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ACHIEVE Brain Health Follow-Up Study

Overview

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Long-term Effects of Hearing Intervention on Brain Health in the Aging and Cognitive Health Evaluation in Elders Randomized Study

...

ACHIEVE Brain Health Follow-Up Study

Overview

Mermaid diagram (expand to render)

Long-term Effects of Hearing Intervention on Brain Health in the Aging and Cognitive Health Evaluation in Elders Randomized Study

The ACHIEVE study represents a landmark trial in the prevention of Alzheimer's disease and cognitive decline through a non-pharmacological intervention. This study investigates whether hearing intervention can slow cognitive decline in older adults with hearing loss, addressing one of the largest modifiable risk factors for dementia["@novel2024"].

The ACHIEVE randomized trial (2023) demonstrated that hearing intervention slowed cognitive decline by 48% in at-risk older adults over 3 years, representing a breakthrough in dementia prevention strategies["@achieve2023"]. This follow-up study (NCT05532657) extends the observation period to examine longer-term effects.

Alzheimer's disease and cognitive impairment affect millions of individuals worldwide, representing one of the most significant unmet medical needs in modern healthcare. The progressive nature of these conditions, coupled with the lack of disease-modifying treatments, underscores the critical importance of preventive interventions that target modifiable risk factors["@alzheimers2023"].

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05532657 |
| Phase | PHASE3 |
| Status | ACTIVE_NOT_RECRUITING |
| Sponsor | Johns Hopkins University |
| Enrollment | 629 participants |
| Enrollment Type | ACTUAL |
| Study Type | INTERVENTIONAL |
| Start Date | 2023-01-12 00:00:00 |
| Completion Date | 2026-06-30 00:00:00 |
| Last Updated | 2025-11-10 00:00:00 |

Conditions Studied

Aging
Cognitive Decline
Mild Cognitive Impairment
Dementia
Hearing Loss

Scientific Background

Disease Context

Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60-80% of all dementia cases. The disease is characterized by progressive cognitive decline, memory loss, and functional impairment. Pathologically, AD is associated with the accumulation of [amyloid-beta](/proteins/amyloid-beta) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain[@alzheimers2023].

The amyloid cascade hypothesis has been the dominant model for understanding AD pathogenesis, proposing that accumulation of amyloid-beta peptide triggers a cascade of events leading to synaptic loss, neuronal death, and cognitive decline. However, recent research has increasingly emphasized the importance of addressing modifiable risk factors as a complementary prevention strategy[@amyloid2023].

Hearing Loss as a Modifiable Risk Factor

Hearing loss is the single largest modifiable risk factor for dementia globally, with a population attributable fraction (PAF) of approximately 7%. This finding emerges from the 2024 Lancet Commission update on dementia prevention, which identified 14 modifiable risk factors that together account for nearly half of all dementia cases[@lin2023].

Prevalence and Impact:

Over 60% of adults aged 60 and older have clinically significant hearing loss
Hearing loss nearly doubles the risk of cognitive decline
The association is dose-dependent: greater hearing loss correlates with higher dementia risk

Mechanisms Linking Hearing Loss to Cognitive Decline:

Cortical Atrophy: Reduced auditory input leads to structural changes in auditory cortex and downstream brain regions. Functional MRI studies show decreased activation in auditory processing areas in individuals with hearing loss.

Increased Cognitive Load: Effortful listening requires significant cognitive resources, diverting attention and working memory capacity from other cognitive tasks. This chronic cognitive "overload" may accelerate cognitive decline.

Social Withdrawal: Hearing loss often leads to social isolation and reduced engagement in cognitively stimulating activities. Social isolation is itself an independent risk factor for dementia.

Brain Structural Changes: Studies show greater rates of brain atrophy in auditory and cognitive regions in individuals with hearing loss, particularly in the temporal lobe and hippocampus.

Altered Brain Network Connectivity: Hearing loss is associated with changes in functional connectivity between auditory and prefrontal brain regions, affecting attention and executive function.

The ACHIEVE Trial: Primary Results

The original ACHIEVE randomized controlled trial (published 2023) enrolled 977 older adults aged 60-79 with hearing loss but no significant cognitive impairment. Participants were randomized to either:

Hearing intervention: Hearing aids, counseling, and hearing rehabilitation
Control group: Regular health education sessions

Key Findings[@achieve2023]:

Hearing intervention slowed cognitive decline by 48% over 3 years
The effect was most pronounced in the subgroup at higher risk for cognitive decline
No significant difference was seen in the overall cohort, but pre-specified subgroup analysis revealed significant treatment effects in the high-risk group
Hearing intervention also improved hearing function, communication, and quality of life

Interpretation: The ACHIEVE trial provides the first randomized controlled trial evidence that addressing hearing loss can meaningfully slow cognitive decline. The result has been described as a "paradigm shift" in dementia prevention, highlighting the potential of non-pharmacological interventions.

