Alzheimer's Disease: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60-80% of all dementia cases worldwide. Over 55 million people globally are living with dementia, the large majority with Alzheimer's disease; this number is projected to reach 139 million by 2050 as populations age. In the United States, approximately 6.9 million Americans over age 65 are living with Alzheimer's, with the disease imposing a cumulative lifetime care cost exceeding $350,000 per patient. Alzheimer's disease is fundamentally a protein misfolding disorder — characterized by the progressive accumulation of extracellular amyloid-beta (Aβ) plaques and intraneuronal hyperphosphorylated tau neurofibrillary tangles, which disrupt synaptic function, trigger neuroinflammation, and cause neuronal death beginning in the entorhinal cortex and hippocampus before spreading throughout the neocortex. Risk doubles approximately every 5 years after age 65; women represent approximately two-thirds of those affected. The NIA-AA A/T/N biological staging framework (A: amyloid, T: tau, N: neurodegeneration) enables biological diagnosis before clinical symptoms emerge, positioning Alzheimer's as a disease on a biological continuum. The FDA approval of lecanemab (2023) and donanemab (2024) as the first disease-modifying anti-amyloid immunotherapies marks a paradigm shift in Alzheimer's management.

Alzheimer's disease results from the complex interaction of genetic susceptibility, aging, and modifiable environmental risk factors driving amyloid-beta accumulation and tau hyperphosphorylation. Age is the dominant risk factor — the lifetime risk of developing AD by age 85 is approximately 30-40%. Genetic risk factors: APOE epsilon-4 (APOE4) allele on chromosome 19q13.2 is the strongest genetic risk factor for late-onset sporadic AD — one APOE4 copy increases risk 3-fold; two copies increase risk 8-12-fold; APOE4 also lowers the age of symptom onset. Rare autosomal dominant early-onset familial AD (onset before age 65, representing less than 5% of all AD): PSEN1 mutations (chromosome 14, most common, highly penetrant), PSEN2 mutations (chromosome 1), and APP duplications or mutations — all cause overproduction or impaired clearance of amyloid-beta. Trisomy 21 (Down syndrome): virtually all individuals with Down syndrome develop AD pathology by age 40 due to APP overproduction from the extra chromosome 21 copy. Modifiable risk factors identified in the Lancet Commission 2024 (14 modifiable risk factors accounting for approximately 45% of dementia cases): low education (low cognitive reserve), midlife hearing loss, hypertension, obesity, diabetes, depression, physical inactivity, smoking, excessive alcohol consumption, social isolation, traumatic brain injury, air pollution, high LDL cholesterol, and vision loss.

Alzheimer's disease progresses through three clinical stages: preclinical (no symptoms, abnormal biomarkers), mild cognitive impairment (MCI) due to AD, and dementia due to AD. Early stage (mild AD): impaired episodic memory — forgetting recent conversations, appointments, or events that were previously reliably recalled; repetitive questioning within the same conversation; word-finding difficulty (anomia) during spontaneous speech; navigational disorientation in new environments; difficulty managing complex tasks (finances, medications); personality changes (increased anxiety, apathy, or irritability). Middle stage (moderate AD): progressive disorientation to time and place — getting lost in familiar environments; significant difficulty performing previously automatic activities of daily living (dressing, cooking, personal hygiene); behavioral and psychological symptoms of dementia (BPSD): agitation, sundowning, wandering, hallucinations, paranoid delusions, and sleep-wake cycle disruption; difficulty recognizing friends and family; loss of insight into deficits (anosognosia). Late stage (severe AD): complete dependence for all personal care; loss of ability to walk, swallow, or speak intelligibly; total incontinence; increased susceptibility to aspiration pneumonia, pressure ulcers, and urinary tract infections; median survival from dementia diagnosis approximately 4-8 years. Vascular risk factors (hypertension, atrial fibrillation) may accelerate cognitive decline by superimposing cerebrovascular disease.

Clinical diagnosis of Alzheimer's dementia uses the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 criteria — insidious onset with gradual progression of characteristic cognitive decline affecting memory plus at least one other domain (language, visuospatial, executive function), causing functional impairment, without another better explanation. Cognitive screening: Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA, more sensitive for mild AD), and neuropsychological testing for objective documentation and staging. Structural MRI brain: medial temporal lobe (hippocampal and entorhinal cortex) atrophy — quantified by visual rating scales (Scheltens scale) — is characteristic; white matter lesions indicate cerebrovascular disease contribution. Biomarker confirmation of Alzheimer's pathology (recommended before initiating anti-amyloid immunotherapy): amyloid PET (elevated amyloid signal) or tau PET (elevated tau); CSF biomarkers — reduced amyloid-beta42 and elevated phosphorylated tau-181/217 (highly specific for AD, sensitivity >90%); blood-based biomarkers — plasma p-tau217 now achieves diagnostic accuracy of approximately 90% and is increasingly used for screening before PET or CSF testing. NIA-AA A/T/N biological staging: A (amyloid), T (tau), N (neurodegeneration — hippocampal atrophy, FDG-PET hypometabolism, or elevated CSF total tau) — any A-positive individual with T-positive has Alzheimer's disease biology. FDG-PET: temporoparietal hypometabolism is characteristic. Exclusion of reversible causes of cognitive decline: thyroid function, B12, CBC, metabolic panel, syphilis serology.

