Neuropathologic Changes of Alzheimer’s Disease and Related Dementias: Relevance to Future Prevention

Article type: Research Article

Authors: White, Lon R.^{a; *} | Corrada, Maria M.^b | Kawas, Claudia H.^b | Cholerton, Brenna A.^c | Edland, Steve E.^d | Flanagan, Margaret E.^e | Montine, Thomas J.^c

Affiliations: [a] Pacific Health Research and Education Institute, Honolulu, HI, USA | [b] Department of Neurology, UC Irvine, Irvine, CA, USA | [c] Department of Pathology, Stanford University, Palo Alto, CA, USA | [d] School of Public Health and Human Longevity Science, University of California at San Diego, School of Public Health, La Jolla, CA, USA | [e] University of Texas Health San Antonio, Biggs Institute for Alzheimer’s and Neurodegenerative Diseases and Department of Pathology, San Antonio, TX, USA

Correspondence: [*] Correspondence to: Lon R. White, MD, MPH, Pacific Health Research and Education Institute, 3375 Koapaka Street, Suite I-540, Honolulu, HI 96819, USA. Tel.: +1 808 564 6421; E-mail: lon@hawaii.edu.

Abstract: Background:Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer’s disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective:Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods:Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results:Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion:Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementias, autopsy, co-morbidity, dementia, neuropathology, polymorbidity, prevention

DOI: 10.3233/JAD-230331

Journal: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 307-316, 2023