Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study

Abstract

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

Fig. 1

ARTAG pathology. Limbic (a–d), brainstem (e–g) and neocortical (h) ARTAG in The 90+ Study. a Severe GFA in gray matter of the amygdala. b Severe TSA in the temporal lobe. c ARTAG frequently co-exists with AD tau pathology. Substantial white matter TSA underlying a severe burden of NFTs in the entorhinal cortex. d Subependymal TSA in the lateral ventricle. e TSA in the medial lemniscus and inferior olive nucleus. f TSA and GFA in the spinal lemniscus in the mesencephalon. g Perivascular TSA around the cerebral aqueduct. h Gray matter GFA in the temporal cortex. Scale bar is 100 um in all images. ARTAG aging-related tau astrogliopathy, GFA granular fuzzy astrocytes, TSA thorn-shaped astrocytes

Fig. 2

Pathological associations with Braak stages. Non-AD pathology and plaque pathology are graphed by increasing Braak stage. Non-AD pathology includes TDP-43 stage and Lewy pathology (lines, on the right axis) as well as HS, cortical ARTAG and CVD (histogram, frequency indicated by the right axis), while plaque pathology is represented as NIA-AA criteria A0–3 and C0–3 values (lines, on the left axis). At low Braak stages (I-III): definite CVD is prevalent in about 15% of individuals; HS and cortical ARTAGs are rare, as are TDP-43 and Lewy pathologies; plaques are restricted to cortical areas (A1) and are only rarely neuritic (C1). At high Braak stages (IV-VI): definite CVD increases to over 30% (p = 0.009); HS increases to over 20% (p = 0.006); cortical ARTAG increases to over 30% (p < 0.001); TDP-43 is commonly found in the amygdala (p < 0.001) but Lewy pathology remains rare; plaques are more widespread (Thal phase, p < 0.001) and neuritic (CERAD, p ≤ 0.001). See Supplemental Table 3 for the full statistics including OR and 95% CI for each measure’s association with Braak stage and Thal phase. ARTAG aging-related tau astrogliopathy, CVD cerebrovascular disease, HS hippocampal sclerosis