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Abstract
Background and Objectives Age is the largest risk factor for dementia. However, dementia is not universal, even among the oldest-old age groups. Following contemporary neuropathologic guidelines, our objectives were to describe the key neuropathologic lesions and their associations with antemortem cognition in oldest-old individuals.
Methods Participants were those enrolled in The 90+ Study, a longitudinal, population-based study of aging/dementia in the oldest old, who agreed to postmortem brain examination. All autopsied brains as of December 2020 were evaluated for the prevalence of Alzheimer disease neuropathologic change (ADNC) and non-ADNC neuropathologic comorbidities. Associations between neuropathologic lesions or the total neuropathologic burden score (sum of the individual scores) and cognition were assessed using multinomial logistic regression and multiple linear regression. Separate regression analyses evaluated relationships between limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) and hippocampal sclerosis (HS) or ADNC/primary age-related tauopathy (PART). Resistance, or failure to develop ADNC/PART, and resilience, inferred from higher-than-expected cognitive functioning, were evaluated in the presence or absence of non-ADNC neuropathologic features.
Results The most common neuropathologic features in the sample (n = 367) were ADNC/PART related. Increased dementia odds were associated with elevated total neuropathologic burden (odds ratio [OR] 1.5, 95% CI 1.3–1.7, p < 0.0001), β-amyloid (OR 1.6, 95% CI 1.2–2.0, p < 0.0001), neurofibrillary tangles (OR 2.6, 95% CI 1.7–4.1, p < 0.0001), and LATE-NC (OR 2.3, 95% CI 1.7–3.1, p < 0.0001), correcting for multiple comparisons. LATE-NC was associated with dementia with (OR 6.1, 95% CI 2.0–18.7, p = 0.002) and without (OR 5.0, 95% CI 2.6–9.7, p < 0.0001) co-occurring HS and increased the odds of dementia among participants with ADNC (OR 5.0, 95% CI 2.7–9.2, p < 0.0001). Resistance to moderate/severe ADNC/PART was rare (3%), but resilience to ADNC/PART was not (55%). Resilience was rarer in the presence of non-ADNC comorbid lesions, particularly LATE-NC. Among those with moderate/severe ADNC/PART, dementia odds increased with each non-ADNC comorbid lesion (e.g., 1 lesion: OR 2.4, 95% CI 1.3–4.5, p < 0.005; 2 lesions: OR 5.9, 95% CI 2.8–12.3, p < 0.0001).
Discussion These results highlight the importance of non-ADNC neuropathologic comorbidity, predominantly LATE-NC, to cognition in the oldest old. Given the cumulative effects of non-ADNC comorbid neuropathologic abnormalities, reducing their prevalence, especially LATE-NC, will be vital to the ultimate goal of reducing dementia burden in the oldest-old individuals.
Glossary
- 3MS=
- Modified Mini-Mental State Examination;
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- ADNC=
- Alzheimer disease neuropathologic change;
- CAA=
- cerebral amyloid angiopathy;
- CIND=
- cognitive impairment, no dementia;
- CVLT-II=
- California Verbal Learning Test II;
- HS=
- hippocampal sclerosis;
- LATE-NC=
- limbic-predominant age-related TDP-43 encephalopathy neuropathologic change;
- LBD=
- Lewy body disease;
- MMSE=
- Mini-Mental State Examination;
- OR=
- odds ratio;
- μVBI=
- microvascular brain injury;
- NFT=
- neurofibrillary tangle;
- NIA-AA=
- National Institute on Aging-Alzheimer's Association;
- PART=
- primary age-related tauopathy;
- TDP-43=
- transactive response DNA-binding protein of 43 kDa
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD, FAAN.
CME Course: NPub.org/cmelist
- Received January 20, 2022.
- Accepted in final form April 22, 2022.
- © 2022 American Academy of Neurology
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