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Alzheimer’s disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+and Vip+inhibitory neuron subtypes. These findings were replicated in other major AD studies.

IMPORTANCE: Modifiable risk factors are hypothesized to account for 30% to 40% of dementia; yet, few trials have demonstrated that risk-reduction interventions, especially multidomain, are efficacious. OBJECTIVE: To determine if a personalized, multidomain risk reduction intervention improves cognition and dementia risk profile among older adults. DESIGN, SETTING, AND PARTICIPANTS: The Systematic Multi-Domain Alzheimer Risk Reduction Trial was a randomized clinical trial with a 2-year personalized, risk-reduction intervention. A total of 172 adults at elevated risk for dementia (age 70-89 years and with ≥2 of 8 targeted risk factors) were recruited from primary care clinics associated with Kaiser Permanente Washington. Data were collected from August 2018 to August 2022 and analyzed from October 2022 to September 2023. INTERVENTION: Participants were randomly assigned to the intervention (personalized risk-reduction goals with health coaching and nurse visits) or to a health education control. MAIN OUTCOMES AND MEASURES: The primary outcome was change in a composite modified Neuropsychological Test Battery; preplanned secondary outcomes were change in risk factors and quality of life (QOL). Outcomes were assessed at baseline and 6, 12, 18, and 24 months. Linear mixed models were used to compare, by intention to treat, average treatment effects (ATEs) from baseline over follow-up. The intervention and outcomes were initially in person but then, due to onset of the COVID-19 pandemic, were remote. RESULTS: The 172 total participants had a mean (SD) age of 75.7 (4.8) years, and 108 (62.8%) were women. After 2 years, compared with the 90 participants in the control group, the 82 participants assigned to intervention demonstrated larger improvements in the composite cognitive score (ATE of SD, 0.14; 95% CI, 0.03-0.25; P = .02; a 74% improvement compared with the change in the control group), better composite risk factor score (ATE of SD, 0.11; 95% CI, 0.01-0.20; P = .03), and improved QOL (ATE, 0.81 points; 95% CI, −0.21 to 1.84; P = .12). There were no between-group differences in serious adverse events (24 in the intervention group and 23 in the control group; P = .59), but the intervention group had greater treatment-related adverse events such as musculoskeletal pain (14 in the intervention group vs 0 in the control group; P < .001). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, a 2-year, personalized, multidomain intervention led to modest improvements in cognition, dementia risk factors, and QOL. Modifiable risk-reduction strategies should be considered for older adults at risk for dementia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03683394