This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
Abstract
Background and Objective Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.
Methods The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51–60 (n = 40), 61–70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline.
Results Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22–0.88), psychiatric symptoms (β = −0.66, 95% CI −1.15 to −0.17), and functional impairment (β = −1.25, 95% CI −2.34 to −0.16). TDP-43 (OR 2.00, 95% CI 1.23–3.35) and microvascular copathology (OR 2.02, 95% CI 1.24–3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = −0.51, 95% CI −0.72 to −0.31) and midfrontal/hippocampal NFT ratio (β = −0.18, 95% CI −0.26 to −0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09–0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46–1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08–0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities.
Discussion Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.
Glossary
- AD=
- Alzheimer disease;
- ADL=
- activities of daily living;
- CDR=
- Clinical Dementia Rating;
- CERAD=
- Consortium to Establish a Registry for AD;
- CI=
- confidence interval;
- DLB=
- dementia with Lewy bodies;
- DRS=
- Dementia Rating Scale;
- H&E=
- hematoxylin & eosin;
- HS=
- hippocampal sclerosis;
- MCI=
- mild cognitive impairment;
- MMSE=
- Mini-Mental State Examination;
- NFT=
- neurofibrillary tangle;
- NIA-AA=
- National Institute on Aging–Alzheimer Association;
- NPI=
- Neuropsychiatric Inventory;
- OR=
- odds ratio;
- PHF=
- paired helical filament;
- POD=
- Pfeffer Outpatient Disability;
- PPA=
- primary progressive aphasia;
- TDP-43=
- TAR DNA binding protein 43;
- UCSD=
- University of California, San Diego
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.
- Received June 9, 2021.
- Accepted in final form November 4, 2021.
- © 2021 American Academy of Neurology
AAN Members
We have changed the login procedure to improve access between AAN.com and the Neurology journals. If you are experiencing issues, please log out of AAN.com and clear history and cookies. (For instructions by browser, please click the instruction pages below). After clearing, choose preferred Journal and select login for AAN Members. You will be redirected to a login page where you can log in with your AAN ID number and password. When you are returned to the Journal, your name should appear at the top right of the page.
AAN Non-Member Subscribers
Purchase access
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Costs and Utilization of New-to-Market Neurologic Medications
Dr. Robert J. Fox and Dr. Mandy Leonard