Alzheimer's disease and its co-pathologies: Implications for hippocampal degeneration, cognitive decline, and the role of APOE ε4

Abstract

Introduction: In neurodegenerative dementias, the co-occurrence and interaction of amyloid β peptide (Aβ), tau pathology, and other pathological lesions confound their individual contributions to neurodegeneration and their modulation by risk factors.

Methods: We analyzed 480 post mortem human brains (ages 50-99) using regression and structural equation models to assess the relationships among Aβ, tau, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), α-synuclein, other age-related lesions, and apolipoprotein E (APOE) ε4, as well as their effects on CA1 neuronal density, brain weight, and cognitive status.

Results: Aβ, tau, LATE-NC, and amygdala-predominant α-synuclein pathology were mutually interdependent. Tau was the strongest predictor of global neurodegeneration, while LATE-NC primarily, but not exclusively, affected hippocampal neuron loss. Small vessel disease correlated with both LATE-NC and α-synuclein, while APOE ε4 was mainly associated with extracellular parenchymal and capillary Aβ pathology.

Discussion: Although Alzheimer's disease pathology plays a central role in brain degeneration, coexisting pathologies can both exacerbate and independently contribute to it. These factors should be considered in patient stratification.

Highlights: In aging individuals, amyloid β peptide (Aβ), tau pathology, limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), and amygdala-predominant α-synuclein pathology were interrelated but contributed independently to neurodegeneration. LATE-NC was the strongest driver of CA1 neuronal loss, while tau burden was the strongest predictor of global brain degeneration. Apolipoprotein E ε4 was associated with both extracellular and capillary Aβ deposits, but not with tau burden. Temporal lobe small vessel disease was associated with both LATE-NC and amygdala-predominant α-synuclein pathology. Neural network models can reliably identify hippocampal pyramidal neurons on hematoxylin-stained histological slides.

Keywords: amyloid β; apolipoprotein E ε4; cerebral amyloid angiopathy; digital pathology; hippocampal degeneration; limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes; medial temporal lobe; mixed dementia; small vessels disease; tau; α synuclein.

FIGURE 1

A, Schematic representation of the study design. B, Representative images from the CA1 subfield of the posterior hippocampus in five different cases, with neurons identified by the trained classifier marked by orange circles. C, Density plot showing the distribution of CA1 neuronal densities in cognitively impaired (CDR > 0, n = 195) and cognitively intact (CDR = 0, n = 200) cases. Cognitive impairment status was unavailable for 85 cases. APOE, apolipoprotein E gene; CDR, Clinical Dementia Rating score.

FIGURE 2

Combinations of neuropathological lesions and their brain degeneration correlates. A, Proportion of cases with specific pathological lesions identified in this study in total sample of 480 cases. B, Overview of combinations of moderate or severe ADNC, αSyn pathology, and LATE‐NC in the study cohort, arranged in descending order of prevalence (left panel). The number of cases in each group, their mean CDR score, and mean age at death are reported (middle panel). Boxplots illustrate neuronal density in the CA1 and brain weight for each combination (right panel). Horizontal bold lines in the boxplots represent median values, box margins indicate the 25th and 75th percentiles, and whiskers display the full range of observed values. A summary of the Kruskal–Wallis analysis with pairwise Wilcoxon tests comparing brain degeneration measures across different combinations can be found in Table S5 in supporting information. Aβ phases, phases amyloid β plaque deposition; ADNC, Alzheimer's disease neuropathologic changes; αSyn, α‐synuclein pathology; CDR, Clinical Dementia Rating score; LATE‐NC, stages of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes; NFT, neurofibrillary tangle; pTau, phosphorylated tau pathology.

