Do amyloid plaques and tau tangles destine a cognitively intact person to decline? Yes, according to researchers led by Oskar Hansson, Lund University, Sweden, and Clifford Jack, Mayo Clinic, Rochester, Minnesota. In a medRxiv preprint uploaded May 25, they report that cognitively normal older adults with plaques and tangles declined much faster than those without either pathology—and faster than those with only plaques. Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment or dementia. Other groups analyzing different cohorts appear to be finding the same thing; papers are under review.

  • Cognition in adults with only plaques faded a bit faster than in controls …
  • ... but worsened rapidly in people with plaques and tangles.
  • They were 19 times likelier to develop MCI than people without those brain deposits.

“This quick progression to MCI is clinically relevant because it tells us that amyloid and tau PET are predictive of imminent cognitive decline,” Alexander Drzezga, University Hospital of Cologne, Germany, told Alzforum. “To consider [amyloid and tau PET positivity] merely as a risk factor, and not manifest disease, may be an underestimation of its malignancy,” the authors wrote.

Co-first authors Rik Ossenkoppele and Alexa Pichet Binette pooled data from 1,325 cognitively intact older adults from seven longitudinal research cohorts and divided them into groups based on their amyloid and tau PET scans: 843 had neither pathology, 328 had only amyloid (A+T-), 55 had amyloid with tau in the medial temporal lobe (A+T+MTL), and 65 had amyloid with tau in the neocortex as well (A+T+Neo). Ossenkoppele said 80 percent of the neocortical-positive participants also had tangles in their MTL, as tau generally spreads from the MTL to the cortex (May 2022 news).

The remaining 34 participants were only tau-positive (A-T+) and were not studied in detail due to the small sample size. The cohorts were the Swedish BioFINDER-1 and -2; the Mayo Clinic Olmsted Study of Aging; the Berkeley Aging Cohort Study; the Harvard Aging Brain Study; the Australian Imaging Biomarkers and Lifestyle Study of Ageing; and the Amsterdam Dementia Cohort.

The researchers tracked scores on the modified preclinical Alzheimer cognitive composite 5 (mPACC5) and Mini-Mental State Exam (MMSE) for an average of 3.5 years after the PET scans. Biomarker-positive participants were an average of seven years older, and had slightly lower baseline MMSE scores, than their biomarker-negative counterparts.

While controls held their ground on the mPACC5 and MMSE, A+T- participants slipped a tad and both A+T+ groups declined steeply. People whose tangles had reached the cortex (A+T+Neo) worsened faster on the MMSE than those whose tangles were limited to the MTL (A+T+MTL), but both groups declined similarly on the mPACC5. Memory slipped equally in both A+T+ groups, but global cognition, semantic fluency, and executive function worsened faster in neocortical-positive participants than in their MTL-positive counterparts, agreeing with previous research (Apr 2022 news).

People with plaques and tangles were likelier to develop MCI or dementia. Compared to controls, A+T- volunteers had a 2.5-fold higher risk of developing MCI, while people with A+T+MTL or A+T+Neo had 15 or 19 times higher risk, respectively. Twenty-one people progressed to all-cause dementia; half were A+T+Neo. They were a whopping 40 times likelier to develop dementia in this time frame than controls, while A+T+MTL people had a 5.5-fold higher risk. A+T- volunteers developed dementia at the same rate as controls.

“This shows us that a person needs both pathologies for cognition to decline,” Drzezga said.

Plaque and Tangle Downfall. Compared to cognitively intact people without AD pathology (A-T-, red) or people with only plaques (A+T-, light blue), people with plaques and tangles in their medial temporal lobes (A+TMTL+, green) or neocortices (A+TNEO+, navy) progressed more quickly to MCI (left). Only the latter were likelier to progress to all-cause dementia within the five-year maximal observation period in this analysis (right). [Courtesy of Ossenkoppele et al., medRxiv, 2022.]

Why did A+T+Neo people have a substantially greater risk of dementia but not MCI than their MTL counterparts? “Tau in the MTL worsens memory, which isn’t enough to diagnose dementia—multiple cognitive domains must be impaired, which is more likely when someone has neocortical tau,” Ossenkoppele told Alzforum.

In terms of how best to diagnose early Alzheimer's disease, this new study affirms the biological approach of the NIA-AA diagnostic criteria, which requires the presence of both types of brain aggregate, but not the presence of clinical symptoms, to call a case “preclinical AD” (Apr 2018 news). This nomenclature was controversial when it was first proposed but is now borne out by data.

Knowing which cognitively intact people are likely to decline in the next few years, and how fast, will help clinical trial recruitment. “It’s hard to know whom to enroll because cognitively normal people have highly variable decline, and some progress very slowly,” Ossenkoppele said. “These findings suggest that scientists should enroll cognitively normal people who are A+T+,” Drzezga agreed.

Notably, this is not the case for fluid-based measurements of phospho-tau, the authors add, as these measures can change much earlier as a response to amyloid deposition, and hence do not foretell measurable cognitive decline within the lifetime of a typical clinical trial.—Chelsea Weidman Burke


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News Citations

  1. Tau-PET Imaging Brings Braak Staging to Life
  2. From Near and Far, Aβ Beckons Tau to Tangle in the Cortex
  3. New Definition of Alzheimer’s Hinges on Biology, Not Symptoms

Further Reading


  1. . The impact of amyloid-beta and tau on prospective cognitive decline in older individuals. Ann Neurol. 2019 Feb;85(2):181-193. Epub 2019 Jan 21 PubMed.

Primary Papers

  1. . Amyloid and Tau PET positive cognitively unimpaired individuals: Destined to decline?. medRxiv, May 25, 2022. medRxiv