Alzheimer's & Cognitive Aging

DSM-5 Minor NCD (MCI) — cognitive criterion

Modest decline; concerns reported AND objective assessment shows 1–2 SD below norm

DSM-5 Minor NCD (MCI) — functioning criterion

Independence in daily functioning is relatively intact

DSM-5 Major NCD (Dementia) — cognitive criterion

Significant decline; concerns reported AND objective assessment shows greater than 2 SD below norm

DSM-5 Major NCD (Dementia) — functioning criterion

Interference with independence in everyday activities

DSM-5 dementia umbrella principle

DSM-5 Major NCD does NOT specify cause; etiology is determined separately by underlying brain pathology

Dementia subtypes by prevalence in the Netherlands (Franke 2018)

AD 65%, VaD 22%, FTD 4%, Lewy Bodies 2%; mixed etiology far more likely in patients over 75

MCI conversion rate

Approximately 50% convert to dementia within 5–10 years; a proportion have no underlying neurodegeneration

MCI treatment

No intervention proven to delay or prevent conversion; management involves reassessment, psychoeducation, and early cognitive training

Alzheimer's disease definition

Most common dementia (~70% of cases); neurodegenerative; first and most prominent symptom is gradually progressive memory loss; neuropsychiatric symptoms (depression, apathy, anxiety) are also common

AD final stage

Completely dependent, confused, and incontinent

AD diagnostic criteria

(1) Major NCD confirmed; (2) vague onset with gradual progression over months–years; (3) impairment in at least 2 domains (memory, EF, language, visuospatial); (4) no substantial concurrent CVD, neurological, or psychiatric disease

AD neuropathology

Extracellular plaques of amyloid-beta protein AND intracellular tangles of tau protein leading to neurodegeneration and atrophy; confirmed post-mortem only

AD MRI findings

Extreme cortical shrinkage, severely enlarged ventricles, extreme hippocampal shrinkage

AD EEG findings

Slowing of alpha activity

AD PET findings

Reduced cerebral glucose metabolism

Amyloid cascade hypothesis

Amyloid-beta is the primary driver of AD; clearing it is the main therapy target; clinical efficacy is inconclusive; criticism includes unclear cause vs consequence and failed treatments

Vascular hypothesis of AD

Vascular risk factors reduce blood flow and oxygen, causing a metabolic reaction that leads to overproduction of amyloid-beta

Most currently accepted AD causal model

Combined amyloid and vascular hypothesis

AD non-modifiable risk factors

Age, female sex, genetic predisposition

AD modifiable risk factors

12 lifestyle factors including exercise, diet, and mental activity (Kessels Fig 19.2)

CDR 0.5 (MCI stage)

Memory complaints, subtle decline, independence intact; initial complaints include forgetting recent events, appointments, and word-finding problems

CDR 1 (Mild dementia)

Language production declines, orientation in time and place declines, planning and performing activities declines → clear daily limitations

CDR 2 (Moderate dementia)

More extensive impairments; increased dependency on others; basic ADL such as dressing become difficult

CDR 3 (Severe dementia)

Completely dependent, confused, incontinent

AD treatment — mild to moderate

Cholinesterase inhibitors

AD treatment — moderate to severe

Memantine (NMDA antagonist)

AD treatment — always first step

Psychoeducation

NPA in AD — Stage 1 Complaints analysis

Interview patient AND close relative separately; anosognosia common so patient may trivialise or deny; ask about subjective complaints, onset, psychiatric symptoms, daily independence, family and medication history; screening with MMSE

NPA in AD — Stage 2 Problem analysis

Test memory (early = anterograde LTM decline; late = retrograde and semantic too), EF (cognitive flexibility, planning), attention (mental flexibility, divided), and visuospatial and language; tests include Visual Association Test, word recall, TMT, Stroop, digit span, clock drawing

NPA in AD — neuropsychiatric symptoms

Depression, anxiety, apathy, social disengagement, irritability, psychosis (hallucinations/delusions), agitation/aggression/wandering, motor unrest, sleep/eating problems, olfactory dysfunction, seizures (10–20%, usually late stages), motor signs (late)

NPA in AD — Stage 3 Diagnosis

Medical history + clinical exam + neuroimaging + NPA

Posterior Cortical Atrophy (PCA)

Atypical AD variant; prominent visuospatial deficits, memory relatively intact ("visual variant"); atrophy in parietal and occipital regions

Logopenic PPA (LvPPA)

Atypical AD variant; predominant language and communication deficits; memory and EF affected later ("language variant"); left temporal asymmetric atrophy; 75% have underlying AD pathology

Behavioural/Dysexecutive AD variant

Atypical AD variant; behaviour, EF, and social cognition decline; ranges from disinhibition to apathy; mimics bvFTD; biomarkers needed to differentiate; atrophy in frontal lobe

Typical vs Atypical AD

Typical AD has prominent memory impairment and atrophy starting in mediotemporal lobe; atypical AD has other prominent cognitive impairments and atrophy in different cortical regions; ALL have the same underlying neuropathology (amyloid + tau)

AD certainty increases with

Formal neuropsychological assessment, neuroimaging (CT/MRI/PET), CSF analyses, and genetic mutation (very rare); neuropathology confirmed only post-mortem

AD seizures

Occur in 10–20% of AD patients, usually in late stages

AD motor signs

Appear late in the disease course

AD olfactory dysfunction

Present in AD as a neuropsychiatric/non-cognitive symptom

AD anosognosia in clinical interview

Patient may trivialise or deny problems; always interview a close relative separately; this is why heteroanamnesis is essential in the diagnostic cycle

NPA Stage 4 in AD

Indication for treatment — follows diagnosis in the diagnostic cycle

Neuropsychiatric symptoms of AD — full list

Depression, anxiety, apathy, social disengagement, irritability, psychosis (hallucinations/delusions), agitation/aggression/wandering, motor unrest, sleep and eating problems, olfactory dysfunction, seizures (10–20%, usually late), and motor signs (late)

Language — general and aging

Generally stable overall across the lifespan; confrontation naming is the exception (stable to age 70 then declines)

Older adults performance crossover

Older adults outperform younger adults on crystallised tasks but perform worse on fluid tasks

Cognitive retraining — strategy training

Strategy training targets memory, reasoning, and processing speed; ACTIVE trial showed 10 sessions → less decline in instrumental ADL at 5 years

Cognitive retraining — home vs lab

Home video training is 74% as effective as lab-based training (ACTIVE trial)

Protective lifestyle factors — intellectual activities

Puzzles, reading, bridge, and music all support cognitive aging

Protective lifestyle factors — exercise

Especially cardiovascular exercise is protective against cognitive decline

Protective lifestyle factors — social engagement

Travel, cultural events, and socialising are associated with better cognitive aging

Observational study limitation (lifestyle-cognition)

Lifestyle-cognition studies are largely observational; causal direction is unclear — it is possible that cognitively healthier people are more active rather than activity causing better cognition

Neural reserve vs neural compensation

Neural reserve = efficiency of existing networks; neural compensation = recruitment of alternative networks when primary networks fail; both form cognitive reserve

Dedifferentiation (STAC)

Older adults use MORE brain areas for working memory and episodic tasks on fMRI than younger adults; reflects less selective, less efficient processing; part of the scaffolding response to age-related decline