A new study confirms that many cognitively normal older adults harbor neurodegenerative changes akin to Alzheimer’s disease (AD), but without amyloid-β (Aβ) deposits.

These changes are associated with cerebrovascular disease and cognitive performance, which suggests that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD, say Miranka Wirth, PhD, from the Helen Wills Neuroscience Institute, University of California, Berkeley, and colleagues.

Their study was published online October 28 in JAMA Neurology.

“We defined abnormality thresholds of various markers in Alzheimer’s cohorts and then we projected these thresholds to our sample of cognitively normal older adults,” Dr. Wirth commented toMedscape Medical News. “We found that 25% of our sample had Alzheimer’s-like patterns in neurodegenerative markers without being positive for β-amyloid.”

“We’re not saying the biomarker model is wrong,” she added. “But it may be that the biomarker changes happen a long time before a reduction in cognition is seen. These changes are related to the vascular burden in the brain, and the people who showed these changes did have lower cognition, although still in the normal range, so we believe they may develop dementia in future. We will follow them up to see if that happens.”

“In the prevailing model of Alzheimer’s at present, β-amyloid is the central factor. Our research is more evidence that it is not just about β-amyloid. Perhaps we need to rethink risk of dementia based on these other markers.”

Participants included 72 cognitively normal adults (48 women; mean age, 75 years) in the Berkeley Aging Cohort. The researchers quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships between Aβ deposition, white matter lesions (WMLs; a marker of cerebrovascular disease), and cognitive function.

They found that 21 individuals (29.2%) had 1 abnormal biomarker in AD regions; 7 (9.7%) had abnormal cortical thickness, 6 (8.3%) had abnormal fluorine-18 fluorodeoxyglucose positron emission tomography (PET) and 8 (11.1%) had abnormal hippocampal volume. Eight individuals (11.1%) had more than 1 abnormal biomarker in relevant brain regions.

The researchers note that the proportions of abnormal neurodegenerative biomarkers in this cohort were “highly similar” to those in the Mayo Clinic Study of Aging, a community sample in which 29% of cognitively normal individuals had 1 abnormal biomarker and 8% had more than 1 abnormal biomarker.

They also note that the abnormal thinning within cortical AD regions they saw in this cognitively normal group “matched degree and topographic distribution” of cortical thinning seen in patients with AD.

Accumulation of abnormal neurodegenerative biomarkers was related to lower cognitive function (memory performance and executive function) and larger WML volumes, they report.

Of note, 19 individuals who harbored at least 1 abnormal neurodegenerative biomarker (26% of the entire group) had no Aβ deposition, as judged by PET imaging with the amyloid tracer Pittsburgh compound B.

The researchers say their study is limited by its cross-sectional nature and small sample size, which also restricted the analyses of different combinations of abnormal neurodegenerative biomarkers.

In general, however, the findings support “converging data” from multiple studies suggesting that abnormality in neurodegenerative biomarkers can occur in cognitively normal older people regardless of Aβ deposition, the researchers say. This “needs consideration in preclinical stages of AD,” they conclude.