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The Pascoal Lab (PI: Tharick Pascoal, MD, PhD; Associate Professor of Psychiatry and Neurology) and colleagues have published recent research findings in Alzheimer's & Dementia and Nature Aging examining biomarkers and pathophysiological progression of Alzheimer's disease.

“These two publications contribute to our understanding of the biomarkers and pathophysiological processes associated with the progression of tau pathology in Alzheimer's disease, which is closely related to clinical progression and is a target for the next generation of clinical trials in Alzheimer's,” said Dr. Pascoal.

Plasma P-Tau231 and P-Tau217 Inform on Tau Tangles Aggregation in Cognitively Impaired Individuals

Brain accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the hallmark pathological features of Alzheimer's disease. Quantification of brain deposits of Aβ and tau proteins in living people can increase the accuracy of a clinical diagnosis when assessing cognitively impaired individuals, and inform on the risk of progression to dementia in cognitively unimpaired individuals. However, combining plasma biomarkers with demographic information (age and sex) may lead to more accurate detection of Alzheimer's disease than plasma biomarkers alone.

To improve detection of Alzheimer’s disease pathology, investigators including Pamela Lukasewicz Ferreira, PhD (Research Assistant Professor of Psychiatry); Bruna Bellaver, PhD (Research Assistant Professor of Psychiatry); Douglas Leffa, MD, PhD (PGY2 psychiatry resident); William Klunk, MD, PhD (Distinguished Professor Emeritus of Psychiatry); Victor Villemagne, MD (Professor of Psychiatry); Ann Cohen, PhD (Associate Professor of Psychiatry); Dana Tudorascu, PhD (Associate Professor of Psychiatry and Biostatistics); Thomas Karikari, PhD (Assistant Professor of Psychiatry); and senior author Dr. Pascoal, from Pitt Psychiatry, assessed 225 individuals (138 cognitively unimpaired elderly adults, 53 participants with mild cognitive impairment, and 34 with Alzheimer’s disease) to clarify the complementary contribution of each plasma biomarker, and combined with demographic information, to elucidate the state of brain deposition of Aβ and tau tangles. 

The scientists found that in cognitively unimpaired study participants, only plasma p-tau231 and p-tau217+ significantly improved the performance of the demographics in detecting Aβ-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In cognitively impaired study participants, p-tau217+ and glial fibrillary acidic protein significantly contributed to demographics to identify both Aβ-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity.

Ferreira PCL, Therriault J, Tissot C, Ferrari-Souza JP, Benedet AL, Povala G, Bellaver V, Leffa DT, Brum W, Lussier FZ, Bezgin G, Servaes S, Vermeiren M, Macedo AC, Cabrera A, Stevenson J, Triana-Baltzer G, Kolb H, Rahmouni N, Klunk WE, Lopez OL, Villemagne VL, Cohen A, Tudorascu DL, Zimmer ER, Karikari TK, Ashton NJ, Zetterberg H, Blennow K, Gauthier S, Rosa-Neto P, Pascoal TA.
Alzheimer's & Dementia. 2023; 19: 4463-4474. https://doi.org/10.1002/alz.13393 

Apoeε4 Potentiates Amyloid Β Effects on Longitudinal Tau Pathology

The mechanisms by which the apolipoprotein E ε4 allele influences the pathophysiological progression of Alzheimer’s disease are poorly understood. Investigators including Bruna Bellaver, PhD (Research Assistant Professor of Psychiatry); Pamela Lukasewicz Ferreira, PhD (Research Assistant Professor of Psychiatry); Douglas Leffa, MD, PhD (PGY2 psychiatry resident); Ann Cohen, PhD (Associate Professor of Psychiatry); William Klunk, MD, PhD (Distinguished Professor Emeritus of Psychiatry); and senior author Dr. Pascoal, from Pitt Psychiatry, tested the association of apolipoprotein E ε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. The team longitudinally assessed 94 individuals across the aging and Alzheimer’s disease spectrum who underwent clinical assessments, apolipoprotein genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ (AZD4694) and tau (MK-6240) at baseline, as well as a two-year follow-up tau-PET scan. Co-author Firoza Lussier, MSc (Research Program Administrator) provided important data support. 

The investigators found that APOEε4 carriership potentiates amyloid-β effects on longitudinal tau accumulation over two years. The APOEε4-potentiated Aβ effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. These results suggest that the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the living human brain.

Ferrari-Souza JP, Bellaver B, Ferreira PCL, Benedet AL, Povala G, Lussier FZ, Leffa DT, Therriault J, Tissot C, Soares C, Wang YT, Chamoun M, Servaes S, Macedo AC, Vermeiren M, Bezgin G, Kang MS, Stevenson J, Rahmouni N, Pallen V, Poltronetti NM, Cohen A, Lopez OL, Klunk WE, Pascoal TA.
Nature Aging 3, 1210–1218 (2023). https://doi.org/10.1038/s43587-023-00490-2