Impact of Alzheimer’s disease risk factors on memory function and amyloid levels in early midlife

Paris Fisher, BA

Massachusetts General Hospital – Research Assistant

Scientific Abstract

Background: Preclinical risk for Alzheimer’s disease (AD), including amyloid (Aβ) deposition, begins 10-15 years prior to AD diagnosis. In addition to genetics, hypertension (HYP), type 2 diabetes (T2D), and major depressive disorder (MDD) in midlife are major risk factors for AD. We hypothesize that in midlife, these risk factors will be related to poor cognitive performance and increased Aβ deposition, prior to the onset of overt clinical symptoms.

Methods: High- (HR) and low-risk (LR) subjects (N=83; ages 50-70 yrs) were recruited from the MGB Biobank, initiating the Healthy Aging Translational CoHort (HATCH). HR subjects have genetic risk (APOE4) plus HYP, T2D, and/or MDD; LR subjects have no genetic or clinical risk factors. Cognitive function was assessed using the Face-Name Associative Memory Test (FN), 6-Trial Selective Reminding Test (SRT), Verbal Fluency Task (FAS/CAT), and Digit Span (DS). Aβ deposition was detected through PET using C-11PiB. We compared memory performance and Aβ levels between HR and LR groups and evaluated both cumulative and individual impact of each clinical risk factor on memory function.

Results: Overall, HR was associated with lower cognitive performance (FN: F=14.30, p<0.001; CAT: F=7.02, p<0.01; DS: F=4.65, p<0.03) and higher Aβ deposition in the brain (F=4.01, p<0.05) compared to LR. Effects in HR were predominantly driven by HYP and T2D. Those with HYP had poor performance on all tests (FN: F=11.75, p<0.01; SRT: F=5.04, p<0.05; CAT: F=8.14, p<0.01; DS: F=7.73, p<0.01). Likewise, T2D presence negatively impacted performance in all cognitive domain (FN: F=8.57, p<0.01; SRT: F=5.26, p<0.05; CAT: F=7.77, p<0.01; DS: F=6.38, p=0.01). MDD alone was only related to associative memory (FN: F=4.29, p<0.05).

Conclusions: In midlife, genetic risk plus poor cardiometabolic health were associated with lower memory performance across all cognitive domains, while the impact of MDD was limited to associative memory. Significantly higher levels of Aβ were also detected in HR individuals. These results suggest that genetic and clinical risk factors for AD may help identify early targets for intervention in those at risk of AD later in life.

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research Areas


Paris Fisher, BA, Kyoko Konishi, PhD, Sarah Aroner, PhD, Dmitry Prokopenko, PhD, Brianna Smith, BS, Enejda Senko, MS, Harlyn Aizley, EdM, Anne Remington, MA, Alexandra Touroutoglou, PhD, Jonathan Rosand, MD, Bradford Dickerson, MD, Rudolph Tanzi, PhD, Jill Goldstein, PhD

Principal Investigator

Jill Goldstein, PhD