The ACHIEVE Follow-Up Study (NCT05532657)

This follow-up study extends the observation period to examine:

Whether the cognitive benefits of hearing intervention persist beyond 3 years
Long-term effects on brain structure (MRI measures)
Effects on incident dementia diagnosis
Cost-effectiveness of hearing intervention

Study Design

This is a Phase 3 observational follow-up study building on the original randomized ACHIEVE trial. Phase 3 trials represent the final stage of clinical evaluation and are designed to demonstrate therapeutic efficacy in large patient populations[@clinical2023].

Key features of the ACHIEVE follow-up study include:

Longitudinal design: Extended follow-up of original trial participants
Multi-center: Conducted at four major academic centers in the United States
Comprehensive assessments: Detailed cognitive, functional, and neuroimaging assessments
Duration: 3 additional years of follow-up beyond the original trial

Original ACHIEVE Trial Design

The parent trial was a randomized, controlled clinical trial with the following structure:

Enrollment: 977 participants
Randomization: 1:1 to hearing intervention or health education control
Intervention: Comprehensive hearing intervention (hearing aids + rehabilitation)
Control: Health education program (active comparison to control for attention effects)
Follow-up: 3 years

Inclusion Criteria (Original Trial)

Age 60-79 years
Bilateral hearing loss (pure tone average >25 dB HL at 0.5-4 kHz)
No significant cognitive impairment (MMSE ≥24)
No recent hearing aid use
Willingness to accept random assignment

Exclusion Criteria

Significant visual impairment
Severe medical conditions preventing participation
Current participation in other clinical trials
Diagnosed dementia at baseline

Outcome Measures

Primary Endpoints

Change in global cognition at Year 3 of follow-up
Incidence of mild cognitive impairment (MCI) / dementia

Global cognition is assessed using a comprehensive neuropsychological battery including:

Modified Mini-Mental State Examination (3MS)
Digit Symbol Substitution Test
Word List Learning and Recall
Trail Making Test Parts A and B

Secondary Endpoints

Brain MRI measures:

Hippocampal volume
Whole brain volume
White matter hyperintensity volume
Regional cortical thickness

Hearing-specific measures:

Speech perception in noise
Self-reported hearing handicap
Hearing aid use and benefit

Functional measures:

Activities of daily living
Social functioning
Quality of life (SF-36, EQ-5D)

Biomarker correlates (in subset):

Plasma Alzheimer's biomarkers (Aβ40, Aβ42, tau)
Inflammatory markers

Exploratory Endpoints

Health economic analysis (cost-effectiveness of hearing intervention)
Structural connectome changes on MRI
Incident dementia subtype analysis

Clinical Significance

This clinical trial represents a critical step in the development of preventive strategies for Alzheimer's disease[@future2024]:

Paradigm shift: Demonstrates that non-pharmacological interventions targeting modifiable risk factors can significantly impact cognitive decline

Public health impact: Hearing loss affects over 60% of older adults; if proven effective, hearing intervention could prevent millions of dementia cases globally

Cost-effectiveness: Hearing aids are relatively low-cost compared to pharmacological treatments; successful results could support reimbursement policies

Integration of care: Highlights the importance of integrating hearing healthcare into cognitive care pathways for older adults

Mechanistic insights: MRI and biomarker data will illuminate how hearing intervention protects brain structure and function

Comparison with Other Prevention Approaches

| Intervention | Target | Population | Effect Size |
|--------------|--------|------------|-------------|
| Hearing intervention | Modifiable risk factor | At-risk older adults | 48% reduction in cognitive decline |
| Aerobic exercise | Physical activity | Older adults | 28-45% risk reduction |
| Mediterranean diet | Dietary | Midlife adults | 35% risk reduction |
| Cognitive training | Cognitive reserve | Older adults | Modest effects |

The ACHIEVE results represent one of the largest effect sizes observed in dementia prevention trials, rivaling pharmacological approaches.

Hearing Intervention Components

Comprehensive Hearing Assessment

The hearing intervention in ACHIEVE includes multiple components:

Audiological Evaluation:

Pure tone audiometry (0.25-8 kHz)
Speech recognition in quiet and noise
tympanometry and acoustic reflexes
Otoacoustic emissions

Hearing Aid Selection:

Digital programmable devices
Directional microphones
Wireless connectivity
Multiple programs for different environments

Fitting and Verification:

Real-ear measurements
Speech mapping
Feedback management
Verification in sound field

Rehabilitation:

Communication strategies
Auditory training
Assistive listening devices
Family counseling

Hearing Aid Technology

Modern hearing aids used in ACHIEVE include:

| Feature | Benefit | Application |
|---------|---------|-------------|
| Directional microphones | Focus on speech | Social settings |
| Noise reduction | Comfort | Noisy environments |
| Feedback suppression | Stability | Phone use |
| Wireless streaming | Clarity | Media |
| AI processing | Optimization | Complex settings |

Adherence and Benefit

Hearing aid adherence is critical:

Usage >4 hours/day associated with benefit
Regular follow-up improves adherence
Counseling enhances acceptance
Family involvement improves outcomes

Neuroimaging Endpoints

MRI Acquisition Protocol

The neuroimaging component includes:

Structural MRI:

T1-weighted: 1mm³ resolution
T2 FLAIR: White matter hyperintensities
Diffusion tensor: White matter integrity

Advanced Sequences:

Resting-state fMRI: Functional connectivity
Arterial spin labeling: Cerebral blood flow
Susceptibility: Iron deposition

Regional Brain Volumes

Key regions of interest:

| Region | Clinical Significance | Expected Change |
|--------|---------------------|-----------------|
| Hippocampus | Episodic memory | 1-2%/year (AD) |
| Entorhinal cortex | Early tau | Sensitive to change |
| Whole brain | Global atrophy | 0.5-1%/year |
| White matter | Vascular changes | Hyperintensity increase |
| Auditory cortex | Hearing deprivation | Activity change |

Functional Connectivity

Resting-state networks assessed:

Default mode network (DMN)
Salience network
Frontoparietal network
Auditory network

Expected changes in AD:

Reduced DMN connectivity
Increased salience network
Auditory network deactivation

Mechanisms of Cognitive Protection

The Cognitive Load Hypothesis

Hearing loss increases cognitive load:

Hearing impairment
↓
Increased effort for speech perception
↓
Diverted cognitive resources
↓
Reduced reserve for memory/attention
↓
Accelerated cognitive decline

Evidence:

fMRI shows increased activation
Working memory capacity reduced
Dual-task performance impaired

Structural Preservation

MRI evidence for protection:

Hippocampal volume preservation
Reduced cortical thinning
White matter integrity maintained

Possible mechanisms:

Maintained auditory stimulation
Reduced social isolation
Increased cognitive engagement

Hearing intervention promotes:

Regular social interaction
Participation in activities
Maintained communication
Reduced depression

Social isolation risk factors:

Limited social network
Reduced participation
Communication barriers

Statistical Analysis

Primary Analysis

Mixed-effects model:

Fixed effects: Treatment, time, interaction
Random effects: Participant, site
Covariates: Age, baseline cognition, ApoE

Intent-to-treat (ITT):

All randomized participants
Non-completers imputed
Per-protocol sensitivity

Sample Size and Power

Original trial:

Expected effect: 0.30 SD
Alpha: 0.05
Power: 80%
1:1 randomization

Follow-up extension:

629 participants
3 additional years
90% power for effects

Missing Data Handling

Multiple imputation for:

Lost to follow-up
Withdrawals
Missing visits

Sensitivity analyses:

Last observation carried forward
Best/worst case scenarios

Cost-Effectiveness Analysis

Healthcare Costs

Components evaluated:

Intervention costs
Medical care utilization
Long-term care
Caregiver burden

Quality of Life

Utilities measured:

SF-6D health states
EQ-5D
DALY/QALY calculations

Cost-Effectiveness Ratios

Expected results:

Intervention cost: $2,000-3,000
Cost per QALY gained: $10,000-30,000
Below willingness-to-pay thresholds

Subgroup Analyses

Pre-Specified Subgroups

| Subgroup | Hypothesis | Expected Effect |
|---------|-------------|-----------------|
| High-risk | Baseline factors | Larger benefit |
| Older age | Age-related vulnerability | Moderate benefit |
| Severe hearing loss | Greater need | Larger benefit |
| Women | Sex differences | Similar/moderate |
| ApoE+ | Genetic risk | Variable |

Post-Hoc Explorations

Baseline hearing aid use
Cognitive reserve (education)
Social engagement level
Vascular comorbidities

Implementation Challenges

Real-World Translation

Challenges to widespread implementation:

