade ago, Nelson and colleagues proposed that PART was a separate disease from AD (Nov 2014 news). However, because PART was diagnosed at autopsy, longitudinal data about how these people progress, and if they develop AD, was unknown.
To find out what happens during PART, co-first authors Alejandro Costoya-Sánchez at U Santiago de Compostela and Alexis Moscoso at U Gothenburg analyzed amyloid and tau PET, structural MRI, CSF Aβ42/40 ratios, p-tau181 levels, and cognitive test scores from 965 participants from three cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the AVID-A05 study. Half were women, their average age 74, 93 percent were Caucasian.
Of all participants, 250 were PET amyloid-negative (A-) and had no tau in their medial temporal lobes (TMTL-), 451 were A+TMTL+, meaning they had AD, and 264 were A-TMTL+, which the authors used as an in vivo analog of PART. “It seems like the A-TMTL+ phenotype overlaps very broadly with PART,” Nelson noted.
At baseline, people with AD had widespread tangles throughout their temporal, parietal, and frontal lobes, whereas in PART, tangles were mostly in the MTL. Over three years, PART participants accumulated few tangles, adding an average of 0.02 SUVR per year, mainly in their temporal lobes. People with AD, on the other hand, racked up almost three times as many tangles annually throughout their cortices (see image below).
PARTial Tauopathy and Atrophy. In the PART brain, neurofibrillary tangles deposit only in the medial temporal lobe (top left), which shrank slowly over time (bottom left). In AD, tau accumulation (top right) and atrophy (bottom right) were widespread. [Courtesy of Costoya-Sánchez et al., JAMA Neurology, 2023.]
Atrophy and global cognitive decline mirrored tangle accumulation. In PART, only the MTL shrank, and people tallied an average of 1.6 points higher each year on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11), where a higher score means worse cognition. In AD, the entire temporoparietal region atrophied, and people added an average of 3.1 points annually to their ADAS-Cog11. “These results suggest that tau accumulation in amyloid-negative individuals is not a benign process, … although the rates of progression are significantly slower compared to [those] in amyloid-positive participants,” the authors wrote.
Amyloid accumulation diverged, as well. While AD participants added an average of three Centiloids per year, those with PART accrued no plaques over the short follow-up period of up to three years. This was true whether the scientists measured plaques via CSF Aβ42/40 or by PET using a low positivity threshold 12 Centiloids, rather than the more common 24.
P-Tau in PART. CSF p-tau181 levels start higher in AD (red) than in PART (green, left), but increase at similar annual rates (right). Controls in blue. [Courtesy of Costoya-Sánchez et al., JAMA Neurology, 2023.]
CSF p-tau181 bucked the trend. While it was lower in PART than AD at baseline, it rose at almost the same rate in both (see image above). What does it mean that a commonly used marker for AD-related tauopathy rose at a similar rate with or without amyloid? This p-tau isoform may not be exclusively related to amyloid-dependent tau pathology, but might reflect the type of tau tangles, say the researchers. “Tau deposits in both diseases consist of three-repeat/four-repeat neurofibrillary tangles,” Grothe wrote.
Henrik Zetterberg, also at U Got, interpreted the p-tau data differently. “Considering the magnitude of the absolute increase in CSF p-tau181 concentration in amyloid-positive compared with -negative individuals, we can conclude that amyloid pathology is the main driver of CSF p-tau181 increase, although a small, and likely clinically irrelevant, effect of non-amyloid-related tau pathology on CSF p-tau181 concentration cannot be excluded,” he wrote (comment below).—Chelsea Weidman Burke
- Costoya-Sánchez A, Moscoso A, Silva-Rodríguez J, Pontecorvo MJ, Devous MD Sr, Aguiar P, Schöll M, Grothe MJ, Alzheimer’s Disease Neuroimaging Initiative and the Harvard Aging Brain Study. Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity. JAMA Neurol. 2023 Aug 14; PubMed.
- Landau SM, Mormino EC. Tau Pathology Without Aβ-A Limited PART of Clinical Progression. JAMA Neurol. 2023 Aug 14; PubMed.