Alzheimer’s Disease Co-pathology and its Influence on Biofluid Biomarkers in Autopsied Subjects from the PPMI Study David Coughlin MD MTR1, Kristy Hwang MD1,2, Ece Bayram MD PhD1, Douglas Galasko MD1 1. University of California San Diego Department of Neurosciences La Jolla CA 92037 2. Long Beach VA Medical Center, Long Beach CA Objective: To examine the relationship between biofluid biomarkers and post-mortem pathological findings in autopsied subjects from the Parkinson’s Progression Marker Initiative (PPMI) with a focus on Alzheimer’s disease (AD) co-pathology. Methods: CSF measurements Platform Aβ1-42 Elecsys (Roche) total-tau (t-tau) Elecsys (Roche) phosphorylated tau (p-tau181) Elecsys (Roche) Total CSF alpha-synuclein (aSyn) ELISA (Biolegend) aSyn-Seeding Amplification assay (aSyn-SAA) Amprion Serum measurements Platform Neurofilament light chain (sNfL) Simoa (Quanterix) Please see www.ppmi-info.org for more details Autopsies were performed per local methods. Biofluid markers and clinical features from PD cases with no or low AD neuropathological change (PD-ADNC) and PD cases with intermediate or high AD neuropathological change (PD+ADNC) were compared cross sectionally at last available assay and longitudinally. Data used in the preparation of this research were obtained from the (PPMI database (www.ppmi-info.org/access-data-specimens/download- data). For up-to-date information on the study, visit www.ppmi-info.org . Conclusions • AD co-pathology is common and associated with more rapid cognitive and motor decline in the PPMI autopsy-validated cohort. • CSF biomarkers can accurately identify AD co- pathology in vivo. • High rates of genetic variants may result in bias in current dataset • The PPMI autopsy cohort will provide unique opportunities to examine relationships between clinical, imaging, biofluid biomarkers and histopathological changes as it expands. PD-ADNC N=11 PD+ADNC N=9 Clinical Features p (t-test, fisher exact) Age onset N=10 60.7 (12.3) N=8 65.1 (5.1) 0.4 Sex 4 Female, 7 Male 3 Female, 6 Male 1.0 Disease Duration (y) N=10 11.4 (5.4) N=8 10.4 (3.4) 0.6 UPDRS-III (OFF, last) N=9 34.4 (8.8) 43.3 (20.6) 0.25 MoCA (last) N=9 23.4 (4.6) 19.2 (6.6) 0.12 LRRK2, GBA GBA: N409S N=1 LRRK2: R1441G N=1 G2019S N=2 GBA: N409S N=2 LRRK2: G2019S N=1 NA APOE Genotype 2/4: 1, 3/3: 7, 3/4: 1 2/4: 1, 2/4:1 3/3: 4 3/4: 1 E4 dominant: 0.6 Last Biofluid Assessments (mean (SD). Test-death interval 5.1y [IQR 2.9-7.2] P (LR controlling for test-death) CSF Aβ1-42 pg/ml N=7 887 (315) N=7 544 (254) 0.06 CSF t-tau/Aβ1-42 N=7 0.20 (0.06), N=7 0.47 (0.13) 0.02 CSF p-tau/Aβ1-42 N=7 0.017 (0.005) N=7 0.030 (0.01) 0.04 CSF total-αSyn pg/ml N=7 1378 (444) N=7 1099 (289) 0.2 CSF aSyn-SAA N=8 8/8 positive N=8 8/8 positive NA Serum NfL N=9 18.9 (8.3) 27.6 (11.9) 0.1 Neuropathological Features p (fisher exact) Braak aSyn 5/6: 4 6/6: 7 5/6: 1 6/6: 8 0.3 Braak Tau B0:1, B1:6, B2:4 B2:6, B3:3 0.007 CERAD Plaque Stage C0:10, C1:1 C2:2, C3:7 <0.001 Thal Aβ Phase A0:4, A1:5, A2:1 A2:2, A3:7 <0.001 AD Neuropath. Change Not: 5, Low: 6 Inter.: 6, High: 3 <0.001 TDP-43 None: 7, Hipp: 1, MF: 1 None: 6, Hipp:2 1.0 Cerebral Amyloid Ang. None:4 Mild:2 Mod.:2 None:3 Mild:1 Mod.:3 Severe:1 0.7 Hippocampal Sclerosis 1 2 0.7 Arteriolosclerosis None:3, Mild:2, Mod:3 None:1, Mild:2, Mod;5, Severe:1 0.7 Results: Data from 22 autopsied subjects was available (17/22 from Stanford University). One subject had MSA and another had a LRRK2 G2019S mutation without Lewy body pathology (both aSyn-SAA negative). 11 cases were PD-ADNC and 9 were PD+ADNC as below. Contact: David Coughlin MD MTR. dacoughlin@ucsd.edu P<0.001 P values reflect results of group differences in GLM models Longitudinal Changes P<0.001 P<0.001 P=0.003 P<0.001 P<0.001 P=0.3 A. Clinical B. Biomarkers