Antihypertensive medications ameliorate Alzheimer's disease pathology by slowing its propagation

Affleck, Andrew J.; Sachdev, Perminder S.; Stevens, Julia; Halliday, Glenda M.

doi:10.1002/trc2.12060

Cited by 14 publications

(38 citation statements)

References 38 publications

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“…Nonetheless, other interventions may have more subtle effects on amyloid burden, either directly or indirectly. Some examples would be BACE1 inhibitors [ 60 ], drugs with other targets which have downstream amyloid effects [ 61 ], or non-pharmacological therapies and multi-domain preventive trials such as those being tested in World-Wide FINGERS [ 62 , 63 ]. As such, 20% reduction of amyloid accumulation may be a relevant target to detect, especially in a short 1-year Proof-of-Concept study.…”

Section: Discussionmentioning

confidence: 99%

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

et al. 2021

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Background Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. Results Although highly correlated to DVR (ρ = .96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.

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Section: Discussionmentioning

confidence: 99%

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

et al. 2021

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“…Treating hypertension with medication may at least partially moderate these negative effects on brain health. For example, a recent autopsy study of 96 AD cases and 53 pathological controls found that antihypertensive medication use was associated with a less extensive spread of AD pathology in the brain [ 227 ].…”

Section: Promoting Successful Cognitive Agingmentioning

confidence: 99%

Promoting Successful Cognitive Aging: A Ten-Year Update

Krivanek

Gale

McFeeley

et al. 2021

JAD

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A decade has passed since we published a comprehensive review in this journal addressing the topic of promoting successful cognitive aging, making this a good time to take stock of the field. Because there have been limited large-scale, randomized controlled trials, especially following individuals from middle age to late life, some experts have questioned whether recommendations can be legitimately offered about reducing the risk of cognitive decline and dementia. Despite uncertainties, clinicians often need to at least make provisional recommendations to patients based on the highest quality data available. Converging lines of evidence from epidemiological/cohort studies, animal/basic science studies, human proof-of-concept studies, and human intervention studies can provide guidance, highlighting strategies for enhancing cognitive reserve and preventing loss of cognitive capacity. Many of the suggestions made in 2010 have been supported by additional research. Importantly, there is a growing consensus among major health organizations about recommendations to mitigate cognitive decline and promote healthy cognitive aging. Regular physical activity and treatment of cardiovascular risk factors have been supported by all of these organizations. Most organizations have also embraced cognitively stimulating activities, a heart-healthy diet, smoking cessation, and countering metabolic syndrome. Other behaviors like regular social engagement, limiting alcohol use, stress management, getting adequate sleep, avoiding anticholinergic medications, addressing sensory deficits, and protecting the brain against physical and toxic damage also have been endorsed, although less consistently. In this update, we review the evidence for each of these recommendations and offer practical advice about behavior-change techniques to help patients adopt brain-healthy behaviors.

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“…25 Eight studies (also) performed logistic regression analysis, with (history of) hypertension, AHM use, or SBP and DBP as continuous predictors, and dichotomized NP and NFT or Braak and CERAD as outcomes. 22,23,27,29,[30][31][32][33] Another four studies (also) performed ordinal regression analysis, predicting categorical measures of NP and NFT with continuous measures of BP, history of hypertension, and/or AHM use. 20,[26][27][28]…”

Section: Statistical Analysis Methods Usedmentioning

confidence: 99%

“…Ten were from the United States, [19][20][21][22][23][24][25][26][27][28] three from Europe, [29][30][31] one from Australia, 32 and one from Asia (Sri Lanka). 33 Ten collected clinical data prospectively before death, 19,20,22,23,[25][26][27][28][29]31 four retrospectively after death, 24,30,32,33 and one before and after death. 21 Ten studies included community-dwelling older people, recruited from the general population and/or retirement homes.…”

Section: Study Design and Participant Characteristicsmentioning

confidence: 99%

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Hypertension and Alzheimer's disease pathology at autopsy: A systematic review

Abdulrahman

Dalen

Brok

et al. 2022

Alzheimer's & Dementia

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Hypertension is an important risk factor for Alzheimer's disease (AD) and all‐cause dementia. The mechanisms underlying this association are unclear. Hypertension may be associated with AD neuropathological changes (ADNC), but reports are sparse and inconsistent. This systematic review included 15 autopsy studies (n = 5879) from observational cohorts. Studies were highly heterogeneous regarding populations, follow‐up duration, hypertension operationalization, neuropathological methods, and statistical analyses. Hypertension seems associated with higher plaque and tangle burden, but results are inconsistent. Four studies (n = 3993/5879; 68%), reported clear associations between hypertension and ADNC. Another four suggested that antihypertensive medication may protect against ADNC. Larger studies with longer follow‐up reported the strongest relationships. Our findings suggest a positive association between hypertension and ADNC, but effects may be modest, and possibly attenuate with higher hypertension age and antihypertensive medication use. Investigating interactions among plaques, tangles, cerebrovascular pathology, and dementia may be key in better understanding hypertension's role in dementia development.

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Antihypertensive medications ameliorate Alzheimer's disease pathology by slowing its propagation

Cited by 14 publications

References 38 publications

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

Strategies to reduce sample sizes in Alzheimer’s disease primary and secondary prevention trials using longitudinal amyloid PET imaging

Promoting Successful Cognitive Aging: A Ten-Year Update

Hypertension and Alzheimer's disease pathology at autopsy: A systematic review

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