The development and convergence of co-pathologies in Alzheimer's disease

Abstract

Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer's disease, but their prevalence and severity dramatically increase in Alzheimer's disease. To investigate how plaques, tangles, age and apolipoprotein E ε4 (APOE ε4) interact with co-pathologies in Alzheimer's disease, we analysed 522 participants ≥50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer's disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38-1.94, P < 0.01), LATE-NC (1.48, 1.16-1.88, P < 0.01), and Lewy bodies (1.45, 1.15-1.83, P < 0.01), but APOE ε4 only associated with CAA (4.80, 2.16-10.68, P < 0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15-1.46, P < 0.01), while Lewy bodies associated with younger ages (0.90, 0.81-1.00, P = 0.04), and APOE ε4 only associated with CAA (2.36, 1.52-3.65, P < 0.01). A longer disease course only associated with LATE-NC (1.06, 1.01-1.11, P = 0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50-3.30, P < 0.01), LATE-NC (5.24, 3.11-8.83, P < 0.01), and Lewy bodies (2.41, 1.51-3.84, P < 0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77-9.28, P < 0.01), LATE-NC (5.54, 2.33-13.15, P < 0.01), and Lewy bodies (4.76, 2.07-10.95, P < 0.01). Increased amyloid phase associated with CAA (2.27, 1.07-4.80, P = 0.03) and Lewy bodies (6.09, 1.66-22.33, P = 0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer's disease dementia. CAA interacted with plaques and tangles especially in APOE ε4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.

Keywords: Alzheimer’s disease; CAA; TDP-43; a-synuclein; co-pathology.

Figure 1

Clinicopathological correlations along the Alzheimer’s disease spectrum. Increasing cognitive decline as measured by the CDR scale correlates with increasing levels of ADNC, CAA, LATE-NC and Lewy body pathology in two different cohorts. Intermediate and high ADNC and CAA were uncommon in CDR 0 cases but were observed in a majority with mild dementia (CDR 1). Almost half of participants with moderate to severe dementia (CDR 2 and 3) had additional LATE-NC and Lewy body pathologies. CDR scores were obtained within 2 years of death for 343 CNDR participants and 1340 NACC participants.

Figure 2

Co-pathology distribution and severity is related to Alzheimer’s disease pathology. In the CNDR and NACC cohorts, CAA, LATE-NC and Lewy body prevalence increase at higher levels of ADNC, primarily driven by increases in moderate to severe levels of deposits. In both cohorts, CAA prevalence approximately doubles from low to high ADNC. LATE-NC prevalence between PART and high ADNC is 4-fold higher in the CNDR cohort and 3-fold higher in the NACC cohort. Lewy body prevalence between low and high ADNC is 5-fold higher in the CNDR cohort and more than doubles in the NACC cohort, reflecting increases in both the limbic/neocortical and amygdala-predominant patterns. In the NACC cohort, both LATE-NC and Lewy body pathology are more prevalent in PART and low ADNC cases, perhaps reflecting age-related incidental levels of each as the mean (SD) age of death for the NACC PART/low ADNC cohort was 86.0 (9.6) years compared to the equivalent CNDR cohort at 74.2 (11.7) years. AD = Alzheimer’s disease.