FIGURE 3

Heatmap displaying the results of a semi‐partial Spearman correlation of neuropathological lesions, corrected for age at death. Stars indicate significance levels of P values adjusted using the Bonferroni–Holm correction (* P value < 0.05, ** P value < 0.01, *** P value < 0.001). The shade of each tile represents the strength and direction of the correlation. The order of tiles has been arranged using hierarchical clustering with complete linkage. A square highlights the spectrum of Alzheimer's disease‐related lesions that are strongly intercorrelated. Aβ, represents the phase of amyloid β plaque deposition in the brain; AmyP, amygdala‐predominant pattern; AGD, argyrophilic grain disease; αSyn, α‐synuclein pathology; ARTAG, aging‐related tau astrogliopathy; AS, severity of atherosclerosis of the circle of Willis; CAA, severity of cerebral amyloid angiopathy; CAA type 1, type 1 of cerebral amyloid angiopathy; CR, caudo‐rostral pattern; GVD, stage of granulovacuolar degeneration; LATE‐NC, stages of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes; Hirano bodies, severity of Hirano body pathology; NP, CERAD neuritic plaque score; pTau, represents the Braak NFT stage of phosphorylated tau pathology; pTDP‐43 DG, phosphorylated TDP‐43 in the dentate gyrus; SVD, small vessel disease score.

FIGURE 4

Heatmap showing standardized coefficients from multiple linear regression analyses evaluating brain degeneration measures as dependent variables and neuropathological lesions as independent variables. Regression models were adjusted for age at death, sex, and cohort (A, Series 1) and for the overall severity of Alzheimer's disease neuropathological changes (B, Series 2). The colors of the tiles represent the direction and strength of the coefficients for each neuropathological lesion. Asterisks indicate P values after Bonferroni‐Holm correction within each panel (* P value < 0.05, ** P value < 0.01, *** P value < 0.001). Aβ, represents the phase of amyloid β plaque distribution in the brain; AGD, argyrophilic grain disease; αSyn, α synuclein pathology; AmyP, amygdala‐predominant pattern; ARTAG, aging‐related tau astrogliopathy; AS, severity of atherosclerosis of the circle of Willis; CAA, severity of cerebral amyloid angiopathy; CAA type 1, type 1 of cerebral amyloid angiopathy; CDR, Clinical Dementia Rating score; CR, caudo‐rostral pattern; GVD, stage of granulovacuolar degeneration; LATE‐NC, stage of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes; Hirano bodies, severity of Hirano body pathology; NP, CERAD score for neuritic plaque pathology; pTau, phosphorylated tau; pTDP‐43 DG, phosphorylated TDP‐43 in the dentate gyrus; SVD, small vessel disease score.

FIGURE 5

Structural equation models were used to investigate the relationships between neuropathological lesions associated with the AD spectrum and measures of brain degeneration. Model 1 (n = 480) examined the associations between AD‐related lesions and neuronal density in the posterior CA1 region. The association between LATE‐NC and CAA was not significant and was excluded from subsequent models. Model 2 (n = 367) explored the effect of the APOE ε4 gene dose on the accumulation of neuropathological lesions. A complementary model incorporating CAA type 1 is presented in Figure S8 in supporting information. Additionally, we analyzed the association between brain lesions and total brain weight in Model 3 (n = 333) and between neuropathological lesions and global cognitive impairment, as measured by the CDR, in Model 4 (n = 397). All directional relationships included in the models are represented by arrows. The color of each arrow indicates the sign of the estimate, except for non‐significant (NS) path estimates (P value ≥ 0.5), which are shown in gray. Standardized estimates for paths involving brain degeneration parameters are indicated at the tip of each arrow. Aβ, reprensents the phase of amyloid β plaque deposition; AD, Alzheimer's disease; αSyn, αsynuclein pathology; AmyP, amygdala predominant pattern; APOE, apolipoprotein E gene; CAA, severity of cerebral amyloid angiopathy; CDR, Clinical Dementia Rating score; LATE‐NC, stages of limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological changes; pTau, represents the Braak NFT stage for the distribution of phosphorylated tau.