IMPORTANCE: Criteria for preclinical Alzheimer disease (AD) propose β-amyloid 
(Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, 
some cognitively normal older individuals harbor neural injury similar to 
patients with AD, without concurrent Aβ burden. Such findings challenge the 
proposed sequence and suggest that Aβ-independent precursors underlie AD-typical 
neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and 
non-Aβ factors as well as neurodegeneration within AD regions in cognitively 
normal older adults. The study quantified neurodegenerative abnormalities using 
imaging biomarkers and examined cross-sectional relationships with Aβ 
deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; 
and cognitive functions.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in a community-based 
convenience sample of 72 cognitively normal older individuals (mean [SD] age, 
74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the 
Berkeley Aging Cohort.
INTERVENTION: Each individual underwent a standardized neuropsychological test 
session, magnetic resonance imaging, and positron emission tomography scanning.
MAIN OUTCOMES AND MEASURES: For each individual, 3 AD-sensitive 
neurodegeneration biomarkers were measured: hippocampal volume, glucose 
metabolism, and gray matter thickness, the latter 2 sampled from cortical 
AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker 
was age adjusted, dichotomized into a normal or abnormal status (using cutoff 
thresholds derived from an independent AD sample), and summarized into 0, 1, or 
more than 1 abnormal neurodegenerative biomarker. Degree and topographic 
patterns of neurodegenerative abnormalities were assessed and their 
relationships with cognitive functions, WML volume, and Aβ deposition 
(quantified using carbon 11-labeled Pittsburgh compound B positron emission 
tomography).
RESULTS: Of our cognitively normal elderly individuals, 40% (n = 29) displayed 
at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no 
evidence of elevated Pittsburgh compound B retention. In those people who were 
classified as having abnormal cortical thickness, degree and topographic 
specificity of neurodegenerative abnormalities were similar to patients with AD. 
Accumulation of neurodegenerative abnormalities was related to poor memory and 
executive functions as well as larger WML volumes but not elevated Pittsburgh 
compound B retention.
CONCLUSIONS AND RELEVANCE: Our study confirms that a substantial proportion of 
cognitively normal older adults harbor neurodegeneration, without Aβ burden. 
Associations of neurodegenerative abnormalities with cerebrovascular disease and 
cognitive performance indicate that neurodegenerative pathology can emerge 
through non-Aβ pathways within regions most affected by AD.