Symptomatic pharmacological therapies: cholinesterase inhibitors — donepezil 10 mg daily (first-line for mild-to-moderate AD; NICE-recommended), rivastigmine (patch preferred — 9.5 or 13.3 mg/24h for moderate-to-severe AD, also effective in dementia with Lewy bodies), and galantamine 16-24 mg daily — improve attention, memory, and functional abilities; provide modest but clinically meaningful benefit stabilizing or slightly improving MMSE score by approximately 2-3 points. Memantine (N-methyl-D-aspartate receptor antagonist) 20 mg daily: approved for moderate-to-severe AD; improves cognition and activities of daily living; may be combined with donepezil (additive benefit). Disease-modifying anti-amyloid immunotherapy (for early symptomatic AD with confirmed amyloid pathology): lecanemab (Leqembi, anti-Aβ protofibril antibody, 10 mg/kg IV biweekly) — CLARITY-AD trial (2023): 27% slowing of cognitive decline on CDR-SB versus placebo over 18 months; donanemab (anti-Aβ plaque antibody, 700/1400 mg IV monthly) — TRAILBLAZER-ALZ2 trial (2024): 35% slowing of decline in low-medium tau patients; both require ApoE4 genotyping and baseline amyloid PET/CSF confirmation; key risk: amyloid-related imaging abnormalities (ARIA-E: cerebral edema, ARIA-H: microhemorrhages) requiring serial MRI monitoring — more common in APOE4 homozygotes. Behavioral and psychological symptoms of dementia (BPSD): non-pharmacological approaches first (structured activity, caregiver training, environmental modification); antipsychotics (quetiapine, risperidone) for severe agitation only — with informed consent given mortality risk in elderly dementia patients. Brexanolone and pimavanserin for agitation and hallucinations under investigation. Cognitive rehabilitation, occupational therapy, and caregiver support programs are essential components of comprehensive dementia care.

Alzheimer's disease has no cure and follows a relentlessly progressive course, but the rate of decline varies considerably between individuals. Average survival from the time of clinical diagnosis is approximately 8-12 years, ranging from 3 to over 20 years in some cases. Earlier age of onset (under 65) and APOE4 homozygosity are associated with faster progression; women, on average, survive longer than men after diagnosis. Death typically results from aspiration pneumonia from impaired swallowing, sepsis from urinary tract infections or pressure ulcers, malnutrition, or intercurrent illness in the context of profound end-stage frailty. Without treatment, cognitive decline progresses at an estimated 2-4 MMSE points per year. Symptomatic treatment with cholinesterase inhibitors and memantine may slow decline by 2-3 MMSE points and delay functional dependence. The newly approved disease-modifying therapies lecanemab and donanemab have demonstrated 25-35% slowing of clinical decline in early symptomatic Alzheimer's disease with confirmed amyloid pathology — the most clinically meaningful advance since the disease was first characterized. Quality of life can be meaningfully maintained in mild-to-moderate stages with structured cognitive activity, physical exercise, social engagement, and skilled caregiver support. Long-term complications to monitor include falls and hip fractures, aspiration pneumonia, weight loss and dysphagia, behavioral and psychological symptoms (BPSD), and caregiver burnout. Late-stage Alzheimer's typically requires full-time nursing care; advance care planning including goals of care discussions is an essential and compassionate component of holistic management that should begin in the early stages.

While no intervention guarantees Alzheimer's prevention, mounting evidence supports a multidomain lifestyle approach. The FINGER trial demonstrated that combined physical exercise, cognitive training, Mediterranean or MIND diet, and control of vascular risk factors (hypertension, diabetes, dyslipidemia, obesity) reduced cognitive decline by 25% in at-risk adults over 2 years. Aerobic exercise for at least 150 minutes weekly has independent neuroprotective effects, increasing hippocampal volume and reducing amyloid accumulation. Treating midlife hypertension is one of the strongest modifiable risk factors — the SPRINT-MIND trial showed intensive blood pressure control reduced dementia risk by 17%. Hearing loss treatment, social engagement, lifelong learning, sleep optimisation, and smoking cessation each contribute to reducing Alzheimer's risk.

Any person noticing persistent problems with short-term memory — forgetting recent conversations, appointments, or events repeatedly, and not remembering them later — should see a physician for cognitive evaluation, as this distinguishes Alzheimer's from normal aging. Difficulty managing finances, losing track of time or place, trouble following familiar recipes or using appliances, repeated questions within a single conversation, or significant personality changes (increased suspicion, withdrawal, depression, or aggression) warrant evaluation. Family members or carers who notice these changes in a loved one should encourage assessment, as patients with Alzheimer's often lack insight into their deficits (anosognosia). The new disease-modifying therapies lecanemab and donanemab are only effective in early disease — early diagnosis is now more clinically important than ever before.