Overview & Epidemiology

1. What is Alzheimer’s Disease?

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder defined by two pathological hallmarks first described by Alois Alzheimer in his 1906 case report on Auguste Deter:

• Extracellular amyloid plaques — aggregates of the amyloid-β (Aβ) peptide, predominantly the 42-residue isoform Aβ₄₂.
• Intraneuronal neurofibrillary tangles — paired helical filaments of hyperphosphorylated tau protein.

On top of these is layered progressive neuronal loss, beginning in the entorhinal cortex and hippocampus and spreading along well-mapped anatomical trajectories — the Braak stages covered in Part II. Synaptic dysfunction and neuroinflammation are increasingly seen as integrating mechanisms that link the proteinopathies to clinical decline.

2. The Dementia Spectrum

Dementia is a clinical syndrome of acquired, progressive cognitive decline severe enough to interfere with daily function. AD is its commonest cause but far from the only one:

In autopsy series, mixed pathology is the rule rather than the exception — especially in the very old, where vascular damage, Lewy bodies, TDP-43, and hippocampal sclerosis (LATE) commonly accompany AD changes.

3. Clinical Phenotype

The classical (amnestic) presentation of AD evolves over years through three broad clinical phases:

Cognitive domains (in approximate order of involvement)

• Episodic memory — recent events, conversations; reflects medial-temporal-lobe involvement.
• Executive function — planning, multi-step tasks, set-shifting.
• Visuospatial — getting lost, copying figures; parietal involvement.
• Language — word-finding (anomia), semantic loss.
• Behaviour — apathy is the commonest neuropsychiatric symptom; agitation, depression, psychosis appear later.
• Motor function — preserved early; gait disorder, incontinence, immobility appear in late disease.

Atypical (~15%) presentations include posterior cortical atrophy (visual cortex first), logopenic primary progressive aphasia (language first), and frontal-variant AD (behaviour first) — all amyloid-positive but with non-amnestic onset.

4. Global Burden

The age-standardised incidence in high-income countries has actually fallen ~13% per decade since the 1980s — better cardiovascular control, smoking reduction, education, and treatment of midlife hypertension. Yet absolute case numbers continue to risebecause populations are aging faster than incidence is falling. By 2050 dementia prevalence is projected to ~139 million (Lancet Commission 2020 update; GBD 2019 Dementia Collaborators).

Demographic patterns:

• Age — AD prevalence ~3% at age 65–74, ~17% at 75–84, ~32% at ≥85. Doubles every ~5 years above age 65.
• Sex — women have ~2× the lifetime risk of men, only partially explained by greater longevity.
• Geography — ~60% of cases in low- and middle-income countries; growing fastest there.
• Ethnicity — in the USA, Black and Hispanic adults have higher prevalence than non-Hispanic White at any given age, partly attributable to vascular co-pathology.

5. Risk Factors

The Lancet Commission on Dementia Prevention (Livingston et al., Lancet 2020 + 2024 update) identified 14 modifiable risk factors that, if addressed across the life course, could prevent or delay an estimated ~45% of dementia cases:

Non-modifiable risk factors: age (the dominant factor), female sex, family history, and the APOE-ε4 allele: one copy ~3× risk, two copies ~12× risk relative to ε3/ε3 (covered in detail in Part V).

6. Disease Stages — CDR & FAST

Two staging instruments dominate clinical use:

• Clinical Dementia Rating (CDR) — six domains scored 0 (none) → 0.5 (questionable) → 1 (mild) → 2 (moderate) → 3 (severe). Sum-of-boxes gives finer resolution. Used universally in trials.
• Functional Assessment Staging Tool (FAST) — 7 stages from normal (1) to severe dementia with loss of speech, ambulation, and continence (7). Useful for hospice eligibility.

Average CDR progression in untreated AD is ~1 unit per ~1.5–2 years; anti-amyloid monoclonals slow this by ~25–35% on the CDR-Sum-of-Boxes (lecanemab CLARITY-AD and donanemab TRAILBLAZER-ALZ-2 readouts).

7. Lifetime Trajectory of AD

The biomarker trajectory of AD — mapped most clearly by Jack et al.(Lancet Neurol 2010, 2013) using the DIAN cohort of autosomal-dominant familial AD — shows that pathology accumulates for 15–25 years before symptoms:

1. Aβ accumulation begins first — CSF Aβ42 declines and amyloid PET begins to rise ~20 yrs before symptom onset.
2. Tau pathology follows ~5–10 yrs later, beginning in entorhinal cortex; CSF p-tau217 rises in parallel.
3. Neurodegeneration (FDG-PET hypometabolism, hippocampal atrophy) emerges ~5–10 yrs before clinical symptoms.
4. Cognitive decline begins as MCI; CDR transitions from 0 → 0.5.
5. Dementia — CDR ≥1, functional decline, loss of independence.

This long preclinical phase is both an opportunity and a frustration: there is a wide therapeutic window, but no current drug targets the earliest molecular events before plaques and tangles form. The A4 study (anti-amyloid in cognitively normal amyloid-PET-positive adults) is testing primary prevention.

8. A Brief History

• 1906 — Alois Alzheimer presents the case of Auguste Deter (51 yo, dementia, plaques and tangles on autopsy) at Tübingen.
• 1910 — Emil Kraepelin coins “Alzheimer’s disease” in his Handbook.
• 1968 — Roth, Tomlinson & Blessed correlate plaque count with cognitive scores: pathology drives clinical disease.
• 1976 — Davies and Maloney show cholinergic deficit in AD brain — basis of cholinesterase inhibitors.
• 1984 — Glenner and Wong purify Aβ from cerebrovascular amyloid; Masters and Beyreuther repeat from plaques (1985).
• 1987 — APP gene cloned; located on chromosome 21 (the “Down syndrome connection” explained).
• 1991 — First APP missense mutations linked to early-onset familial AD (Goate et al.).
• 1992 — Hardy & Higgins articulate the amyloid cascade hypothesis.
• 1993 — APOE-ε4 identified as the major late-onset risk allele (Strittmatter, Saunders, Roses).
• 1995 — Presenilin 1 and 2 cloned (Sherrington, Levy-Lahad).
• 1993–96 — Tacrine, donepezil, rivastigmine, galantamine: cholinesterase inhibitor era.
• 2003 — Memantine approved (NMDA partial antagonist).
• 2004 — First amyloid-PET imaging with PiB ([Klunk & Mathis]).
• 2018 — NIA-AA biological “ATN” framework.
• 2021 — Aducanumab accelerated approval — controversial; later withdrawn.
• 2023 — Lecanemab full approval (CLARITY-AD, NEJM 2023): 27% slowing of CDR-SB decline.
• 2024 — Donanemab full approval (TRAILBLAZER-ALZ-2, JAMA 2023): 35% slowing in low/medium tau.
• 2024 — Plasma p-tau217 emerges as accurate, accessible AD biomarker.

9. Where This Course Goes

The remainder of the course descends into the molecular and clinical detail behind the picture sketched here: