Dementia And Alzheimer’s Disease

• Functional decline due to cognitive deficits

• 2010 : 35 million people worldwide, 2030: 60 million, 2050: 115 million worldwide.

• Ireland: 4,000 new cases every year- currently around 50,000

• AD- most common cause

• Insidious onset after age 70

• Predominantly amnestic symptoms

• Gradually progressive

Pathology of AD

1906

Multimodal Pathological Mechanisms

- Lifestyle Events/ Risk Factors

- Vascular Risk Factors- Neuroinflammation- Genetic Risk Factors

Amyloid hypothesis…sink and tap….

…and interplay of vascular ischaemia and brain blood flow

Everyone develops Tau pathology as they age Some people develop Amyloid pathology too In them- Tau pathology spreads and prompts a microglial and

astrocytic neuro-inflammatory response This leads to AD Vascular, metabolic and other factors impinge

What most agree on..

NINCDS ADRDA Alzheimer's Diagnostic Criteria Mc Khann 1984

Definitions and terminology around AD and the like…

NIA Alz Assoc Working Group Criteria 2011 (Mc Khann)

Predictive markers and symptoms of AD

Do these criteria transfer to clinical relevance??

Prodromal AD: 60% progression to AD within 2.5 years versus 4-18%

So what should the diagnostic paradigm for AD look like now??

Multi-domain Cognitive, psychological, physical Assessment- Hospital Anxiety Depression Scale- GDS- Cornell Scale Depression in Dementia- Delirium screening- Frontal Assessment Battery- Addenbrookes Cognitive Examination

Executive Function

Biomarkers are no longer just part of AD research….

Biomarker of neuronal injury.. Global cortical and Medial temporal lobe atrophy (CT/MRI)

Normal Prodromal/Mild AD Advanced AD

CSF Amyloid and neuronal injury biomarkers…

• INBIND consensus document

• Online training module

• 4 week turnaround

• Central Lab in SJH:• ↓Aβ 42

• ↑Tau

• ↑ P-tau

http://www.tcd.ie/research/inbind/resources/CSFbiomarkermodule/index.html

AD CSF profile

Amyloid PET scans: Florbetaben (Priamal April 2017)Others: Florbetapir (Eli Lilly) and Flutemetamol (GE healthcare)

FlorbetabenShelf life up to 10 hours

AD- “Dangers” of an early diagnosis…

REDUNDANT DEBATE!!!

Timely diagnosis…

Identification and management of reversible causes or alternative diagnosis

Symptomatic treatment

INFORMATION AND EDUCATION

Patient directed advance care planning

CARER SUPPORT

Mobilisation of support

Management of BPSD- DEPRESSION/ ANXIETY etc.

Key thing is to

ensure support

services in

place

Dementia Prevention- FINGER study (Finnish)

A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus

control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial

Kivipelto Lancet June 2015

- 1250 participants, population sample, high risk vascular with MCI- Standardised Exercise Program with 3 individually tailored

assessments by physio aerobic/non aerobic, balance and posture- 3 meetings with dietician- Cognitive training: group and individual sessions- Social activities mediated though group sessions- Vascular and metabolic risk factors monitored- Control group: Given information - Only 12% drop out!!- Seven year extension underway

25% higher

83% higher

150% higherOR 1.31

Cognitive Stimulation…

Wisconsin Registry for Alzheimer’s Prevention (WRAP) 1500 participants

339 (Age 40-65) (Mean age 60) 69% female Cognitively normal

Overall activities measured and “CAS Games: cards, crosswords, puzzles)

Amnestic MCI participants 12 week computer based memory-attention program Improvements in episodic memory and recall At 6 month f/u assessment improvements maintainedNeuropsychologica, 2012

Brain Imaging and Behaviour, 2015

AD Treatments…A lot of false dawns and reporting

Disease- modifying treatments

Solanezumab (Eli Lilly)- Passive Immunotherapy humanized monoclonal

IgG1 antibody directed against Aβ peptide- Phase 1 demonstrated changes in CSF/Plasma Aβ

- EXPEDITION 1+2 Phase 3 trial in 2,000 Mild/mod AD, Monthly infusion: Negative overall but…Statistically significant benefit was seen in a pooled analysis of patients with mild AD in both trials

- EXPEDITION 3: 2,100 Mild AD and Amyloid+ Missed primary endpoint!!

- Also: EXPEDITION PRO study (Amyloid +MCI)- just started enrolling

Creneuzumab (Genetech)- Very similar to Solaneuzamab- CREAD Study Phase 3 study in Prodromal AD

started 2016- Graduated dosing protocol

Aducanumab (Biogen)

- High-affinity, fully human IgG1 monoclonal antibody binds aggregated forms of Aβ, not monomer. In the brain it preferentially binds parenchymal over vascular amyloid- important from SE perspective

- Nature paper Sept 2016- Aducanumab- Phase 2 study 165 mild AD: 4 doses and placebo. Removed amyloid and slowed decline!!

- Monthly infusion for a year- Very few SE’s but a third had ARIA-E’s- Phase 3 studies started ENGAGE and EMERGE

STUDY’S (MCI and Mild AD and PET/CSF amyloid +)

- Recent 2 year data maintained positive results.

AD prevention studies

DIAN (Dominantly inherited AD Network) (Treatment arm- 2 years Rx with Solaneuzamab or Ganteneurmab) Age 18-80 years and First degree relative with AD gene.

A4 study: Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (PET+) (Rx 39 months Solanuzamab) Age 65-85

Alzheimer’s Prevention Initiative: Autosomal Dominant AD study (300 members of Colombian family with rare genetic

mutation) Crenezumab Generation Study: 1,300 Cog normal people (Age 60-75) APOE ε4 +/+: CAD106 (GSK

active immunotherapy vs CNP520 (Amgen BACE inhibitor)

In Summary….

International political/societal commitment (G8 declaration)

Better understanding of “life course” of AD- more accurate diagnosis

Pipeline of potential treatments…very cautious optimism!!

Have started thinking in terms of AD Prevention

Key message: Healthy Heart equals Healthy Brain!!

Thank you