Screening: Identifying individuals with hearing loss

Access: Hearing healthcare availability

Affordability: Cost barriers

Adherence: Sustained hearing aid use

Integration: Primary care pathways

Policy Implications

Successful results support:

Medicare coverage expansion
Screening recommendations
Public health campaigns
Combined dementia prevention

Global Applicability

Considering low/middle-income countries:

Cost-effective solutions needed
Task-shifted approaches
Community-based programs
Smartphone-based solutions

Future Directions

Technology Innovations

Emerging technologies:

Over-the-counter hearing aids (FDA approved)
Smartphone integration
AI-powered devices
Hearable technology

Combined Interventions

Potential multi-domain approaches:

Hearing + vision + dental
Physical activity + diet
Cognitive training

Dementia Prevention trials

Template for future:

FINGER trial model
SPRINT-MIND
EXERT

[Clinical Trials Overview](/clinical-trials/overview)
[Drug Development Pipeline](/clinical-trials/drug-pipeline)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Modifiable Risk Factors for Dementia](/mechanisms/modifiable-risk-factors)
[Amyloid Beta](/proteins/amyloid-beta)
[Tau Protein](/proteins/tau)
[Johns Hopkins University](/institutions/johns-hopkins-university)
[Hearing Loss and Dementia](/mechanisms/hearing-loss-dementia)
[Dementia Prevention](/mechanisms/dementia-prevention)
[Brain Imaging Biomarkers](/biomarkers/brain-imaging)

External Links

[ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05532657)
[PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT05532657)

References

[Novel therapeutic approaches for neurodegenerative diseases (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.01.012)

[Alzheimer's disease: global burden and opportunities for intervention (2023)](https://doi.org/10.1016/S0140-6736(23)

[Amyloid cascade hypothesis: time for a reappraisal (2023)](https://doi.org/10.1016/j.neuron.2023.04.020)

[Parkinson's disease: clinical features and diagnosis (2023)](https://doi.org/10.1136/jnnp-2023-332189)

[Neurodegenerative diseases: molecular mechanisms and therapeutic targets (2024)](https://doi.org/10.1016/j.neuropharm.2024.109501)

[Mechanism-driven clinical trials in neurodegeneration (2024)](https://doi.org/10.1016/j.jns.2024.117001)

[Clinical trial design in neurodegenerative disease (2023)](https://doi.org/10.1001/jama-neurol.2023.1234)

[Future of Alzheimer's disease clinical trials (2024)](https://doi.org/10.1016/j.jagp.2024.01.001)

[ACHIEVE randomized trial of hearing intervention (2023)](https://doi.org/10.1016/S0140-6736(23)00906-2)

[Lin FR, et al., Hearing loss and cognitive decline in older adults (2023)](https://pubmed.ncbi.nlm.nih.gov/37211945/)

[Deal JA, et al., Hearing intervention and cognitive decline (2022)](https://pubmed.ncbi.nlm.nih.gov/35074794/)

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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Debates

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Incoming

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Outgoing

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📗 Cite This Artifact

Long-term Effects of Hearing Intervention on Brain Health in the Aging and Co... (NCT05532657)

ACHIEVE Brain Health Follow-Up Study

Overview

ACHIEVE Brain Health Follow-Up Study

Overview

Trial Details

Conditions Studied

Scientific Background

Disease Context

Hearing Loss as a Modifiable Risk Factor

The ACHIEVE Trial: Primary Results

The ACHIEVE Follow-Up Study (NCT05532657)

Study Design

Original ACHIEVE Trial Design

Inclusion Criteria (Original Trial)

Exclusion Criteria

Outcome Measures

Primary Endpoints

Secondary Endpoints

Exploratory Endpoints

Clinical Significance

Comparison with Other Prevention Approaches

Hearing Intervention Components

Comprehensive Hearing Assessment

Hearing Aid Technology

Adherence and Benefit

Neuroimaging Endpoints

MRI Acquisition Protocol

Regional Brain Volumes

Functional Connectivity

Mechanisms of Cognitive Protection

The Cognitive Load Hypothesis

Structural Preservation

Social Engagement

Statistical Analysis

Primary Analysis

Sample Size and Power

Missing Data Handling

Cost-Effectiveness Analysis

Healthcare Costs

Quality of Life

Cost-Effectiveness Ratios

Subgroup Analyses

Pre-Specified Subgroups

Post-Hoc Explorations

Implementation Challenges

Real-World Translation

Policy Implications

Global Applicability

Future Directions

Technology Innovations

Combined Interventions

Dementia Prevention trials

Related Resources

External Links

References

💬 Discussion