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. 2022;85(3):1309-1320.
doi: 10.3233/JAD-210673.

Association of APOE ɛ4 and Plasma p-tau181 with Preclinical Alzheimer's Disease and Longitudinal Change in Hippocampus Function

Alireza Salami  1   2   3   4 , Rolf Adolfsson  5 , Micael Andersson  1   2 , Kaj Blennow  6   7 , Anders Lundquist  2   8 , Annelie Nordin Adolfsson  5 , Michael Schöll  6   9   10 , Henrik Zetterberg  6   7   10   11 , Lars Nyberg  1   3   12
Affiliations

Association of APOE ɛ4 and Plasma p-tau181 with Preclinical Alzheimer's Disease and Longitudinal Change in Hippocampus Function

Alireza Salami et al. J Alzheimers Dis. 2022.

Abstract

Background: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer's disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers.

Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity.

Methods: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding.

Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity.

Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning.

Keywords: APOE; Alzheimer’s disease; fMRI; hippocampus; longitudinal; magnetic resonance imaging; p-tau181; phosphorylated tau; population-based.

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Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0673r1).

Figures

Fig. 1
Fig. 1
a) Flowchart of cross-sectional AD-case –control study with Wave 3 (W3) as study baseline, and (b) longitudinal imaging study with Wave 5 as study baseline. –/–, not included in the present study; W, wave; S, sample.
Fig. 2
Fig. 2
P-tau181 levels for cases and controls. a) Median p-tau181 levels as a function of time to/from AD onset. Number of subjects in each group is indicated. b) Median p-tau181 levels as a function of time to/from AD onset as a function of APOE status. Number of subjects in each group is indicated. c) Distribution of individual p-tau181 levels for AD cases and controls, where arrows indicate tentative cut-off for elevated values (see text). d) Percentage with p-tau181 levels exceeding the cut-off for controls and AD cases as a function of time to/from diagnosis. Error-bars are 25/75-percentile in (a) and (b). “*” denotes a group difference, p < 0.05.
Fig. 3
Fig. 3
Longitudinal brain-imaging study. a) Longitudinal change in p-tau181 levels in relation to APOE status. b) Longitudinal change in hippocampus activity and (c) connectivity as a function of p-tau181 levels (high/rising versus low) and APOE status (ɛ4 carrier, ɛ4+ versus non-carrier, ɛ4–). d) Change in memory performance between waves 6-7. Error-bars are standard error of mean in (b) and (c). Error-bars are standard deviation in (d). Error-base are 25/75-percentile in (a). “*” denotes a group difference with p < 0.05 in (a) and (b), and within group change with p < 0.05 in (c) and (d).
See this image and copyright information in PMC

References

    1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923. - PubMed
    1. Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: Normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2, a006312. - PMC - PubMed
    1. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C, Alzheimer’s Disease Neuroimaging I, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527. - PMC - PubMed
    1. Therriault J, Benedet AL, Pascoal TA, Mathotaarachchi S, Chamoun M, Savard M, Thomas E, Kang MS, Lussier F, Tissot C, Parsons M, Qureshi MNI, Vitali P, Massarweh G, Soucy JP, Rej S, Saha-Chaudhuri P, Gauthier S, Rosa-Neto P (2020) Association of Apolipoprotein E epsilon4 with medial temporal tau independent of amyloid-beta. JAMA Neurol 77, 470–479. - PMC - PubMed
    1. Jack CR Jr. (2020) Preclinical Alzheimer’s disease: A valid concept. Lancet Neurol 19, 31. - PubMed

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