Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies

Abstract

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

Keywords: Age-related tauopathy; Alzheimer disease neuropathologic change; CDR; Cerebrovascular disease; Corticobasal degeneration; Frontotemporal lobar dementia; Lewy body dementia; Limbic-predominant age-related TDP-43 encephalopathy; MMSE; Pick disease; Progressive supranuclear palsy.

Fig. 1

Linear regression analysis demonstrating strong correlation between the total number of neuropathologic variables identified at autopsy (including ADNC, PART, LBD, LATE-NC, hippocampal sclerosis, FTLD-TDP, ALS/MND, Pick disease, PSP, CBD, CVD, CTE, prion disease, AGD, and MSA) and (a) global CDR, (b) CDR sum of boxes, and (c) MMSE (size of each data point corresponds to the number of subjects)

Fig. 2

Correlation matrix assessing different autopsy-proven neuropathologic findings across 6,262 subjects in the NACC dataset. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001

Fig. 3

Multivariate logistic regression analysis demonstrating the odds ratios (OR) and 95% confidence intervals of cognitive impairment in the presence of ADNC (level 2–3), definite PART (Braak III-IV), LBD (stage 2–3), LATE-NC (stage 2–3), hippocampal sclerosis, FTLD-TDP, ALS/MND, Pick disease, PSP, CBD, and CVD in terms of (a) global CDR, (b) CDR sum of boxes, and (c) MMSE. CTE, MSA, and prion disease were included as covariates in multivariate analysis model but are not shown here for simplicity. Multivariate logistic regression analysis performed on progressive levels/stages of ADNC, LBD, LATE-NC, infarcts, hemorrhage, arteriolosclerosis, white matter rarefaction, and cerebral amyloid angiopathy in terms of (d) global CDR, (e) CDR sum of boxes, and (f) MMSE. Multivariate logistic regression analysis was also performed on progressive Braak stage, Thal phase, CERAD NP score, and CAA (with LBD, LATE-NC, and CVD used as covariates) in terms of (g) global CDR, (h) CDR sum of boxes, and (i) MMSE

Fig. 4

Multivariate logistic regression analysis demonstrating the odds ratios (OR) and 95% confidence intervals of impairment for global CDR, CDR sum of boxes, MMSE, logical memory immediate recall (LMI), logical memory delayed memory (LMD), digit span forward (DSF), digit span backward (DSB), trail making test A (TMT-A), trail making test B (TMT-B), Wechsler adult intelligence scale digit symbol substitution (WAIS DS), animal fluency (Animals), vegetable fluency (Vegetables), and Boston naming test (BNT) in the four most commonly identified neuropathologies, (a) ADNC, (b) LBD, (c) LATE-NC, and (d) CVD (including infarcts/lacunes, hemorrhages/microhemorrhages, moderate-severe arteriolosclerosis, and moderate-severe white matter rarefaction). Significance and odds ratios for each cognitive/neuropsychological test was determined in the context of ADNC, PART, LBD, LATE-NC, hippocampal sclerosis, FTLD-TDP, ALS/MND, Pick disease, PSP, CBD, CVD, CTE, prion disease, AGD, and MSA

Fig. 5

Multivariate logistic regression analysis demonstrating the odds ratios (OR) and 95% confidence intervals of an individual having (a) at least one APOE ε2 allele or (b) at least one APOE ε4 allele with the presence of each pathology: ADNC (level 2–3), definite PART (Braak III-IV), LBD (stage 2–3), LATE-NC (stage 2–3), hippocampal sclerosis, FTLD-TDP, ALS/MND, Pick disease, PSP, CBD, and CVD, as well as an increasing number of total pathologic findings